literature review on complications of diabetes mellitus

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Global trends in diabetes complications: a review of current evidence

• Published: 31 August 2018
• Volume 62 , pages 3–16, ( 2019 )

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• Jessica L. Harding 1 ,
• Meda E. Pavkov 1 ,
• Dianna J. Magliano 2 , 3 ,
• Jonathan E. Shaw 2 &
• Edward W. Gregg 1  

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In recent decades, large increases in diabetes prevalence have been demonstrated in virtually all regions of the world. The increase in the number of people with diabetes or with a longer duration of diabetes is likely to alter the disease profile in many populations around the globe, particularly due to a higher incidence of diabetes-specific complications, such as kidney failure and peripheral arterial disease. The epidemiology of other conditions frequently associated with diabetes, including infections and cardiovascular disease, may also change, with direct effects on quality of life, demands on health services and economic costs. The current understanding of the international burden of and variation in diabetes-related complications is poor. The available data suggest that rates of myocardial infarction, stroke and amputation are decreasing among people with diabetes, in parallel with declining mortality. However, these data predominantly come from studies in only a few high-income countries. Trends in other complications of diabetes, such as end-stage renal disease, retinopathy and cancer, are less well explored. In this review, we synthesise data from population-based studies on trends in diabetes complications, with the objectives of: (1) characterising recent and long-term trends in diabetes-related complications; (2) describing regional variation in the excess risk of complications, where possible; and (3) identifying and prioritising gaps for future surveillance and study.

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In recent decades, large increases in diabetes prevalence have been demonstrated in virtually all regions of the world, with 415 million people worldwide now living with diabetes [ 1 ]. This is most concerning because an increase in diabetes prevalence will increase the number of chronic and acute diseases in the general population, with profound effects on quality of life, demand on health services and economic costs. Macrovascular complications of diabetes, including coronary heart disease, stroke and peripheral vascular disease, and microvascular complications, such as end-stage renal disease (ESRD), retinopathy and neuropathy, along with lower-extremity amputations (LEA), are responsible for much of the burden associated with diabetes. There is also growing recognition of a diversifying set of causally-linked conditions, including cancers, ageing-related outcomes (e.g. dementia), infections and liver disease. Since current data suggests that rates of all-cause and cardiovascular disease (CVD) mortality are decreasing in individuals with diabetes [ 2 ], trends in other complications of diabetes may become proportionately more prominent in the future.

Despite widespread international assessment of the growth of diabetes prevalence, quantification of the international burden and variation in the incidence of diabetes-related complications is notably lacking. This stems largely from the fact that data systems and population-based studies assessing diabetes complications are concentrated in Europe, North America and other high-income countries, with little to no availability in low- and middle-income countries, where the absolute increase in diabetes prevalence is largest. The lack of both uniform diagnosis of diabetes and of standardised measurement of diabetes-related complications has caused additional barriers in comparing trends worldwide. In this review, we synthesise data from adult population-based studies on trends in diabetes complications based on original articles, review articles and meta-analyses, with the objectives of: (1) characterising recent and long-term trends in diabetes-related complications; (2) describing regional variation in the excess risk of complications, where possible; and (3) identifying and prioritising gaps for future surveillance and study.

To this end, we conducted an extensive review of the literature in order to identify the majority of relevant publications. However, we did not adopt the formalities of a systematic literature review. Relevant publications were identified through a PubMed and Medline search using the following medical subject heading (MesH) terms: Diabetes Mellitus AND Diabetes Complications OR Mortality; End-Stage Renal Disease; Hyperglycaemia; Amputations; Cardiovascular Disease; Retinopathy; Nephropathy; Infections; Cancer; Dementia AND Epidemiology AND Trend. We also hand-searched reference lists of identified publications to determine additional eligible articles. The search was limited to papers in the English language. Throughout this Review, unless otherwise stated, data are reported among populations of people with diabetes, not general populations. All studies included were population-based, not clinic-based. Where more than one study per country (per outcome) existed, we chose the study reporting the most recent trends.

Macrovascular complications

CVD is a major cause of death and disability among people with diabetes. As the number of people with diabetes is predicted to increase, it is expected that the number of people with CVD will also increase [ 2 ]. However, data from several studies suggest that risk of CVD in people with diabetes has been declining since the 1990s (Table 1 ). Despite these improvements, people with diabetes continue to have a two- to fourfold higher risk of hospitalisation for major CVD events and CVD-associated clinical procedures compared with those without diabetes [ 2 ].

CVD mortality

Among the general population, mortality rates owing to CVD have declined in most high-income countries [ 12 ]. However, worldwide, CVD remains a leading cause of death in both people with and without diabetes [ 2 , 13 ], and individuals with diabetes still have a two- to fourfold increased rate of CVD mortality compared with those without [ 14 ]. Data from several studies suggest a decline in CVD-associated mortality among people with diabetes.

In the USA, a 53% relative decline in CVD mortality was observed between 1988 and 1994, and 2010 and 2015, as well as a reduction in the excess risk between populations with and without diabetes [ 15 ]. In Australia, a 50% decline in CVD-mortality rates was observed between 2000 and 2011 [ 16 ] and, in Iceland, a 46% decline was observed between 1993 and 2004 [ 17 ]. In Canada, in-hospital mortality for acute myocardial infarction (AMI) and stroke fell by 44.1% and 17.1%, respectively, between 1992 and 1999, but individuals with diabetes were still 1.6 times more likely to die from these events than those without diabetes [ 3 ]. Similar declines for CVD mortality in individuals with type 1 diabetes have also been shown in Australia [ 16 ] and Switzerland [ 18 ].

Microvascular complications

LEAs are a major complication for adults with diabetes because of their physical, economical and psychosocial burden. Since several aetiological pathways are associated with conditions leading to LEAs, LEAs are also an important indicator of the success of preventive care, such as that targeting glycaemic control, CVD risk factor management, and screening and treatment of people at high risk of foot complications. Population-based studies indicate that, in general, there have been reductions in the rates of LEAs between 1982 and 2011 (by ~3% to 85%) across diverse populations [ 9 , 19 , 20 , 21 , 22 , 23 ] (Fig. 1 and Table 2 ). Only two studies have specifically examined trends among people with type 1 diabetes; significant declines were observed in Spain [ 24 ] and non-significant declines were seen in Australia [ 21 ].

Trends in LEAs among people with diabetes, by country, between 1988 and 2011. Data in the figure were derived from population-based studies of countries or major regions of countries in which rates of LEAs were examined using the same methods within populations over time. Differences in absolute rates between countries may be affected by variation in age and differences in criteria for diagnosis of both LEA and diabetes. Data are intended to be interpreted as trends over time and should not be used for comparison of absolute rates between countries at any one time point. a Unadjusted rate; b rate per 100,000 person-years. This figure is available as part of a downloadable slideset

Among the 13 countries and major regions of countries with available data, the decline in total LEA incidence appears to be driven by declines in major LEAs (Fig. 2 a, Table 2 ). Smaller relative declines have been reported for minor LEAs, with some countries even reporting increases (Fig. 2 b, Table 2 ). This suggests that there may be a relative increase in the number of minor LEAs being performed in the clinical setting to prevent major LEAs. There also remain important disparities in rates of LEA between subgroups within populations. For example, in the USA, decreases in LEA rates are mainly attributable to greater reductions in LEAs in the elderly, with reductions in rates in young and middle-age people being modest [ 22 ]. In addition, the number of LEAs remain higher in non-whites and the male population in the USA [ 25 ], and large geographical differences exist [ 26 ].

Trends in ( a ) major and ( b ) minor LEAs among people with diabetes, by country, between 1982 and 2010. Data in the figure were derived from population-based studies of countries or major regions of countries in which rates of LEAs were examined using the same methods within populations over time. Differences in absolute rates between countries may be affected by variation in age and differences in criteria for diagnosis of both LEA and diabetes. Data are intended to be interpreted as trends over time and should not be used for comparison of absolute rates between countries at any one time point. a Unadjusted rate. This figure is available as part of a downloadable slideset

Worldwide, it is estimated that 80% of ESRD cases are caused by diabetes or hypertension [ 28 ]. Between 2002 and 2015, steep increases (approximately 40–700%) in the incidence of diabetes-associated ESRD were reported for Russia, the Philippines, Malaysia, the Republic of Korea, the Jalisco region of Mexico and Singapore, as well as Australia, Taiwan, Bosnia and Herzegovina and Scotland. In the USA, the increase was 11% for the same period [ 28 ] (Fig. 3 ). By contrast, diabetes-associated ESRD incidence declined over the same period in Austria (by 26%), Belgium (16%), Finland (11%), Denmark (2%), and Sweden (1%). All of these rates are reported for overall country-specific populations, not for diabetes populations, and increases likely reflect the increasing prevalence of both type 1 and type 2 diabetes in these populations [ 28 ].

Trends in the incidence rate (per million people in the general population/year) of diabetes-related ESRD, by country, between 2002 and 2015. The graph was generated based on data from the United States Renal Data System ( USRDS) annual data report 2017 [ 28 ]. This figure is available as part of a downloadable slideset

Among adults with type 2 diabetes, the incidence of ESRD declined by approximately 6% per year between 2000 and 2012 in a nationwide study of Chinese participants [ 29 ]. In the USA, incidence of ESRD in those with diabetes declined by 28% between 1990 and 2010, with a statistically significant decrease across all age groups after the year 2000 [ 19 ]. This decline was smaller than for other reported complications of diabetes, such as AMI, stroke, LEAs and death from hypoglycaemia, possibly owing to more inclusive criteria for initiating renal replacement therapy in the earlier years and large reductions in cardiovascular complications, both improving morbidity and mortality rates among people with diabetes.

Trends in the incidence of treated ESRD (i.e. dialysis initiation) among people with diabetes are also known to differ by race/ethnicity. In the USA, the incidence rate of treated ESRD declined between 2000 and 2013, by 28%, 22%, 14%, and 13% in American Indian/Alaska Native, Hispanic, non-Hispanic white and non-Hispanic black people with diabetes, respectively. Within the same timeframe, ESRD incidence remained relatively stable in Asian individuals with diabetes [ 30 ].

According to the United States Renal Data System (USRDS) reports, of all new cases of diabetes-associated ESRD, an estimated 91% were attributable to type 2 diabetes. Epidemiological data on trends in the incidence of treated ESRD in type 1 diabetes are less clear, partly because type 1 diabetes is less frequent than type 2 diabetes and also because of uncertainties related to the diagnosis of type 1 diabetes; young people with diabetes or those treated with insulin are often misclassified as having type 1 diabetes. Nonetheless, a review of ESRD in eight countries or regions of Europe, and in non-indigenous Canadians and Australians, found that incidence of type 1 diabetes-related ESRD declined between 1998 and 2002 [ 31 ]. Unlike type 2 diabetes, there are no studies among national cohorts with type 1 diabetes populations as the denominator; however, several cohort studies indicate that for a given duration of type 1 diabetes, people diagnosed in more recent decades have a lower incidence of ESRD than those diagnosed in the 1960s and 1970s [ 32 ]. Declines in type 1 diabetes-related ESRD may be attributed to the widespread use of renin–angiotensin system inhibitors and statin therapy at younger ages in this population, and recent improvements in insulin delivery technologies. On the other hand, in Taiwan, the incidence of type 1 diabetes-related ESRD increased substantially between 1999 and 2010 (from 0.13 to 3.52 per 1000 people; p  < 0.001) [ 33 ].

Retinopathy

Retinopathy affects approximately one third of adults with diabetes and represents the leading cause of blindness in these individuals [ 34 ]. Despite how common diabetic retinopathy is, there are few population-based data on incidence trends. Of the few studies that do report objectively measured annual incidence of retinopathy over time, findings are mixed (Table 3 ).

Generally, population-based studies conducted from the 1990s onwards report a 50–67% lower incidence of diabetic retinopathy compared with earlier studies [ 34 ]. A meta-analysis of 28 studies and 27,120 participants with type 1 and type 2 diabetes showed that the pooled incidence of proliferative diabetic retinopathy was lower in 1986–2008 (2.6%) compared with 1975–1985 (19.5%) [ 35 ]. Likewise, in the Pittsburgh Epidemiology of Diabetes Complications Study, incidence of proliferative diabetic retinopathy reduced from 38% in 1965–1969 to 26.5% in 1975–1980 [ 36 ]. These trends are likely to be owing to earlier identification and treatment of both diabetes and diabetic retinopathy and reductions in smoking rates. Moreover, lessons learned from the UK Prospective Diabetes Study (UKPDS) and DCCT trial, leading to better glycaemic and blood pressure control in diabetes, may have also contributed to the reduced incidence of diabetic retinopathy over recent years.

Information on trends in the prevalence or incidence of neuropathy are virtually non-existent due to the lack of data from repeated population surveys. Surveillance data from the US Diabetes Surveillance System (USDSS) show that the rate of hospitalisations for neuropathy (both first admission and any readmissions) increased by 42.1% (from 29.7 to 42.2 per 1000 people with diabetes) between 2000 and 2014; although these data are likely influenced by changes in coding of neuropathy and increased awareness of neuropathy among individuals with diabetes [ 37 ]. Historical data from the Pittsburgh Epidemiology of Diabetes Complications Study indicate a decline in the incidence of distal symmetrical polyneuropathy in participants with a 25-year duration of type 1 diabetes who were diagnosed between 1970 and 1974 compared with those diagnosed between 1965 and 1969 [ 36 ].

Acute complications

Acute complications of diabetes, such as diabetic ketoacidosis (DKA), the hyperglycaemic hyperosmolar state (HHS), lactic acidosis and hypoglycaemia are largely preventable, yet they still account for high morbidity and mortality among people with diabetes and contribute significantly to the high costs of diabetes care [ 43 ]. In the USA, the SEARCH for Diabetes in Youth study reported that 29% of individuals aged <20 years with type 1 diabetes, and 10% with type 2 diabetes presented with DKA at diagnosis [ 44 ]. The incidence of DKA in children and adolescents with type 1 diabetes also remains high, with approximately 1–12 episodes per 100 patient-years [ 43 ]. Comparable population-based data for adults are not currently available.

Overall, data suggest that DKA-related mortality and hospitalisation rates for acute complications are decreasing among people with diabetes (Table 4 ). However, in the USA, since 2010, significant increases in hospitalisations for hyperglycaemia and death from hyperglycaemic crisis have been reported by the USDSS, although continued declines in hospitalisations for hypoglycaemia were observed [ 37 ].

Decreasing temporal trends in hospitalisations and deaths from acute diabetes complications suggest improvements in in-hospital management of DKA and HHS and outpatient care, and better patient education in disease management. Reasons for increases in acute complications, as observed in the USA, are, at this stage, unclear.

Non-cardiovascular mortality

Diabetes is associated with a diverse set of specific, non-cardiovascular causes of death. An international meta-analysis of 97 prospective studies representing 820,900 individuals with diabetes and 123,205 deaths throughout North America and Europe found that diabetes was associated with an increased risk for mortality from several cancers (17–116% increased risk, depending on the cancer site), renal disease, infections, liver disease, digestive system disorders, falls, pneumonia, mental health issues, intentional self-harm, external causes, nervous system disorders, chronic obstructive pulmonary disease (COPD) and related conditions, and other non-cancer, non-vascular causes [ 48 ].

Observations of trends in non-cardiovascular mortality are restricted to a few studies. In the USA, the rate of cancer-related deaths declined by 16% every 10 years between 1988–1994 and 2010–2015, while the rate of non-vascular, non-cancer-related deaths declined by a smaller magnitude (8% every 10 years) [ 15 ]. In Australia, age-standardised mortality rates (ASMRs) for all-cause, CVD and diabetes decreased significantly between 2000 and 2011, while cancer-related ASMRs remained unchanged in people with type 1 and type 2 diabetes [ 16 ]. Data from the same national registry in Australia demonstrated that cancer is now the second leading cause of death among people with diabetes, increasing from 25% of all deaths to 35% between 1997 and 2010 [ 49 ]. Similar findings have been reported in the USA [ 50 ] and Taiwan [ 51 ]. This is important in light of the increasing prevalence of diabetes that is coinciding with an ageing population, the latter being an inherent risk factor for both diabetes and cancer.

All-cause mortality

Mortality rates due to diabetes are often estimated from vital statistics systems (based on death certificate data), the efficacy of which may be affected by diabetes prevalence, coding practices and country-level awareness of diabetes. Therefore, to adequately monitor mortality rates among populations with diabetes, rates should ideally be estimated among defined cohorts with diagnosed diabetes. However, data on all-cause and cause-specific mortality among people with diabetes are difficult to compare and come from a relatively small number of high-income countries within North America, Europe, Australia and Asia. Population-based data on all-cause mortality from several of these countries are shown in Fig. 4 and Table 5 . These data are intended to be interpreted as trends over time, rather than as a comparison of absolute rates between countries, as methodologies differ between the studies. Nonetheless, a consistent reduction in mortality among people with diabetes (either type 2 diabetes or all [type 1 and type 2] diabetes) has been observed since the late 1980s, ranging from a 4% relative decline in mortality among Taiwanese women with diabetes (27% in Taiwanese men) between 2000 and 2009 [ 51 ], to a 37% decline in Canadians between 1996 and 2009 [ 52 ].

Trends in all-cause mortality among people with diabetes, by country, between 1988 and 2015. Data in the figure were derived from population-based studies of countries or major regions of countries in which all-cause mortality rates were examined using the same methods within populations over time. Differences in absolute rates between countries may be affected by variation in age, differences in diabetes diagnosis, country-level awareness of diabetes and collection of vital statistics. Data are intended to be interpreted as trends over time and should not be used for comparison of absolute rates between countries at any one time point. a Rate per 100,000 person-years. This figure is available as part of a downloadable slideset

Studies that compare populations with and without diabetes show that the relative difference between the two populations is decreasing over time, but excess risk remains among people with diabetes, even at more recent time points [ 53 ]. For example, in Ontario, Canada, the mortality rate ratio decreased from 1.90 (95% CI 1.86, 1.94) in 1996 to 1.51 (95% CI 1.48, 1.54) in 2009 [ 52 ], and similar declines have been noted in the UK [ 52 ], USA [ 15 ] and Australia [ 49 ].

For type 1 diabetes, there is a 3–18-fold excess risk for death compared with individuals without diabetes [ 54 ]. However, continued improvements in mortality rates have been noted by a few studies. For example, in the USA, between 1950 and 2009, marked declines in the number of deaths attributed to type 1 diabetes were observed across all age groups (by 45–90%) [ 54 ]. An analysis by the Centers for Disease Control and Prevention also showed a 61% decrease in diabetes-related mortality prior to age 20 years between 1968–1969 and 2008–2009 [ 55 ]. Outside of the USA, Japan and Finland reported declines in mortality rates of 69% and 8%, respectively, when comparing mortality among those diagnosed with childhood-onset type 1 diabetes in 1965–1969 with those diagnosed in 1975–1979 [ 56 ]. The smaller declines in Finland are most likely explained by the lower absolute mortality in this country as compared with Japan [ 56 ]. In Norway, mortality rates among individuals diagnosed with type 1 diabetes between 1973 and 1982, before 15 years of age, was reduced by 81% (from 286 to 53 per 100,000 person-years) compared with those diagnosed in 1999–2012 [ 57 ]. In Australia, mortality rates among individuals with type 1 diabetes who were diagnosed before 45 years of age declined by 33% between 2000 and 2011 [ 16 ].

Emerging complications of diabetes

The increase in diabetes incidence since the 1980s, combined with declining mortality among people with diabetes, has increased the total years of life spent with diabetes. Longer life expectancy among those with diabetes has also driven the emergence of newly recognised complications, including cancer, infections and physical and cognitive disability. Observations of trends in ‘emerging’ diabetes complications are restricted to a few select studies.

Individuals with diabetes have an increased risk for tuberculosis, severe gram-positive infections, hospital-acquired postoperative infections, urinary tract infections (UTIs) and tropical diseases compared with people without diabetes [ 63 ]. Whether the rate of infections among populations with diabetes has changed over time is not clear. In the USA, data from the National Vital Statistics System show that the per cent of deaths with infections listed anywhere on the death certificate decreased from 3.1% in 1999 to 2.7% in 2010 in people with diabetes and from 4.5% to 4.1% in people without, with respiratory tract infections accounting for the highest percentage of deaths in both groups [ 63 ]. An analysis of data from the National Nursing Home Surveys between 1999 and 2004 showed that the age-standardised proportion of nursing home residents with infections among people with diabetes increased from 6.1% to 10.3% between 1999 and 2004, while in people without diabetes this increased from 6.0% to 8.5% [ 63 ]. In Spain, a 61.3% increase in hospitalisation rates for sepsis was observed between 2008 and 2012 [ 64 ], though changes in ICD-9-clinical modification (ICD-9-CM; www.cdc.gov/nchs/icd/icd9cm.htm ) codes make it difficult to assess the change in sepsis over time.

A growing body of research suggests that people with diabetes are at increased risk for major depressive disorder [ 65 ], anxiety [ 66 ], eating disorders (particularly in female adolescents with type 1 diabetes) [ 67 ], serious mental illness (e.g. schizophrenia) [ 68 ], dementia [ 69 ], and several domains of disability, including mobility loss, reduced instrumental activities of daily living (IADL) or basic activities of daily living, and work disability [ 70 ]. Again, whether risk has changed over time remains unknown as for many of these complications, prospective data with adequate follow-up is not available. For depression, two studies have explored trends over time. In Spain, the prevalence of depression among hospitalised individuals with type 2 diabetes increased significantly from 3.5% to 5.8% between 2001 and 2011, with increases being much higher in women [ 71 ]. In Finland, the use of antidepressants was more common in people with diabetes compared with those without and use of these drugs increased more rapidly between 1997 and 2007 in people with diabetes, particularly younger individuals with type 2 diabetes [ 72 ]. For physical disability, data from the USA show that the prevalence of both impaired mobility and IADLs have not changed in recent decades, while work disability declined from 23.8% in 1997 to 17.9% in 2006; however, this then increased to 19.7% in 2011 [ 70 ]. In relative terms, similar trends in rates of disability were reported among the non-diabetic population, but, in absolute terms, rates over time were smaller (from 9.8% in 1997 to 5.8% in 2010).

This review of international trends in diabetes-related complications reveals several key conclusions (see Text box); first, rates of LEAs, acute complications, CVD and all-cause and CVD-related mortality among populations of people with diabetes are declining. Data on trends in ESRD, diabetic retinopathy and neuropathy, non-CVD-related causes of death and ‘emerging’ complications in these populations are scarce, however, and, as such, conclusions are limited. Second, in spite of notable declines in several diabetes complications, people with diabetes remain at significantly higher risk for these complications compared with people without diabetes. Third, declines in all-cause and CVD-related mortality are leading to proportional increases in other forms of morbidity, including renal disease, infections, cancers, and physical and cognitive disability, with important implications for the clinical and public health burden of diabetes. Last, there is a genuine lack of comparable data on trends in rates of diabetes complications, specifically from low- and middle-income countries. Therefore, conclusions drawn from this work are limited to about a dozen high-income countries in North America, Europe and East Asia and, as such, this leaves the status of global trends in diabetes complications unclear.

The explanation for the decline in rates of diabetes complications among selected countries around the world is likely multifactorial, involving trends in the underlying risk factors of the population and changes in preventive care and medical treatment. Reductions in macrovascular complications in high-income countries are likely influenced by improved pharmacotherapy, CVD treatment procedures and better prevention strategies [ 73 ]. For example, large reductions in smoking rates occurred in the 1970s and 1980s, followed by gradual reductions thereafter [ 74 , 75 ]. Blood pressure control also improved in the 1980s and 1990s, driven by new evidence for treatment efficacy from clinical trials and better awareness of blood pressure as a key risk factor for CVD [ 74 , 75 ]. In addition, lipid levels have declined over time, likely due to increased use of lipid-lowering medications as well as reductions in trans-fat intake [ 73 , 76 ]. These improvements in risk factor management in high-income countries have likely had additional benefits in terms of microvascular complications, which have been further buoyed by improvements in glycaemic control since 2000 [ 73 , 76 , 77 ]. In the USA, the improvements in risk factors are also likely driven by improvements in the organisation of care and initiatives to improve quality of diabetes care. Whether improvements in risk factors, treatment options and medical care also occurs in the majority of other countries in the world is unclear due to the lack of continuous monitoring systems.

Trends in rates of diabetes complications are also influenced by background trends in mortality. For example, the large reductions in CVD-related mortality in populations with diabetes that have been observed in the USA, Australia and several other countries in Northern Europe have increased survival rates, resulting in proportional increases in other causes of death, including those due to cancer, renal disease and infections.

The interpretation of trends in rates of diabetes complications also depends on which denominator population (diabetes or whole population) is used. This review has focused primarily on the average risk for the average person with diagnosed diabetes, independent of changes in prevalence of diabetes in the underlying population. When rates are calculated as the frequency of diabetes-related complications in the general population, many countries reveal flat or even increasing trends because the increases in diabetes prevalence offset reductions in risk of complications within the diabetic population [ 19 ]. For example, while the average adult with diabetes in the USA has a lower risk of CVD than in previous decades, the average adult in the general population has an increased risk of diabetes-related CVD than in previous decades because of the large increase in diabetes prevalence. The fact that trends differ depending on the choice of general population denominator is a reminder that the burden of the wide spectrum of complications in those with diabetes will ultimately be influenced by efforts to prevent diabetes.

In this review, we have highlighted the scarcity of data outside North America, Europe and high-income Asia-Pacific countries, leaving the global status of diabetes complications rates unclear, especially in low and middle-income countries. This gap in data stems largely from the lack of population-based systems quantifying healthcare utilisation because surveys and cohort studies are generally inadequate for the assessment of diabetic complications. The comparison of trends in complications has also been hampered by varied reporting methods, definitions of complications and methods to identify people with diabetes. Future monitoring of global trends in diabetes complications could be enhanced by implementing standardised reporting methods and establishing practical registries that suit the dual needs of population monitoring and providing feedback and decision support for clinical systems.

Abbreviations

Acute myocardial infarction

Age-standardised mortality rates

Cardiovascular disease

Diabetic ketoacidosis

End-stage renal disease

Hyperglycaemic hyperosmolar state

Instrumental activities of daily living

Lower-extremity amputation

United States Diabetes Surveillance System

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Acknowledgements

The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

The interpretation and reporting of the ESRD data supplied by the United States Renal Data System (USRDS) are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government.

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Harding, J.L., Pavkov, M.E., Magliano, D.J. et al. Global trends in diabetes complications: a review of current evidence. Diabetologia 62 , 3–16 (2019). https://doi.org/10.1007/s00125-018-4711-2

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DOI : https://doi.org/10.1007/s00125-018-4711-2

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• Published: 23 July 2015

Type 2 diabetes mellitus

• Ralph A. DeFronzo 1 ,
• Ele Ferrannini 2 ,
• Leif Groop 3 ,
• Robert R. Henry 4 ,
• William H. Herman 5 ,
• Jens Juul Holst 6 ,
• Frank B. Hu 7 ,
• C. Ronald Kahn 8 ,
• Itamar Raz 9 ,
• Gerald I. Shulman 10 ,
• Donald C. Simonson 11 ,
• Marcia A. Testa 12 &
• Ram Weiss 13  

Nature Reviews Disease Primers volume  1 , Article number:  15019 ( 2015 ) Cite this article

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• Diabetes complications
• Type 2 diabetes

Type 2 diabetes mellitus (T2DM) is an expanding global health problem, closely linked to the epidemic of obesity. Individuals with T2DM are at high risk for both microvascular complications (including retinopathy, nephropathy and neuropathy) and macrovascular complications (such as cardiovascular comorbidities), owing to hyperglycaemia and individual components of the insulin resistance (metabolic) syndrome. Environmental factors (for example, obesity, an unhealthy diet and physical inactivity) and genetic factors contribute to the multiple pathophysiological disturbances that are responsible for impaired glucose homeostasis in T2DM. Insulin resistance and impaired insulin secretion remain the core defects in T2DM, but at least six other pathophysiological abnormalities contribute to the dysregulation of glucose metabolism. The multiple pathogenetic disturbances present in T2DM dictate that multiple antidiabetic agents, used in combination, will be required to maintain normoglycaemia. The treatment must not only be effective and safe but also improve the quality of life. Several novel medications are in development, but the greatest need is for agents that enhance insulin sensitivity, halt the progressive pancreatic β-cell failure that is characteristic of T2DM and prevent or reverse the microvascular complications. For an illustrated summary of this Primer, visit: http://go.nature.com/V2eGfN

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Acknowledgements

The authors acknowledge grants from: the South Texas Veterans Healthcare System to R.A.D.; the National Institutes of Health (grants R01DK24092 to R.A.D.; DK58845 and P30 DK46200 to F.B.H.; R01 DK-040936, R01 DK-049230, R24 DK-085836, UL1 RR-045935, R01 DK-082659 and R24 DK085610 to G.I.S.; P30 DK036836 to C.R.K. Novo Nordisk Foundation for Basic Metabolic Research and the University of Copenhagen to G.I.S. and C.R.K.; DVA-Merit Review grant and VA San Diego Healthcare System to R.H.; National Institute for Diabetes and Digestive and Kidney Disease (grant P30DK092926) to W.H.; the Swedish Research Council (grants 2010–3490 and 2008–6589) and European Council (grants GA269045) to L.G.; Italian Ministry of University & Research (MIUR 2010329EKE) to E.F.; the Patient-Centered Outcomes Research Institute (PCORI) Program Award (CE1304-6756) to D.C.S. and M.A.T.; NovoNordisk Foundation to the NNF Center for Basic Metabolic Research to J.H. W.H. acknowledges the Michigan Center for Diabetes Translational Research and I.R. thanks R. Sprung for editorial assistance.

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Diabetes Division, Department of Medicine, University of Texas Health Science Center, South Texas Veterans Health Care System and Texas Diabetes Institute, 701 S. Zarzamoro, San Antonio, 78207, Texas, USA

Ralph A. DeFronzo

CNR Institute of Clinical Physiology, Pisa, Italy

Ele Ferrannini

Department of Clinical Science Malmoe, Diabetes & Endocrinology, Lund University Diabetes Centre, Lund, Sweden

University of California, San Diego, Section of Diabetes, Endocrinology & Metabolism, Center for Metabolic Research, VA San Diego Healthcare System, San Diego, California, USA

Robert R. Henry

University of Michigan, Ann Arbor, Michigan, USA

William H. Herman

University of Copenhagen, Kobenhavn, Denmark

Jens Juul Holst

Department of Nutrition, Harvard T.H. Chan School of Public Health and Department of Epidemiology, Harvard T.H. Chan School of Public Health and Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Frank B. Hu

Harvard Medical School and Joslin Diabetes Center, Boston, Massachusetts, USA

C. Ronald Kahn

Division of Internal Medicine, Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel

Howard Hughes Medical Institute and the Departments of Internal Medicine and Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut, USA

Gerald I. Shulman

Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Donald C. Simonson

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

Marcia A. Testa

Department of Human Metabolism and Nutrition, Braun School of Public Health, Hebrew University, Jerusalem, Israel

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Introduction (R.R.H.); Epidemiology (F.B.H.); Mechanisms/pathophysiology (L.C.G., C.R.K., E.F., G.I.S. and R.A.D.); Diagnosis, screening and prevention (W.H.H.); Management (R.A.D.); Quality of life (D.C.S. and M.A.T.); Outlook (I.R., J.J.H. and R.W.); overview of Primer (R.A.D.).

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Correspondence to Ralph A. DeFronzo .

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The authors declare the following potential COI: (1) R.A.D.: Research Grant Support - AstraZeneca, Bristol Myers Squibb, Janssen; Speaker's Bureau - AstraZeneca, Novo Nordisk, Advisory Board/Consultant - AstraZeneca, Janssen, Novo Nordisk, Boehringer Ingelheim, Lexicon, Intarcia; (2) E.F.: Research Grant Support - Boehringer Ingelheim, Eli Lilly; Consultant/Speaker Bureau-Boehringer Ingelheim, Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Takeda, Medtronic, Intarcia; (3) C.R.K. serves as a consultant for Medimmune, Merck, Five Prime Therapeutics, CohBar, Antriabio, and Catabasis; (4) L.G. has no conflict of interest; (5) R.H. has received grant support from Hitachi, Janssen, Eli Lilly, Sanofi-Aventis and Viacyte and is a consultant/advisory board member for Alere, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clin Met, Eisai, Elcelyx, Gilead, Intarcia, Isis, Janssen, Merck, Novo Nordisk, Sanofi-Aventis, and Vivus; (6) W.H.H. has no conflict of interest; (7) J.J.H. has received grant support from Novartis and Merck and is a consultant/advisory board member for Glaxo, Smith, Kline, Novo Nordisk, and Zealand Pharmaceuticals; (8) M.A.T. has no conflict of interest; (9) R.W. serves as a consultant for Medtronics and Kamada and is on the speaker's bureau for Medtronics and Novo Nordisk; (10) F.H. has received research support from California Walnut Commission and Metegenics; (11) G.I.S. serves on scientific advisory boards for Merck and Novartis and he has received research grant support from Gilead Pharmaceuticals; (12) D.C.S. has no conflict of interest; (13) I.R. – Advisory Board: Novo Nordisk, Astra Zeneca/BMS, MSD, Eli Lilly, Sanofi, Medscape Cardiology; Consultant: Astra Zeneca/BMS, Insuline; Speaker's Bureau: Eli Lilly, Novo Nordisk, Astra Zeneca/BMS, J&J, Sanofi, MSD, Novartis, Teva; Shareholder: Insuline, Labstyle.

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DeFronzo, R., Ferrannini, E., Groop, L. et al. Type 2 diabetes mellitus. Nat Rev Dis Primers 1 , 15019 (2015). https://doi.org/10.1038/nrdp.2015.19

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• Published: 08 June 2020

Predictive models of diabetes complications: protocol for a scoping review

• Ruth Ndjaboue   ORCID: orcid.org/0000-0002-4716-6505 1 ,
• Imen Farhat 1 , 2 ,
• Carol-Ann Ferlatte 1 , 2 ,
• Gérard Ngueta 3 ,
• Daniel Guay 4 ,
• Sasha Delorme 5 ,
• Noah Ivers 6 ,
• Baiju R. Shah 7 ,
• Sharon Straus 8 ,
• Catherine Yu 9 &
• Holly O. Witteman 1 , 3  

Systematic Reviews volume  9 , Article number:  137 ( 2020 ) Cite this article

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Metrics details

Diabetes is a highly prevalent chronic disease that places a large burden on individuals and health care systems. Models predicting the risk (also called predictive models) of other conditions often compare people with and without diabetes, which is of little to no relevance for people already living with diabetes (called patients). This review aims to identify and synthesize findings from existing predictive models of physical and mental health diabetes-related conditions.

We will use the scoping review frameworks developed by the Joanna Briggs Institute and Levac and colleagues. We will perform a comprehensive search for studies from Ovid MEDLINE and Embase databases. Studies involving patients with prediabetes and all types of diabetes will be considered, regardless of age and gender. We will limit the search to studies published between 2000 and 2018. There will be no restriction of studies based on country or publication language. Abstracts, full-text screening, and data extraction will be done independently by two individuals. Data abstraction will be conducted using a standard methodology. We will undertake a narrative synthesis of findings while considering the quality of the selected models according to validated and well-recognized tools and reporting standards.

Predictive models are increasingly being recommended for risk assessment in treatment decision-making and clinical guidelines. This scoping review will provide an overview of existing predictive models of diabetes complications and how to apply them. By presenting people at higher risk of specific complications, this overview may help to enhance shared decision-making and preventive strategies concerning diabetes complications. Our anticipated limitation is potentially missing models because we will not search grey literature.

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The World Health Organization identifies diabetes as one of the four priority non-communicable conditions [ 1 ]. In 2017, more than 693 million people were affected by diabetes worldwide and projections point to a sustained rise in its prevalence in the next decades [ 1 ]. The burden of diabetes on individuals and health care systems is primarily attributed to complications from diabetes including macrovascular complications (e.g., heart attack, stroke) or microvascular complications (e.g., blindness, amputation, renal failure) [ 1 , 2 ]. Early identification of people with diabetes at increased risk of complications is an important challenge for clinicians [ 3 ]. Models predicting the risk (also called predictive models) of diabetes complications can facilitate the identification of people at higher risk and inform health decision-making regarding preventive actions or treatments to avoid or delay complications [ 4 ].

Models that assess the risk of developing diabetes or that use it as a predictor variable for other outcomes are not informative for someone who is already living with diabetes (i.e., patient) [ 5 , 6 ]. Similarly, predictive models of other conditions in people with diabetes often compare people with and without diabetes, which is of little to no relevance for patients [ 7 , 8 , 9 ]. A preliminary search for reviews on the topic was conducted in two databases (MEDLINE, Embase), and results suggest that existing reviews of predictive models of diabetes-related complications focus mostly on macrovascular complications [ 10 , 11 ] and rarely on the range of other diabetes complications [ 4 , 12 ]. This scoping review will contribute to filling these gaps.

We aim to identify and synthesize existing predictive models of physical and mental health conditions associated with diabetes, in people with prediabetes and any type of diabetes mellitus (hereafter called “patients”). Our objective is to describe the features of selected validated predictive models for risk of diabetes complications.

Methods/design

In this scoping review, we will use well-established scoping review methods, namely the framework developed by the Joanna Briggs Institute [ 13 , 14 ] and Levac and colleagues [ 15 ] while paying attention to the methodological limitations of original studies as often recommended in systematic reviews [ 16 ]. In some epidemiological contexts, such as the one we are focusing on, it is important to assess studies’ qualities even if it does not add to the methodological strength of the scoping review itself. For example, in an ongoing scoping review, authors aimed to assess the number of validated prediction rules that exist for spinal cord injury management and to provide evidence of the psychometric properties of these prediction rules, especially with regard to its clinical impact [ 17 ]. Although their scoping approach does not aim to assess the overall effectiveness of these prediction rules in their respective settings, their systematic appraisal of data quality will help readers make informed use of their findings. In another ongoing study, authors aimed to “produce a scoping review which in its data analysis will draw on methods typically associated with qualitative systematic reviews” and acknowledged that the diversity of data “presents a potential challenge from the perspective of interrater reliability and consistency in analysis” [ 18 ].

To include a diversity of perspectives and ensure that our review focuses on diabetes complications that are relevant to patients [ 19 ], our research team include researchers (RN, IF, GN, HW) and stakeholders such as clinicians (CF, BS, CY, NI, SS) and patients with type 1 and type 2 diabetes (DG, DA, HW). Stakeholders were involved in this study as collaborators and co-authors, not participants. Patients in our research team (hereafter called Expert Patients) were recruited through Diabetes Action Canada (DAC), a national Patient-Oriented Research Network that includes patients to bring expertise in diabetes care [ 20 ]. Expert Patients were recruited to DAC through professional and personal networks and community-based organizations and from respondents to a national survey [ 21 ]. Using a patient-centered approach, the team co-developed the protocol. We integrated patient’ priorities by developing our research questions, search strategy terms, and outcome measures based on what Expert Patients shared concerning what matters to them, and also by building on findings of a recent patient-centered study [ 21 ]. Expert Patients (DG, SD) will be involved in each step of the research process, including the definition of the objective, the main analysis, the preliminary and final results, and the discussion. We will discuss preliminary and final results with a broader committee of six to ten Expert Patients. We will use the services of two information specialists to validate our search strategy and selection criteria at least twice before the end of this review.

Eligibility criteria

The population targeted by this scoping review consists of people of all ages, genders, and ethnicities affected by diabetes. We will consider prediabetes and  any type of diabetes, including type 1, and type 2 diabetes [ 22 ], and data that have been collected at the individual level, not the group level [ 23 ]. We will consider both treated and non-treated individuals. Studies mixing people with and without diabetes will not be considered, unless they performed separate stratified analyses for individuals with diabetes and without diabetes. Studies of pregnant women and/or gestational diabetes will be excluded because it is a different clinical condition. Studies that are restricted to people who do not have diabetes will not be considered. Models based on the Framingham Risk Score of cardiovascular conditions will not be considered as this score was originally derived from a general population free of diabetes [ 24 ]. Studies involving people not meeting our eligibility criteria will be excluded.

We will consider both clinically diagnosed and self-reported physical and mental conditions experienced by patients as a consequence of living with diabetes. Studies focusing on social or economic consequences of diabetes will not be included in this review, because findings are likely to be highly dependent on country of residence and health insurance status and thus are unlikely to be modifiable at the individual level. We plan to sort models by diabetes type and by groups (e.g., sub-group) of diabetes complications, physical (e.g., macrovascular and microvascular conditions), and mental (e.g., depression and anxiety) health problems. Death from all causes and death from non-diabetes complications will be analyzed separately. With the collaboration of Expert Patients and researchers, we drafted a preliminary and non-exhaustive list of diabetes complications that were relevant for patients (Table 1 ).

(1) We will consider evidence coming from all countries and settings and published between 2000 and 2018. We will not consider articles prior to 2000 because both diabetes treatment and modeling approaches have greatly improved in the last two decades. The date of publication will not be included in the search strategy. Rather, we will simply order the results by date of publication and will not consider those outside the period 2000–2018. (2) We will include only full-text peer-reviewed published studies with original results as they are expected to exhibit high-quality models and detailed methodology. For this reason, we will not consider abstracts only or duplicates and do not intend to search the grey literature. (3) No language restrictions will be applied. During the full-text screening, potentially relevant articles written in a language other than English or French will be translated by a member of our team when possible. If we do not have anyone with expertise in that language, we will first use free translation tools (e.g., Google Translate, DeepL) to determine if the publication is likely to meet our inclusion criteria, and if so, we will engage professional translation services. (4) We will only consider studies with a longitudinal design and quantitative data. Specifically, we will consider prospective cohort studies and nested case-control studies [ 25 ]. We will not apply restrictions as to the length of follow-up as the time may vary for diverse reasons. Screening tools/studies, retrospective case-control studies, and cross-sectional studies will not be considered. Focusing on predictive models implies that we will not consider explicative ones, that is, those evaluating factors associated with diabetes complications as potential determinants or confounders rather than predictors. We will consider diverse candidate/potential predictors of diabetes complications, including personal characteristics, socioeconomic factors, clinical factors, and environmental factors. (5) We will focus only on prognostic models and not include diagnostic models in this review. We will consider both development and validation studies, as some studies presenting predictive models are focused on derivation and internal validation and others on external validation. The sample size for model validation can come from the same study population, from another study population, or from both. We will exclude partial and full predictive models that were not validated, either internally or externally.

Search strategy and information source

Our diverse team co-built the search strategy of this scoping review. A predefined list of potential predictors and complications [ 4 ] was established in collaboration with six Expert Patients who were not members of our research team in order to better capture what matters to diverse patients. This list will be used as a starting point for study selection and will be revised during the full-text screening process (Table 2 ). The search strategy will combine groups of keywords customized to each database (i.e., MeSH terms where appropriate) pertaining to (1) population (treated and untreated patients affected by prediabetes and diabetes), (2) concept (diabetes complications, potential predictors), and (3) context (prediction modeling features). Prediction models seldom report the individual predictors included in the final model as the central message is about accuracy (discrimination and calibration). However, knowing which, how, and what candidate predictors have been assessed can help explore potential bias (e.g., selection bias) in data that may, in turn, influence the features of predictive models [ 26 , 27 ]. For this reason, we will add potential predictors in our search strategy. Search terms are selected to capture international terminology. We intend to run a search at the start and again just before final data extraction to identify studies published after our baseline search date and before we write the article for possible inclusion in our review. As mentioned in eligibility criteria, there will be no restrictions in terms of date, language, age, or design.

We will search for eligible studies in two electronic scientific databases: Ovid MEDLINE and Embase. In addition, we will perform snowballing of reference lists of selected papers at the full-text screening stage [ 28 ]. To complement these sources, we will contact experts in the field to ask if they know about any published work we may have missed. We tested our search strategy for MEDLINE (Ovid) in June 2018 and for Embase in October 2018 (see Appendixes 1 , 2 , and 3 ). We had the search appraised by a second librarian using PRESS in October 2018 [ 29 ].

Data management

The detailed references and abstracts identified will be pooled in EndNote, a reference management software [ 30 ]. We will use EndNote to remove duplicates and store references before moving to another tool to screen references and extract data. Duplicates will be removed using the automatic function in EndNote and manually during screening. Screening by title, abstract, and full text will be conducted using Microsoft Excel [ 31 ] to provide a comprehensive step-by-step record of the selection process based on our selection criteria. A detailed screening form with the inclusion and exclusion criteria will be developed and tested (see Appendixes 1 and 2 , Tables 4 and 5). All members of the screening team will be trained on how to use Microsoft Excel and the screening form before we start.

Selection process

Articles will be excluded if at least one of the criteria was clearly not met. We will retain any article that cannot be excluded solely based on abstract review. We will set aside all articles that are systematic or narrative literature reviews whose subject clearly relates to our objective to consult at a later stage, as mentioned previously.

Given that reviewers have diverse research backgrounds and levels of experience, we plan to screen titles and abstracts in two different steps to make sure that they have a similar understanding of the eligibility criteria. A preliminary convenience sample of 50 titles will be screened by all reviewers, and we will assess the degree of agreement among raters, discuss any disagreement in groups, and only proceed above a predetermined threshold of interrater agreement (such as 70%). Then, pairs of reviewers from among the seven team members (CF, IF, JC, SC, SRB, JM, YY) will independently screen a subset of titles based on the Population-Concept-Context (PCC) criteria. After titles are screened independently by two reviewers, the results will be pooled and agreement will be calculated for each pair. If agreement is optimal, all titles retained by at least one reviewer will be considered for abstract screening. If agreement is not optimal, title screening will be repeated by independent reviewers until we meet the target of 0.7 or higher. Reviewers will meet at the beginning, midpoint, and final stages of the abstract review process to discuss discrepancies related to study selection and refine the search strategy if needed [ 15 ]. Once abstract screening has been completed by two independent reviewers, the results will be pooled and agreement will be calculated for each pair of reviewers. When agreement is optimal, all remaining disagreements will be discussed between the two reviewers. If agreement is not optimal, two independent reviewers will screen abstracts until we meet the target agreement of 0.7 or higher. A third reviewer will screen abstracts where there are discrepancies and discuss all remaining disagreements in meetings with the two initial reviewers. Full-text copies of articles selected based on abstracts will be retrieved and translated if needed. Two independent reviewers from our team (RN, CRB, TP) will screen the full text of all selected references. Each pair of reviewers will compare their results and discuss any disagreement. If there are too many disagreements, a third reviewer will repeat the full-text screening. Differences and disagreements between reviewers will be discussed in group meetings to reach a consensus. All remaining discrepancies will be resolved by one researcher (GN, HW).

Data collection process

The team will collectively build a standardized extraction grid with all relevant data items to guide data extraction. Three independent reviewers (RN, TP, CRB) will pilot test the grid using a subset of five to twenty full-text articles selected for extraction. They will then meet to determine whether data are missing from the form or not needed. Data extraction will be performed in duplicate by two independent reviewers from our team (RN, TP, CRB). The corresponding authors of retained articles may be contacted to request any information missing in the extraction grid. The three reviewers will resolve discrepancies through discussion and with input from two members of our team (RN, HW) when necessary.

Data extraction

Since there are no checklists of items to consider in data extraction for scoping reviews on risk prediction models, we considered aspects of a well-known checklist for systematic reviews [ 32 ] that aligns with the scoping review methodology to design (and, in future, report) our data extraction process [ 15 ]. Full-text data extraction will be done by two independent reviewers (TP, CRB) using an Excel spreadsheet. A third reviewer (RN, GN) will review any studies where there is a discrepancy between the two independent reviewers that they are not able to resolve. Although scoping reviews do not usually include quality assessment, when dealing with epidemiological models, it is important to pay attention to the methodology and the design of original studies [ 17 ]. Two independent reviewers trained in epidemiology (RN, IF, GN) will be involved in assessing potential selection and information bias in selected studies and will discuss the potential impact of bias on the features and accuracy of selected models. Final selection of articles will be undertaken in duplicate following data extraction to confirm relevance of the chosen articles. Any study selected by only one reviewer will be discussed to reach mutual agreement. We will record the reasons for which each article is excluded. Here again, a third reviewer will review each study when there are discrepancies that cannot be resolved by the two independent reviewers.

We will use the pre-publication version of the PROBAST [ 33 ], which includes a template and a detailed user guide to identify five domains in which methodological limitations might exist in studies using risk prediction models. These domains are as follows: (1) participant selection (e.g., selection bias caused by exclusion of eligible participants or loss at follow-up); (2) predictors (e.g., differential or non-differential misclassification of predictors, change in predictor for some participants over time); (3) outcomes (e.g., outcome definition and standardized classification of all participants); (4) sample size and participation flow (e.g., inappropriate time interval between predictor and outcome measurements, handling of missing data); and (5) analyses (e.g., evaluation of performance measures such as calibration, discrimination, (re)classification, and net benefit [ 34 , 35 , 36 ]; handling of non-binary predictors) (Table 3 ). Other methodological issues will also be considered (e.g., duration and timing of exposure, selective reporting of results in a way that depends on the findings) [ 37 ]. Also, if both predictors and outcomes were measured using self-report methods, we will evaluate potential common method bias [ 25 ].We will use the same spreadsheet for data abstraction and for quality assessment. We will make sure that we adequately capture all relevant content and methods from selected papers and summarize information on the internal and external validity of each selected model from each selected study. Consistent with the PROBAST tool, we will sort studies in three groups: high quality, moderate/acceptable quality, and low quality. These data will help assess data quality during data analysis and interpretation.

Analysis and synthesis

This protocol adheres to the Preferred Reporting Items in Systematic Reviews and Meta-analyses extension for protocols (PRISMA-P) [ 38 ] and scoping reviews (PRISMA-ScR) [ 39 ] (see the Additional file 1 ). After data from included studies are summarized in an extraction table, we will follow three distinct steps: analysis (models features, discrimination, calibration and validation), reporting (synthesizing characteristics of included studies), and discussion (comparison with previous reviews) [ 15 , 40 ]. The analysis and synthesis will focus on diabetes complications and the methodological features of selected models [ 11 ]. We will use qualitative approaches to evaluate and synthesize quantitative estimates accurately. When relevant, we will provide in-depth analyses of potential explanations for data inconsistencies (i.e., study design, selection/participation, data measurements, etc.). Finally, we will propose how to consistently report the risk of diabetes complications in predictive models in ways that will be helpful for patients and clinicians.

Discussion and conclusion

The current review may not provide meta-analytical estimates because we expect to retrieve a highly diverse set of risk prediction models. This may preclude a quantitative synthesis if the available data do not meet the criteria for homogeneity in methods used to measure predictors and outcomes and assess biases potentially affecting internal validity. Heterogeneity is one of the main reasons for skepticism about meta-analyses of non-experimental studies [ 25 , 41 ], which represent the great majority of studies on our topic [ 4 , 6 ]. To partly circumvent the pitfalls of heterogeneity, we will attempt to calculate a meta-analytical estimate of experimental studies if there are enough high-quality data with comparable methodological characteristics in our final set of models ( N > 5). However, preliminary search results and consultation with experts revealed that predictive models of diabetes complications often consider some complications as predictors of other complications [ 4 ]. Merging such models during analysis may lead to a highly correlated data and inflation in the estimates of variance [ 42 , 43 ]. In such cases, qualitative approaches are often alternatives used to evaluate and synthesize estimates accurately.

Strengths and limitations of this study

The major strengths of this review will be the inclusion of predictive models of diverse diabetes complications and the combination of multiple and diverse perspectives of patients, clinicians, and researchers. Considering the fact that diabetes complications often vary by diabetes types, we invited one patient partner with type 2 diabetes (DG) and one patient partner with type 1 diabetes (SD) as co-authors to complement the perspective of our senior researcher (HW) who lives with type 1 diabetes. All six Expert Partners that we consulted agreed that all complications considered in this review were equally important. We plan to actively collaborate with a committee of Expert Patients, caregivers, and clinicians in diabetes care. By including a consultation exercise in this scoping review, we intend to “enhance the results, making them more useful to policy makers, practitioners and service users” [ 44 ]. Limitations include using two databases, restricting publication date to 2000–2018, and not searching the grey literature. Also, we will not consider the social and economic outcomes of diabetes.

Dissemination

Ethical approval is not required for this scoping review study since we will only be using secondary data sources. Our findings will be disseminated through peer-reviewed publication and presentation at conferences. Because predictive models are increasingly being appraised and recommended for formal risk assessment in treatment decision-making and clinical guidelines, the proposed scoping review may contribute to support research and risk communication in diabetes care. For example, it may help clinicians better identify people who are at higher risk of diabetes complications and researchers design customizable risk prediction tools for use in diabetes care [ 45 ]. To ensure that our findings about diabetes complications reach patients, we will also circulate them through clinical and patient networks.

Availability of data and materials

Data are available by requesting to the corresponding author.

Abbreviations

Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for protocols

Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews

Prediction study Risk of Bias Assessment Tool

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Acknowledgements

The authors gratefully acknowledge the contributions of Jimmy Chau, Sandrine Comeau, Jean Mardenli, Olivia Drescher, Thierry Provencher, Charlotte Rochefort-Brihay, and Yihong Yu to this project as research assistants; of information experts Frédéric Bergeron and William Witteman, for assistance with search strategy, screening, and selection of articles for the systematic review; and of patients partners Gloria Lourido, André Gaudreau, Jaime Borja, Pascual Delgado, and Patrice Bleau who contributed greatly to this research project as a whole but who were not able to accept the invitation to participate on this particular paper as co-authors due to time constraints. We thank all authors of the original articles who generously gave their time to validate the data we had extracted from their papers. Finally, we thank all study participants for helping us identify ways to improve diabetes care.

Funding for this study comes from two grants from the Canadian Institutes of Health Research (CIHR) FDN-148426 (Foundation grant, PI: Witteman) and SCA-145101 (SPOR chronic disease network grant funding Diabetes Action Canada, PI: Lewis). The CIHR had no role in determining the study design, the plans for data collection or analysis, the decision to publish, nor the preparation of this manuscript. HW is funded by a Research Scholar Junior 2 Career Development Award by the Fonds de Recherche du Québec—Santé. RN holds a postdoctoral fellowship from Diabetes Action Canada and a Fellowship in Medical Decision Making from the Gordon and Betty Moore Foundation and the Society for Medical Decision Making.

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Ruth Ndjaboue, Imen Farhat, Carol-Ann Ferlatte & Holly O. Witteman

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Contributions

HW originally conceptualized the study, which was then led by RN as principal investigator. RN, IF, and CF closely contributed to the design of the study. RN, IF, and CF drafted the first version of the article with early revision by HW and GN. CF, HW, DG, and SS brought expertise in the definition of the search strategy for predictors. CF, HW, and SS brought expertise in the definition of the search strategy for diabetes complications. RN, IF, GN, and BS brought expertise in predictive models. RN, GN, IN, SS, CY, and HW brought methodological expertise in study selection and risk bias assessment. HW, DG, and CY prepared the dissemination plan. RN and SS brought expertise in gender differences. RN, IF, CF, and GN collaborated to draft the grid for extraction data and do pilot screening. All the co-authors critically revised the article and approved the final version for submission for publication. RN and HW had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Correspondence to Ruth Ndjaboue .

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RN is funded by Diabetes Action Canada, a strategic patient-oriented research (SPOR) network in diabetes and its related complications, part of the Canadian Institutes of Health Research (CIHR) SPOR Program in Chronic Disease. Expert Patients were recruited through Diabetes Action Canada, and some co-authors also collaborate with Diabetes Action Canada.

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Ndjaboue, R., Farhat, I., Ferlatte, CA. et al. Predictive models of diabetes complications: protocol for a scoping review. Syst Rev 9 , 137 (2020). https://doi.org/10.1186/s13643-020-01391-w

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• Diabetes mellitus
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• Complication
• Diabetic complication

Systematic Reviews

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Complications of Diabetes Mellitus

• Diabetic Retinopathy |
• Diabetic Nephropathy |
• Diabetic Neuropathy |
• Macrovascular Disease |
• Cardiomyopathy |
• Infection |
• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) |
• Other Complications |
• More Information |

In patients with diabetes mellitus , years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular), or both.

The mechanisms by which vascular disease develops include

Glycosylation of serum and tissue proteins with formation of advanced glycation end products

Superoxide production

Activation of protein kinase C, a signaling molecule that increases vascular permeability and causes endothelial dysfunction

Accelerated hexosamine biosynthetic and polyol pathways leading to sorbitol accumulation within tissues

Hypertension and dyslipidemias that commonly accompany diabetes mellitus

Arterial microthromboses

Proinflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia that impair vascular autoregulation

Microvascular disease underlies 3 common and devastating manifestations of diabetes mellitus:

Retinopathy

Nephropathy

Microvascular disease may also impair skin healing, so that even minor breaks in skin integrity can develop into deeper ulcers and easily become infected, particularly in the lower extremities. Intensive control of plasma glucose can prevent or delay many of these complications but may not reverse them once established.

Macrovascular disease involves atherosclerosis of large vessels, which can lead to

Angina pectoris and myocardial infarction

Transient ischemic attacks and strokes

Peripheral arterial disease

Immune dysfunction is another major complication and develops from the direct effects of hyperglycemia on cellular immunity . Patients with diabetes mellitus are particularly susceptible to bacterial and fungal infections .

Diabetic Retinopathy

Diabetic retinopathy is a common cause of adult blindness in the United States. It is characterized initially by retinal capillary microaneurysms (background retinopathy) and later by neovascularization (proliferative retinopathy) and macular edema. There are no early symptoms, but focal blurring, vitreous or retinal detachment, and partial or total vision loss can eventually develop; rate of progression is highly variable.

Diabetic Nephropathy

Diabetic nephropathy is a leading cause of chronic kidney disease in the United States. It is characterized by thickening of the glomerular basement membrane, mesangial expansion, and glomerular sclerosis. These changes cause glomerular hypertension and progressive decline in glomerular filtration rate (GFR). Systemic hypertension may accelerate progression. The disease is usually asymptomatic until nephrotic syndrome or kidney failure develops.

Diagnosis is by detection of urinary albumin or decline in GFR. Once diabetes is diagnosed (and annually thereafter), urinary albumin level should be monitored so that nephropathy can be detected early. Monitoring can be done by measuring the albumin :creatinine ratio on a spot urine specimen or total urinary albumin in a 24-hour collection. A ratio ≥ 30 mg/g ( ≥ 3.4 mg/mmol) or an albumin excretion of 30 to 299 mg/day signifies moderately increased albuminuria (previously called microalbuminuria) and early diabetic nephropathy. An albumin excretion ≥ 300 mg/day is considered severely increased albuminuria (previously called macroalbuminuria), or overt proteinuria, and signifies more advanced diabetic nephropathy. Typically a urine dipstick is positive only if the protein excretion exceeds 300 to 500 mg/day.

Treatment is rigorous glycemic control combined with blood pressure control. An angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) should be used at the earliest sign of albuminuria ( albumin :creatinine ratio ≥ 30 mg/g [ ≥ 3.4.mg/mmol]), to prevent progression of kidney disease because these medications lower intraglomerular blood pressure and thus have renoprotective effects. However, these medications have not been shown to be beneficial for primary prevention (ie, in patients who do not have albuminuria) ( 1 , 2 , 3 ).

Sodium-glucose cotransporter- 2 (SGLT-2) inhibitors also delay progression of renal disease and should be prescribed in patients with diabetic nephropathy who have an estimated glomerular filtration rate (eGRF) ≥ 20 mL/minute and a urine albumin :creatinine ratio ≥ 200 mg/g.

Fineronone, a nonsteroidal mineralocorticoid receptor antagonist, has also been shown to decrease the risk of progression of diabetic kidney disease and cardiovascular events and can be used in addition to, or instead of, an ACE inhibitor or ARB ( 4 ).

Diabetic nephropathy references

1. Bilous R, Chaturvedi N, Sjølie AK, et al . Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials.  Ann Intern Med 2009;151(1):11-W4. doi:10.7326/0003-4819-151-1-200907070-00120

2. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin -dependent diabetes and normoalbuminuria or microalbuminuria. The EUCLID Study Group.  Lancet 1997;349(9068):1787-1792.

3. Mauer M, Zinman B, Gardiner R, et al . Renal and retinal effects of enalapril and losartan in type 1 diabetes.  N Engl J Med 2009;361(1):40-51. doi:10.1056/NEJMoa0808400

4. Veneti S, Tziomalos K . The Role of Finerenone in the Management of Diabetic Nephropathy.  Diabetes Ther 2021;12(7):1791-1797. doi:10.1007/s13300-021-01085-z

Diabetic Neuropathy

Diabetic neuropathy is the result of nerve ischemia due to microvascular disease, direct effects of hyperglycemia on neurons, and intracellular metabolic changes that impair nerve function. There are multiple types, including

Symmetric polyneuropathy (with small- and large-fiber variants)

Autonomic neuropathy

Radiculopathy

Cranial neuropathy

Mononeuropathy

Symmetric polyneuropathy is most common and affects the distal feet and hands (stocking-glove distribution); it manifests as paresthesias, dysesthesias, or a painless loss of sense of touch, vibration, proprioception, or temperature. In the lower extremities, these symptoms can lead to blunted perception of foot trauma due to ill-fitting shoes and abnormal weight bearing, which can in turn lead to foot ulceration and infection or to fractures, subluxation, and dislocation or destruction of normal foot architecture (Charcot arthropathy). Small-fiber neuropathy is characterized by pain, numbness, and loss of temperature sensation with preserved vibration and position sense. Patients are prone to foot ulceration and neuropathic joint degeneration and have a high incidence of autonomic neuropathy. Predominant large-fiber neuropathy is characterized by muscle weakness, loss of vibration and position sense, and lack of deep tendon reflexes. Atrophy of intrinsic muscles of the feet and foot drop can occur.

Autonomic neuropathy can cause orthostatic hypotension , exercise intolerance, resting tachycardia, dysphagia, nausea and vomiting (due to gastroparesis), constipation and/or diarrhea (including dumping syndrome), fecal incontinence, urinary retention and/or incontinence, erectile dysfunction and retrograde ejaculation, and decreased vaginal lubrication.

Radiculopathies most often affect the proximal lumbar (L2 through L4) nerve roots, causing pain, weakness, and atrophy of the lower extremities (diabetic amyotrophy), or the proximal thoracic (T4 through T12) nerve roots, causing abdominal pain (thoracic polyradiculopathy).

Cranial neuropathies cause diplopia, ptosis, and anisocoria when they affect the 3rd cranial nerve or motor palsies when they affect the 4th or 6th cranial nerve.

Mononeuropathies cause finger weakness and numbness (median nerve) or foot drop (peroneal nerve). Patients with diabetes are also prone to nerve compression disorders, such as carpal tunnel syndrome . Mononeuropathies can occur in several places simultaneously (mononeuritis multiplex). All tend to affect older patients predominantly and usually abate spontaneously over months; however, nerve compression disorders do not.

Diagnosis of symmetric polyneuropathy is by detection of sensory deficits and diminished ankle reflexes. Loss of ability to detect the light touch of a nylon monofilament identifies patients at highest risk of foot ulceration (see figure Diabetic Foot Screening ). Alternatively, a 128-Hz tuning fork can be used to assess vibratory sense on the dorsum of the first toe.

Electromyography and nerve conduction studies may be needed to evaluate all forms of neuropathy and are sometimes used to exclude other causes of neuropathic symptoms, such as radiculopathy not caused by diabetes and carpal tunnel syndrome.

norepinephrine

Diabetic Foot Screening

Macrovascular disease.

Large-vessel atherosclerosis is a result of the hyperinsulinemia, dyslipidemia, and hyperglycemia characteristic of diabetes mellitus. Manifestations are

Diagnosis is made by history and physical examination. Treatment is rigorous control of atherosclerotic risk factors, including normalization of plasma glucose, lipids, and blood pressure, combined with smoking cessation , daily intake of aspirin (if indicated), and statins. A multifactorial approach that includes management of glycemic control, hypertension , and dyslipidemia may be effective in reducing the rate of cardiovascular events. In contrast with microvascular disease, intensive control of plasma glucose alone has been shown to reduce risk in type 1 diabetes but not in type 2 ( 1, 2, 3 glucagon -like peptide-1 (GLP-1) receptor agonists.

Macrovascular disease references

1. ACCORD Study Group; ACCORD Eye Study Group, Chew EY, et al . Effects of medical therapies on retinopathy progression in type 2 diabetes [published correction appears in N Engl J Med 2011 Jan 13;364(2):190] [published correction appears in N Engl J Med 2012 Dec 20;367(25):2458].  N Engl J Med 2010;363(3):233-244. doi:10.1056/NEJMoa1001288

2. Nathan DM, Cleary PA, Backlund JY, et al . Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.  N Engl J Med 2005;353(25):2643-2653. doi:10.1056/NEJMoa052187

3. Zoungas S, Chalmers J, Neal B, et al . Follow-up of blood-pressure lowering and glucose control in type 2 diabetes.  N Engl J Med 2014;371(15):1392-1406. doi:10.1056/NEJMoa1407963

Cardiomyopathy

Diabetic cardiomyopathy is thought to result from many factors, including epicardial atherosclerosis, hypertension and left ventricular hypertrophy, microvascular disease, endothelial and autonomic dysfunction, obesity , and metabolic disturbances. Patients develop heart failure due to impairment in left ventricular systolic and diastolic function and are more likely to develop heart failure after myocardial infarction.

Patients with poorly controlled diabetes mellitus are prone to bacterial and fungal infections because of adverse effects of hyperglycemia on the function of granulocytes and T cells. In addition to an overall increase in risk for infectious diseases, individuals with diabetes have an increased susceptibility to mucocutaneous fungal infections (eg, oral and vaginal candidiasis) and bacterial foot infections (including osteomyelitis ), which are typically exacerbated by lower extremity vascular insufficiency and diabetic neuropathy. Hyperglycemia is a well-established risk factor for surgical site infections.

People with diabetes have a higher risk for severe illness or death from COVID-19 ; either type 1 diabetes or type 2 diabetes is an independent risk factor for COVID-related death ( 1 ). In people with diabetes infected with SARS-CoV-2, higher blood glucose levels have been associated with poorer outcomes, including higher mortality. Several studies have reported an increased risk of new-onset type 1 diabetes associated with COVID-19 ( 2 ); however, other studies have suggested this effect may be due to a delay in diagnosis due to pandemic lockdowns.

Infection references

1. Hartmann-Boyce J, Rees K, Perring JC, et al . Risks of and From SARS-CoV-2 Infection and COVID-19 in People With Diabetes: A Systematic Review of Reviews [published correction appears in Diabetes Care 2022 Jun 2;45(6):1489].  Diabetes Care 2021;44(12):2790-2811. doi:10.2337/dc21-0930

2. D'Souza D, Empringham J, Pechlivanoglou P, Uleryk EM, Cohen E, Shulman R . Incidence of Diabetes in Children and Adolescents During the COVID-19 Pandemic: A Systematic Review and Meta-Analysis.  JAMA Netw Open 2023;6(6):e2321281. doi:10.1001/jamanetworkopen.2023.21281

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Metabolic associated steatotic liver disease (MASLD, formerly nonalcoholic fatty liver disease [NAFLD]), is increasingly common and represents an important comorbidity of type 2 diabetes. Some studies have found that over half of patients with type 2 diabetes have MASLD ( 1 ). MASLD can also occur in patients with metabolic syndrome , obesity , and dyslipidemia in the absence of diabetes mellitus.

Diagnosis of MASLD requires evidence of hepatic steatosis by imaging or histology, and a lack of other causes of fat accumulation (such as alcohol consumption or medications that cause fat accumulation) ( 2 ). MASLD occurs when there is ≥ 5% hepatic steatosis but no evidence of hepatocellular injury. In contrast, metabolic dysfunction-associated steatohepatitis (MASH), formerly nonalcoholic steatohepatitis (NASH), requires both hepatic steatosis ( ≥ 5%) and inflammation with hepatocyte injury. Fibrosis may also occur in MASH and can lead to cirrhosis . The pathogenesis of MASLD is not well understood but is clearly related to insulin resistance, leading to accumulation of triglycerides in the liver.

Individuals with type 2 diabetes can be screened for fibrosis by calculating the fibrosis 4 index for liver fibrosis (FIB-4 index) from age, aminotransferase levels, and platelet count. Further testing to look for fibrosis, with transient elastography or fibrosis blood markers can be performed if the FIB-4 score shows indeterminate or high risk of fibrosis.

3 , 4 , 5 , 6 , 7

MASLD references

1. Lee YH, Cho Y, Lee BW, et al . Nonalcoholic Fatty Liver Disease in Diabetes. Part I: Epidemiology and Diagnosis [published correction appears in Diabetes Metab J 2019 Oct;43(5):731].  Diabetes Metab J 2019;43(1):31-45. doi:10.4093/dmj.2019.0011

2. Cusi K, Isaacs S, Barb D, et al . American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD).  Endocr Pract 2022;28(5):528-562. doi:10.1016/j.eprac.2022.03.010

3. Armstrong MJ, Gaunt P, Aithal GP, et al . Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.  Lancet 2016;387(10019):679-690. doi:10.1016/S0140-6736(15)00803-X

4. Belfort R, Harrison SA, Brown K, et al . A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis.  N Engl J Med 2006;355(22):2297-2307. doi:10.1056/NEJMoa060326

5. Cusi K, Orsak B, Bril F, et al . Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial.  Ann Intern Med 2016;165(5):305-315. doi:10.7326/M15-1774

6. Newsome PN, Buchholtz K, Cusi K, et al . A Placebo-Controlled Trial of Subcutaneous Semaglutide in Nonalcoholic Steatohepatitis.  N Engl J Med 2021;384(12):1113-1124. doi:10.1056/NEJMoa2028395

7. Patel Chavez C, Cusi K, Kadiyala S . The Emerging Role of Glucagon -like Peptide-1 Receptor Agonists for the Management of NAFLD.  J Clin Endocrinol Metab 2022;107(1):29-38. doi:10.1210/clinem/dgab578

Other Complications of Diabetes Mellitus

Diabetic foot complications (skin changes, ulceration, infection, gangrene) are common and are attributable to vascular disease, neuropathy, and relative immunosuppression. These complications can lead to lower extremity amputations.

Certain musculoskeletal disorders are more common in patients with diabetes, including muscle infarction, carpal tunnel syndrome , Dupuytren contracture , adhesive capsulitis, and sclerodactyly .

Patients with diabetes may also develop

Ophthalmologic disease unrelated to diabetic retinopathy (eg, cataracts , glaucoma , corneal abrasions , optic neuropathy )

Hepatobiliary diseases (eg, cirrhosis , gallstones )

Dermatologic disease (eg, tinea infections , lower-extremity ulcers, diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic systemic sclerosis, vitiligo , granuloma annulare , acanthosis nigricans [a sign of insulin resistance])

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More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

American Diabetes Association: Standards of Medical Care in Diabetes Diabetes Care 46 (Supplement 1): 1-291, 2023.

Davies MJ, Aroda VR, Collins BS, et al . Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).  Diabetes Care 2022;45(11):2753-2786. doi:10.2337/dci22-0034

Endocrine Society: Clinical Practice Guidelines : provides guidelines on evaluation and management of patients with diabetes as well as links to other information for clinicians

Holt RIG, DeVries JH, Hess-Fischl A, et al : The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 64(12):2609–2652, 2021. doi: 10.1007/s00125-021-05568-3

Powers MA, Bardsley JK, Cypress M, et al . Diabetes Self-management Education and Support in Adults With Type 2 Diabetes: A Consensus Report of the American Diabetes Association, the Association of Diabetes Care & Education Specialists, the Academy of Nutrition and Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the American Association of Nurse Practitioners, and the American Pharmacists Association.  Diabetes Care 2020;43(7):1636-1649. doi:10.2337/dci20-0023

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Complications of Diabetes Mellitus

• Causes of Diabetes Complications |
• Types of Diabetes Complications |
• Monitoring and Preventing Diabetes Complications |
• More Information |

People with diabetes mellitus have many serious long-term complications that affect many areas of the body, particularly the blood vessels, nerves, eyes, and kidneys.

(See also Diabetes Mellitus .)

There are two types of diabetes mellitus:

Type 1 , in which the body's immune system attacks the insulin -producing cells of the pancreas, and more than 90% of them are permanently destroyed

Type 2 , in which the body develops resistance to the effects of insulin

In both types, the amount of sugar (glucose) in the blood is elevated.

People with either type 1 or type 2 diabetes are likely to have complications as a result of the elevated glucose level. However, because type 2 diabetes may be present for some time before it is diagnosed, complications in type 2 diabetes may be more serious or more advanced when they are discovered.

People with diabetes mellitus may experience many serious, long-term complications. Some of these complications begin within months of the onset of diabetes, although most tend to develop after a few years. Most of the complications gradually worsen. In people with diabetes, strictly controlling the level of glucose in the blood makes these complications less likely to develop or worsen.

Causes of Diabetes Complications

Most complications of diabetes are the result of problems with blood vessels. Glucose levels that remain high over a long time cause both the small and large blood vessels to narrow. The narrowing reduces blood flow to many parts of the body, leading to problems. There are several causes of blood vessel narrowing:

Complex sugar-based substances build up in the walls of small blood vessels, causing them to thicken and leak.

Poor control of blood glucose levels causes the levels of fatty substances in the blood to rise, resulting in atherosclerosis and decreased blood flow in the larger blood vessels.

Types of Diabetes Complications

Blood vessel complications in diabetes.

Atherosclerosis leads to heart attacks and strokes . Atherosclerosis is between 2 and 4 times more common and tends to occur at a younger age in people with diabetes than in people who do not have diabetes.

Over time, narrowing of blood vessels can harm the heart, brain, legs, eyes, kidneys, nerves, and skin, resulting in angina , heart failure , strokes , leg cramps during walking (claudication), poor vision, chronic kidney disease , damage to nerves ( neuropathy ), and skin breakdown.

Infections in diabetes

People with diabetes often develop bacterial and fungal infections typically of the skin and mouth. When the levels of glucose in the blood are high, white blood cells cannot effectively fight infections. Any infection that develops tends to be more severe and takes longer to resolve in people with diabetes. Sometimes, an infection is the first sign of diabetes.

One such infection is a yeast infection called candidiasis . Candida yeast is a normal resident of the mouth, digestive tract, and vagina that usually causes no harm. In people with diabetes, however, Candida can overgrow on mucous membranes and moist areas of the skin causing rashes in those areas.

People with diabetes are also particularly likely to have ulcers and infections of the feet and legs because of poor circulation to the skin. Too often, these wounds heal slowly or not at all. When wounds do not heal, they typically become infected and this can result in gangrene (tissue death) and bone infection ( osteomyelitis ). Amputation of the foot or part of the leg may be needed.

Eye problems in diabetes

Damage to the blood vessels of the eye can cause loss of vision ( diabetic retinopathy ). Laser surgery can seal the leaking blood vessels of the eye and prevent permanent damage to the retina. Sometimes, other forms of surgery or injectable medications may be used. Therefore, people with diabetes should have yearly eye examinations to check for early signs of damage.

Liver damage in diabetes

It is common for people with diabetes to also have steatotic liver disease  (formerly called fatty liver disease), in which abnormal fat deposits collect in the liver. Steatotic liver disease can sometimes progress to more serious liver disease including cirrhosis . Doctors diagnose liver problems if the results of blood tests that measure how well the liver is functioning or imaging of the liver is abnormal, and they confirm the diagnosis with a liver biopsy . Losing weight, maintaining good control of blood sugar levels, and treating high cholesterol can be helpful.

Kidney damage in diabetes

The kidneys can malfunction, resulting in chronic kidney disease that may require dialysis or kidney transplantation . Doctors usually check the urine of people with diabetes for abnormally high levels of protein ( albumin ), which is an early sign of kidney damage. At the earliest sign of kidney complications, people are often given medications that slow the progression of kidney damage, for example, sodium-glucose co-transporter-2 (SGLT2) inhibitors (medications that increase glucose secretion in the urine), angiotensin-converting enzyme (ACE) inhibitors, or angiotensin II receptor blockers (ARBs).

Nerve damage in diabetes

Damage to nerves can manifest in several ways. If a single nerve malfunctions, an arm or leg may suddenly become weak. If the nerves to the hands, legs, and feet become damaged (diabetic polyneuropathy ), sensation may become abnormal, and tingling or burning pain and weakness in the arms and legs may develop. Damage to the nerves of the skin makes repeated injuries more likely because people cannot sense changes in pressure or temperature.

Foot problems in diabetes

Diabetes causes many changes in the body. The following changes in the feet are common and difficult to treat:

Damage to the nerves (neuropathy) affects sensation to the feet, so that pain is not felt. Irritation and other forms of injury may go unnoticed. An injury may wear through the skin before any pain is felt.

Changes in sensation alter the way people with diabetes carry weight on their feet, concentrating weight in certain areas so that calluses form. Calluses (and dry skin) increase the risk of skin breakdown.

Diabetes can cause poor circulation in the feet, making ulcers more likely to form when the skin is damaged and making the ulcers slower to heal.

Because diabetes can affect the body’s ability to fight infections, a foot ulcer, once it forms, easily becomes infected. Because of neuropathy, people may not feel discomfort due to the infection until it becomes serious and difficult to treat, leading to gangrene . People with diabetes are more than 30 times more likely to require amputation of a foot or leg than are people without diabetes.

Foot care is critical (see Foot Care ). The feet should be protected from injury, and the skin should be kept moist with a good moisturizer. Shoes should fit properly and not cause areas of irritation. Shoes should have appropriate cushioning to spread out the pressure caused by standing. Going barefoot is ill advised. Regular care from a podiatrist (a doctor specializing in foot care), such as having toenails cut and calluses removed, may also be helpful. Also, sensation and blood flow to the feet should be regularly evaluated by doctors.

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Monitoring and Preventing Diabetes Complications

At the time of diagnosis and then at least yearly, people with type 2 diabetes are monitored for the presence of diabetes complications, such as kidney, eye, and nerve damage. In people with type 1 diabetes, doctors begin monitoring for complications 5 years after diagnosis. Typical screening tests include the following:

Foot examination to test sensation and look for signs of poor circulation (ulcers, hair loss)

Eye examination (done by an eye specialist)

Urine and blood tests of kidney function

Blood tests for cholesterol levels

Sometimes an electrocardiogram

Worsening of complications can be prevented or delayed by strict blood glucose control or by early treatment with medication. Risk factors for heart problems, such as increased blood pressure and high cholesterol levels , are evaluated at each doctor visit and are treated with medication if necessary.

Proper care of feet and regular eye examinations can help prevent or delay the onset of complications of diabetes.

People with diabetes are vaccinated against Streptococcus pneumoniae , hepatitis B , and COVID-19 , and doctors usually recommend they receive annual flu vaccination because people with diabetes are at risk of infection.

Treatment of high blood pressure and high cholesterol levels, which can contribute to circulation problems, can help prevent some of the complications of diabetes as well. People with diabetes who are between 40 and 75 years are given a statin therapy to lower cholesterol levels and lower cardiovascular risk. People younger than 40 or older than 75 years and with an elevated risk of heart disease also should take a statin.

Another common problem in people with diabetes is gum disease ( gingivitis ), and regular visits to the dentist for cleaning and preventive care are important.

Did You Know...

Prevention of hypoglycemia.

One of the challenges of trying to strictly control the levels of glucose in the blood is that low blood glucose levels ( hypoglycemia ) may occur with some commonly used antihyperglycemic medications (such as insulin or sulfonylureas). Recognizing the presence of low blood glucose is important because treatment of hypoglycemia is an emergency. Symptoms may include hunger pangs, racing heartbeat, shakiness, sweating, and inability to think clearly.

If hypoglycemia is very severe, sugar must get into the body quickly to prevent permanent harm and relieve symptoms. Most of the time, people can eat sugar. Almost any form of sugar will do, although glucose works more quickly than table sugar (typical table sugar is sucrose). Many people with diabetes carry glucose tablets or glucose gel packs. Other options are to drink a glass of milk (which contains lactose, a type of sugar), sugar water, or fruit juice or to eat a piece of cake, some fruit, or another sweet food. In more serious situations, it may be necessary for emergency medical professionals to inject glucose into a vein.

Glucagon can be injected into a muscle or inhaled as a nasal powder and causes the liver to release large amounts of glucose within minutes. Small transportable kits containing a syringe or autoinjector pen filled with glucagon are available for people who frequently have episodes of low blood glucose to use in emergency situations when sugar cannot be ingested by mouth.

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of the resources.

American Diabetes Association : Comprehensive information on diabetes, including resources for living with diabetes

JDRF (previously called Juvenile Diabetes Research Foundation): General information on type 1 diabetes mellitus

National Institute of Diabetes and Digestive and Kidney Diseases : General information on diabetes, including on the latest research and community outreach programs

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Rulla Alsaedi , Kimberly McKeirnan; Literature Review of Type 2 Diabetes Management and Health Literacy. Diabetes Spectr 1 November 2021; 34 (4): 399–406. https://doi.org/10.2337/ds21-0014

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The purpose of this literature review was to identify educational approaches addressing low health literacy for people with type 2 diabetes. Low health literacy can lead to poor management of diabetes, low engagement with health care providers, increased hospitalization rates, and higher health care costs. These challenges can be even more profound among minority populations and non-English speakers in the United States.

A literature search and standard data extraction were performed using PubMed, Medline, and EMBASE databases. A total of 1,914 articles were identified, of which 1,858 were excluded based on the inclusion criteria, and 46 were excluded because of a lack of relevance to both diabetes management and health literacy. The remaining 10 articles were reviewed in detail.

Patients, including ethnic minorities and non-English speakers, who are engaged in diabetes education and health literacy improvement initiatives and ongoing follow-up showed significant improvement in A1C, medication adherence, medication knowledge, and treatment satisfaction. Clinicians considering implementing new interventions to address diabetes care for patients with low health literacy can use culturally tailored approaches, consider ways to create materials for different learning styles and in different languages, engage community health workers and pharmacists to help with patient education, use patient-centered medication labels, and engage instructors who share cultural and linguistic similarities with patients to provide educational sessions.

This literature review identified a variety of interventions that had a positive impact on provider-patient communication, medication adherence, and glycemic control by promoting diabetes self-management through educational efforts to address low health literacy.

Diabetes is the seventh leading cause of death in the United States, and 30.3 million Americans, or 9.4% of the U.S. population, are living with diabetes ( 1 , 2 ). For successful management of a complicated condition such as diabetes, health literacy may play an important role. Low health literacy is a well-documented barrier to diabetes management and can lead to poor management of medical conditions, low engagement with health care providers (HCPs), increased hospitalizations, and, consequently, higher health care costs ( 3 – 5 ).

The Healthy People 2010 report ( 6 ) defined health literacy as the “degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions.” Diabetes health literacy also encompasses a wide range of skills, including basic knowledge of the disease state, self-efficacy, glycemic control, and self-care behaviors, which are all important components of diabetes management ( 3 – 5 , 7 ). According to the Institute of Medicine’s Committee on Health Literacy, patients with poor health literacy are twice as likely to have poor glycemic control and were found to be twice as likely to be hospitalized as those with adequate health literacy ( 8 ). Associations between health literacy and health outcomes have been reported in many studies, the first of which was conducted in 1995 in two public hospitals and found that many patients had inadequate health literacy and could not perform the basic reading tasks necessary to understand their treatments and diagnoses ( 9 ).

Evaluation of health literacy is vital to the management and understanding of diabetes. Several tools for assessing health literacy have been evaluated, and the choice of which to use depends on the length of the patient encounter and the desired depth of the assessment. One widely used literacy assessment tool, the Test of Functional Health Literacy in Adults (TOFHLA), consists of 36 comprehension questions and four numeric calculations ( 10 ). Additional tools that assess patients’ reading ability include the Rapid Estimate of Adult Literacy in Medicine (REALM) and the Literacy Assessment for Diabetes. Tests that assess diabetes numeracy skills include the Diabetes Numeracy Test, the Newest Vital Sign (NVS), and the Single-Item Literacy Screener (SILS) ( 11 ).

Rates of both diabetes and low health literacy are higher in populations from low socioeconomic backgrounds ( 5 , 7 , 12 ). People living in disadvantaged communities face many barriers when seeking health care, including inconsistent housing, lack of transportation, financial difficulties, differing cultural beliefs about health care, and mistrust of the medical professions ( 13 , 14 ). People with high rates of medical mistrust tend to be less engaged in their care and to have poor communication with HCPs, which is another factor HCPs need to address when working with their patients with diabetes ( 15 ).

The cost of medical care for people with diabetes was $327 billion in 2017, a 26% increase since 2012 ( 1 , 16 ). Many of these medical expenditures are related to hospitalization and inpatient care, which accounts for 30% of total medical costs for people with diabetes ( 16 ).

People with diabetes also may neglect self-management tasks for various reasons, including low health literacy, lack of diabetes knowledge, and mistrust between patients and HCPs ( 7 , 15 ).

These challenges can be even more pronounced in vulnerable populations because of language barriers and patient-provider mistrust ( 17 – 19 ). Rates of diabetes are higher among racial and ethnic minority groups; 15.1% of American Indians and Alaskan Natives, 12.7% of Non-Hispanic Blacks, 12.1% of Hispanics, and 8% of Asian Americans have diagnosed diabetes, compared with 7.4% of non-Hispanic Whites ( 1 ). Additionally, patient-provider relationship deficits can be attributed to challenges with communication, including HCPs’ lack of attention to speaking slowly and clearly and checking for patients’ understanding when providing education or gathering information from people who speak English as a second language ( 15 ). White et al. ( 15 ) demonstrated that patients with higher provider mistrust felt that their provider’s communication style was less interpersonal and did not feel welcome as part of the decision-making process.

To the authors’ knowledge, there is no current literature review evaluating interventions focused on health literacy and diabetes management. There is a pressing need for such a comprehensive review to provide a framework for future intervention design. The objective of this literature review was to gather and summarize studies of health literacy–based diabetes management interventions and their effects on overall diabetes management. Medication adherence and glycemic control were considered secondary outcomes.

Search Strategy

A literature review was conducted using the PubMed, Medline, and EMBASE databases. Search criteria included articles published between 2015 and 2020 to identify the most recent studies on this topic. The search included the phrases “diabetes” and “health literacy” to specifically focus on health literacy and diabetes management interventions and was limited to original research conducted in humans and published in English within the defined 5-year period. Search results were exported to Microsoft Excel for evaluation.

Study Selection

Initial screening of the articles’ abstracts was conducted using the selection criteria to determine which articles to include or exclude ( Figure 1 ). The initial search results were reviewed for the following inclusion criteria: original research (clinical trials, cohort studies, and cross-sectional studies) conducted in human subjects with type 2 diabetes in the United States, and published in English between 2015 and 2020. Articles were considered to be relevant if diabetes was included as a medical condition in the study and an intervention was made to assess or improve health literacy. Studies involving type 1 diabetes or gestational diabetes and articles that were viewpoints, population surveys, commentaries, case reports, reviews, or reports of interventions conducted outside of the United States were excluded from further review. The criteria requiring articles to be from the past 5 years and from the United States were used because of the unique and quickly evolving nature of the U.S. health care system. Articles published more than 5 years ago or from other health care systems may have contributed information that was not applicable to or no longer relevant for HCPs in the United States. Articles were screened and reviewed independently by both authors. Disagreements were resolved through discussion to create the final list of articles for inclusion.

PRISMA diagram of the article selection process.

Data Extraction

A standard data extraction was performed for each included article to obtain information including author names, year of publication, journal, study design, type of intervention, primary outcome, tools used to assess health literacy or type 2 diabetes knowledge, and effects of intervention on overall diabetes management, glycemic control, and medication adherence.

A total of 1,914 articles were collected from a search of the PubMed, MEDLINE, and EMBASE databases, of which 1,858 were excluded based on the inclusion and exclusion criteria. Of the 56 articles that met criteria for abstract review, 46 were excluded because of a lack of relevance to both diabetes management and health literacy. The remaining 10 studies identified various diabetes management interventions, including diabetes education tools such as electronic medication instructions and text message–based interventions, technology-based education videos, enhanced prescription labels, learner-based education materials, and culturally tailored interventions ( 15 , 20 – 28 ). Figure 1 shows the PRISMA diagram of the article selection process, and Table 1 summarizes the findings of the article reviews ( 15 , 20 – 28 ).

Findings of the Article Reviews (15,20–28)

SAHLSA, Short Assessment of Health Literacy for Spanish Adults.

Medical mistrust and poor communication are challenging variables in diabetes education. White et al. ( 15 ) examined the association between communication quality and medical mistrust in patients with type 2 diabetes. HCPs at five health department clinics received training in effective health communication and use of the PRIDE (Partnership to Improve Diabetes Education) toolkit in both English and Spanish, whereas control sites were only exposed to National Diabetes Education Program materials without training in effective communication. The study evaluated participant communication using several tools, including the Communication Assessment Tool (CAT), Interpersonal Processes of Care (IPC-18), and the Short Test of Functional Health Literacy in Adults (s-TOFHLA). The authors found that higher levels of mistrust were associated with lower CAT and IPC-18 scores.

Patients with type 2 diabetes are also likely to benefit from personalized education delivery tools such as patient-centered labeling (PCL) of prescription drugs, learning style–based education materials, and tailored text messages ( 24 , 25 , 27 ). Wolf et al. ( 27 ) investigated the use of PCL in patients with type 2 diabetes and found that patients with low health literacy who take medication two or more times per day have higher rates of proper medication use when using PCL (85.9 vs. 77.4%, P = 0.03). The objective of the PCL intervention was to make medication instructions and other information on the labels easier to read to improve medication use and adherence rates. The labels incorporated best-practice strategies introduced by the Institute of Medicine for the Universal Medication Schedule. These strategies prioritize medication information, use of larger font sizes, and increased white space. Of note, the benefits of PCL were largely seen with English speakers. Spanish speakers did not have substantial improvement in medication use or adherence, which could be attributed to language barriers ( 27 ).

Nelson et al. ( 25 ) analyzed patients’ engagement with an automated text message approach to supporting diabetes self-care activities in a 12-month randomized controlled trial (RCT) called REACH (Rapid Education/Encouragement and Communications for Health) ( 25 ). Messages were tailored based on patients’ medication adherence, the Information-Motivation-Behavioral Skills model of health behavior change, and self-care behaviors such as diet, exercise, and self-monitoring of blood glucose. Patients in this trial were native English speakers, so further research to evaluate the impact of the text message intervention in patients with limited English language skills is still needed. However, participants in the intervention group reported higher engagement with the text messages over the 12-month period ( 25 ).

Patients who receive educational materials based on their learning style also show significant improvement in their diabetes knowledge and health literacy. Koonce et al. ( 24 ) developed and evaluated educational materials based on patients’ learning style to improve health literacy in both English and Spanish languages. The materials were made available in multiple formats to target four different learning styles, including materials for visual learners, read/write learners, auditory learners, and kinesthetic learners. Spanish-language versions were also available. Researchers were primarily interested in measuring patients’ health literacy and knowledge of diabetes. The intervention group received materials in their preferred learning style and language, whereas the control group received standard of care education materials. The intervention group showed significant improvement in diabetes knowledge and health literacy, as indicated by Diabetes Knowledge Test (DKT) scores. More participants in the intervention group reported looking up information about their condition during week 2 of the intervention and showed an overall improvement in understanding symptoms of nerve damage and types of food used to treat hypoglycemic events. However, the study had limited enrollment of Spanish speakers, making the applicability of the results to Spanish-speaking patients highly variable.

Additionally, findings by Hofer et al. ( 22 ) suggest that patients with high A1C levels may benefit from interventions led by community health workers (CHWs) to bridge gaps in health literacy and equip patients with the tools to make health decisions. In this study, Hispanic and African American patients with low health literacy and diabetes not controlled by oral therapy benefited from education sessions led by CHWs. The CHWs led culturally tailored support groups to compare the effects of educational materials provided in an electronic format (via iDecide) and printed format on medication adherence and self-efficacy. The study found increased adherence with both formats, and women, specifically, had a significant increase in medication adherence and self-efficacy. One of the important aspects of this study was that the CHWs shared cultural and linguistic characteristics with the patients and HCPs, leading to increased trust and satisfaction with the information presented ( 22 ).

Kim et al. ( 23 ) found that Korean-American participants benefited greatly from group education sessions that provided integrated counseling led by a team of nurses and CHW educators. The intervention also had a health literacy component that focused on enhancing skills such as reading food package labels, understanding medical terminology, and accessing health care services. This intervention led to a significant reduction of 1–1.3% in A1C levels in the intervention group. The intervention established the value of collaboration between CHW educators and nurses to improve health information delivery and disease management.

A collaboration between CHW educators and pharmacists was also shown to reinforce diabetes knowledge and improve health literacy. Sharp et al. ( 26 ) conducted a cross-over study in four primary care ambulatory clinics that provided care for low-income patients. The study found that patients with low health literacy had more visits with pharmacists and CHWs than those with high health literacy. The CHWs provided individualized support to reinforce diabetes self-management education and referrals to resources such as food, shelter, and translation services. The translation services in this study were especially important for building trust with non-English speakers and helping patients understand their therapy. Similar to other studies, the CHWs shared cultural and linguistic characteristics with their populations, which helped to overcome communication-related and cultural barriers ( 23 , 26 ).

The use of electronic tools or educational videos yielded inconclusive results with regard to medication adherence. Graumlich et al. ( 20 ) implemented a new medication planning tool called Medtable within an electronic medical record system in several outpatient clinics serving patients with type 2 diabetes. The tool was designed to organize medication review and patient education. Providers can use this tool to search for medication instructions and actionable language that are appropriate for each patient’s health literacy level. The authors found no changes in medication knowledge or adherence, but the intervention group reported higher satisfaction. On the other hand, Yeung et al. ( 28 ) showed that pharmacist-led online education videos accessed using QR codes affixed to the patients’ medication bottles and health literacy flashcards increased patients’ medication adherence in an academic medical hospital.

Goessl et al. ( 21 ) found that patients with low health literacy had significantly higher retention of information when receiving evidence-based diabetes education through a DVD recording than through an in-person group class. This 18-month RCT randomized participants to either the DVD or in-person group education and assessed their information retention through a teach-back strategy. The curriculum consisted of diabetes prevention topics such as physical exercise, food portions, and food choices. Participants in the DVD group had significantly higher retention of information than those in the control (in-person) group. The authors suggested this may have been because participants in the DVD group have multiple opportunities to review the education material.

Management of type 2 diabetes remains a challenge for HCPs and patients, in part because of the challenges discussed in this review, including communication barriers between patients and HCPs and knowledge deficits about medications and disease states ( 29 ). HCPs can have a positive impact on the health outcomes of their patients with diabetes by improving patients’ disease state and medication knowledge.

One of the common themes identified in this literature review was the prevalence of culturally tailored diabetes education interventions. This is an important strategy that could improve diabetes outcomes and provide an alternative approach to diabetes self-management education when working with patients from culturally diverse backgrounds. HCPs might benefit from using culturally tailored educational approaches to improve communication with patients and overcome the medical mistrust many patients feel. Although such mistrust was not directly correlated with diabetes management, it was noted that patients who feel mistrustful tend to have poor communication with HCPs ( 20 ). Additionally, Latino/Hispanic patients who have language barriers tend to have poor glycemic control ( 19 ). Having CHWs work with HCPs might mitigate some patient-provider communication barriers. As noted earlier, CHWs who share cultural and linguistic characteristics with their patient populations have ongoing interactions and more frequent one-on-one encounters ( 12 ).

Medication adherence and glycemic control are important components of diabetes self-management, and we noted that the integration of CHWs into the diabetes health care team and the use of simplified medication label interventions were both successful in improving medication adherence ( 23 , 24 ). The use of culturally tailored education sessions and the integration of pharmacists and CHWs into the management of diabetes appear to be successful in reducing A1C levels ( 12 , 26 ). Electronic education tools and educational videos alone did not have an impact on medication knowledge or information retention in patients with low health literacy, but a combination of education tools and individualized sessions has the potential to improve diabetes medication knowledge and overall self-management ( 20 , 22 , 30 ).

There were several limitations to our literature review. We restricted our search criteria to articles published in English and studies conducted within the United States to ensure that the results would be relevant to U.S. HCPs. However, these limitations may have excluded important work on this topic. Additional research expanding this search beyond the United States and including articles published in other languages may demonstrate different outcomes. Additionally, this literature review did not focus on A1C as the primary outcome, although A1C is an important indicator of diabetes self-management. A1C was chosen as the method of evaluating the impact of health literacy interventions in patients with diabetes, but other considerations such as medication adherence, impact on comorbid conditions, and quality of life are also important factors.

The results of this work show that implementing health literacy interventions to help patients manage type 2 diabetes can have beneficial results. However, such interventions can have significant time and monetary costs. The potential financial and time costs of diabetes education interventions were not evaluated in this review and should be taken into account when designing interventions. The American Diabetes Association estimated the cost of medical care for people with diabetes to be $327 billion in 2017, with the majority of the expenditure related to hospitalizations and nursing home facilities ( 16 ). Another substantial cost of diabetes that can be difficult to measure is treatment for comorbid conditions and complications such as cardiovascular and renal diseases.

Interventions designed to address low health literacy and provide education about type 2 diabetes could be a valuable asset in preventing complications and reducing medical expenditures. Results of this work show that clinicians who are considering implementing new interventions may benefit from the following strategies: using culturally tailored approaches, creating materials for different learning styles and in patients’ languages, engaging CHWs and pharmacists to help with patient education, using PCLs for medications, and engaging education session instructors who share patients’ cultural and linguistic characteristics.

Diabetes self-management is crucial to improving health outcomes and reducing medical costs. This literature review identified interventions that had a positive impact on provider-patient communication, medication adherence, and glycemic control by promoting diabetes self-management through educational efforts to address low health literacy. Clinicians seeking to implement diabetes care and education interventions for patients with low health literacy may want to consider drawing on the strategies described in this article. Providing culturally sensitive education that is tailored to patients’ individual learning styles, spoken language, and individual needs can improve patient outcomes and build patients’ trust.

Duality of Interest

No potential conflicts of interest relevant to this article were reported.

Author Contributions

Both authors conceptualized the literature review, developed the methodology, analyzed the data, and wrote, reviewed, and edited the manuscript. R.A. collected the data. K.M. supervised the review. K.M. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Prior Presentation

Portions of this research were presented at the Washington State University College of Pharmacy and Pharmaceutical Sciences Honors Research Day in April 2019.

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Oral Manifestations and Complications of Diabetes Mellitus: A review

Affiliation.

• 1 Department of Oral Health, Sultan Qaboos University Hospital, Muscat, Oman;
• PMID: 21969888
• PMCID: PMC3121021

Diabetes mellitus is a chronic disease affecting all age groups. It is one of the leading causes of mortality and morbidity worldwide. Many chronic macrovascular and microvascular complications of diabetes have been reported in the literature with few reports about oral complications. This article aims to review and increase the awareness of oral manifestations and complications of diabetes mellitus and to stimulate research on the subject. It treats in depth some of the complications such as periodontal disease, fungal infection and salivary dysfunction while other complications are mentioned briefly.

Keywords: Complications; Diabetes Mellitus; Fungal; Oral; Periodontitis; Taste.

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• v.5(2); 2016

Effectiveness of diabetes education and awareness of diabetes mellitus in combating diabetes in the United Kigdom; a literature review

Chaudhary muhammad junaid nazar.

1 Department of Nephrology, Shifa International Hospital, Islamabad, Pakistan

Micheal Mauton Bojerenu

2 Department of Internal Medicine, Sickle Cell Unit, Harvard University Hospital, Washington DC, USA

Muhammad Safdar

Jibran marwat.

Diabetes mellitus is a metabolic disorder that is characterized by high blood glucose level, and body cannot produce enough insulin, or does not respond to the produced insulin. In spite of the diabetes education campaigns and programmes, a large number of people in the United Kingdom are living with diabetes. The main objective of the study is to evaluate the role of knowledge and awareness of diabetes in fighting against diabetes and to interpret to which extent is diabetes education successful. The systematic review to be carried out will include literature from 2001 to 2011 in the United Kingdom regarding awareness of diabetes among UK population and effectiveness of diabetes education. Literature will be accessed using search database, British medical journals, and library. Good quality papers will be used for the systematic review. Previous studies about diabetes education will consulted and assessed. This study is going to summarize the efficacy of diabetes education campaigns and programmes which are promising to enhance the awareness The outcome of the review will be the guideline for the government, education centres, researchers, and campaigns to implement more diabetic education programmes and easily accessible diabetes services and education interventions to increase the awareness of risk factors and complications of diabetes to overcome the increasing epidemic of diabetes in the United Kingdom.

Implication for health policy/practice/research/medical education:

Diabetes mellitus is a metabolic disorder, in which there is high blood glucose level, and body cannot produce enough insulin, or the body does not respond to the insulin produced. In spite of the diabetes education campaigns and programmes, a large number of people in the United Kingdom are living with diabetes. The main objective of the study is to evaluate the role of knowledge and awareness of diabetes in fighting against diabetes and to interpret to which extent is diabetes education successful. The outcome of the review will be the guideline for the government, education centres, researchers, and campaigns to implement more diabetic education programmes and easily accessible diabetes services and education interventions to increase the awareness of risk factors and complications of diabetes to overcome the increasing epidemic of diabetes in in the United Kingdom.

Introduction

Diabetes is a serious and life-threatening disease, however it can be managed very well through proper treatment and controlling. Diabetes self-management training and education plays a vital role in the management of diabetes ( 1 ). It is crucial for diabetic patients to be aware of nature, treatment, risk factors and complication of disease due to providing suitable modality to attenuate following complications. In a study to detect the relation between health literacy, complication awareness and diabetic control among patients with type 2 diabetes mellitus, it was concluded that patient awareness scores and health literacy was negatively related to diabetes control ( 2 ). This study was 6 months study, carried out from September 2005 to February 2006 with about 150 Chinese patients.

Materials and Methods

For this review, we used a variety of sources by searching through PubMed, EMBASE, Scopus and directory of open access journals (DOAJ). The search was performed by using combinations of the following key words and or their equivalents; Prevalence of diabetes mellitus, awareness and knowledge about diabetes and its management, diabetes education programmes, effectiveness of diabetes education.

Looking at the study carried out to explore the total prevalence of diabetes mellitus in 2001 in England to support delivery of healthcare services it was estimated that in 2001 the prevalence of diabetes (diagnosed as well as undiagnosed) in England was about 4.5%, affecting more than 2 million persons ( 3 ). It was found that the prevalence of type 2 diabetes was 92% affecting 2000000 persons and the prevalence of type 1 diabetes was nearly 8% affecting 160000 persons. The prevalence of diabetes was estimated to be more in women (5.2%) than men (3.6%). It was also estimated that the prevalence of diabetes was higher in the people from ethnic minority groups than the white people. The estimated prevalence rates are 4.3 for white people, 5.7 for black African/Caribbean, and 6.6 for South Asians and 2.1% for other groups. The prevalence of diabetes was found to be increased rapidly with age as the prevalence was found to be 0.3 in people aged 0–29, 3.3 in those 30–59 and 14% in people over 60 years age.

According to Diabetes UK (2010) in 2009, the prevalence of diabetes in adults over 17 years old is estimated to be 5.1% in England affecting 2213138, 4.5% in Northern Ireland affecting 65066, 4.6% in Wales affecting 146173 and 3.9% in Scotland affecting 209886 people. The total average prevalence of diabetes in 2009 in the United Kingdom is estimated to be 4.26%.

A systematic review was conducted to estimate the age- and sex-specific diabetes prevalence worldwide for years 2010 and 2030 ( 4 ). Studies from 91 countries were selected and it was found from the review findings that the incidence of diabetes among people aged 20–80 years will be 6.5% in 2010 and 286 million adults will be affected in 2010. The prevalence of diabetes will increase to 7.8%, and nearly 440 million adults will be affected by 2030. It was suggested that there will be a 70% increase in the prevalence of diabetes in adults of developing countries and about 21% rise in developed countries. By looking at CHASE study, a cross-sectional survey carried out involving nearly 4800 children aged 9-10 years old recruited from London, Birmingham and Leicester, it is found that South Asians adults, residents of UK are 3 times more prone to develop type 2 diabetes than white Europeans ( 5 , 6 ). These people have higher blood levels of glycated haemoglobin (HbA1c), higher level of C-reactive proteins in the blood, lower level of High-density lipoprotein -cholesterol (HDL-C) and high triglyceride levels than white people. Black African-Caribbean adults residing in the United Kingdom have also most of these diabetic risk factors but these people have high HDL-C levels and low triglyceride levels.

Better diabetic education and knowledge to control and treat diabetes at right time can minimize the chances to develop complications of diabetes and thus reduce morbidity and mortality in diabetics ( 7 , 8 ). It suggests that as the rising figures of people diagnosed with diabetes is becoming a challenge in the United Kingdom so a randomised clinical trial will be run by independent research teams to interpret effective delivery and cost effectiveness of CASCADE (Child and Adolescent Structured Competencies Approach to Diabetes Education) for children and young people involved in this trial. As we know that if diabetes is diagnosed in childhood and bitterly controlled, the chances to develop long-term complications become less. The CASCADE is a multi-centre randomised control trial involving 26 clinics randomly selected as control/intervention groups, including 572 children and young people ( 7 ). Despite of the advanced medications and their delivery systems there is less improvement in control of diabetes in children and young people in the United Kingdom in last decade ( 8 ). So new health delivery systems are needed for children and young people to improve and control the diabetes.

With regards to this, in 2010, fifth national survey was carried out to assess the delivery of UK diabetes services to children and young people and identified changes in service delivery systems since 2002 ( 9 ). One hundred twenty-nine services took part in the survey involving 220 clinics. Ninety-eight percent of paediatric consultants were found having special interest in diabetes whereas in 2002 about 89% of consultants were interested in diabetes. In 88% of services, the diabetes specialist nurse worked alone in paediatric diabetes compared to 53% of the services in 2002. So overall it was concluded that there is much improvement in diabetes services for children providing high quality care, but serious deficiencies still remains.

According to Diabetes UK (2010) most of the people with diabetes type 2 in the United Kingdom are over 60; their level of diabetes knowledge tends to be poorer. According to Diabetes UK (2010) report, the residents of care homes fail to receive diabetes education and screening. A care home resident gets admitted to the hospital for screening and diagnosis of diabetes due to the lack of screening facilities and lack of diabetes education. There are diabetic residents in 6 out of 10 care homes that cannot provide special education ( 10 ).

UK prospective diabetes study has shown that adapting the effective therapy to reduce high blood pressure and high blood glucose level will result in reducing the diabetes complications ( 11 ). Diabetes UK invested more than 2 million on this study ( 11 ). The UK Prospective Diabetes Study, the 20-year study involving 5000 patients with diabetes in the United Kingdom, has revealed that intensive blood glucose level control and adopting better treatment methods can reduce the risk of diabetic retinopathy by a quarter and early renal damage by a third ( 11 ). Intensive management and control of blood pressure in hypertensive patients can reduce the risk of death resulting from life threatening long-term complications of diabetes by a third, vision loss by more than a third and cardiovascular disease by more than a third ( 10 ).

By looking at the data collected between 1st April 2008 and 31st March 2010 from 1421 weight reducing operations carried out, it is found that before surgery 379 of these 1421 patients were having type 2 diabetes ( 11 ). After 1 year of surgery it was found that this number of diabetic patients was decreased to 188 from 379 ( 11 ). Therefore by providing knowledge of advance treatment methods to people helps in controlling the diabetes as educating people about the weight loss surgeries (gastric bypass and gastric bands) can tackle type 2 diabetes as seen in this study.

Diabetes education can improve the quality of life of diabetic patients and can also prevent the costs of long-term complications of diabetes in the patients ( 10 ). As amputation of lower limb in a diabetic patient, a long-term complication of diabetes is a costly intervention, the diabetes education can help in reducing the amputation rate that can lead to large cost savings ( 10 ). Diabetic foot ulcers can develop in patients having diabetes both in type 1 and type 2 diabetes ( 11 ). It has been found, 10% of diabetic individuals may suffer from foot ulcer during their lifetime. Foot ulcer often occurs in the people who develop peripheral diabetic neuropathy and also by wearing tight shoes, by walking on tread mill, having cuts, blisters and also having narrowed arteries; atherosclerotic peripheral arterial disease. The diabetic foot ulcers should not be avoided and diabetic foot needs a special care, otherwise the diabetic foot ulcer can result in the amputation of the foot even the whole lower limb ( 11 ). The risk of lower limb amputation in diabetic patients is 15 to 45 times more than in people with no diabetes ( 10 ). About 25% of hospital admissions of diabetic people in United States and Great Britain are due to diabetic foot complications ( 10 ). The annual incidence of diabetic foot ulcers and amputation are 2.5% to 10.7% and 0.25% to 1.8%, respectively ( 12 ).

In the United States an estimated more than 130 billion dollars in 2002 is the cost of diabetes ( 13 ). Because of these devastating numbers, the cost-efficacy of preventing and treating diabetes, and the cost-effectiveness of diabetes self-management training and medical nutrition therapy to treat diabetes are receiving much attention ( 13 ). While in the United Kingdom, the cost of diabetes to the National Health Service (NHS) stands at approximately £1 million per hour, and is increasing rapidly. Diabetes accounts for approximately a tenth of NHS budget each year, a total exceeding £9 billion ( 11 ). With regards to this a systematic review was carried out involving 26 articles including randomized controlled trials, retrospective database analyses, meta-analysis, prospective, quasi-experimental and, to evaluate the cost-effectiveness of diabetes education. The results of more than half of the studies reviewed were indicated positive association between diabetes education and decreased cost. The findings of these studies indicate that diabetes self-management education (DSME) has more benefits in reducing the costs associated with diabetes intervention. Study agreed with this finding by conducting a 12-month study involving primary care trusts in the United Kingdom to assess the long-term clinical and cost-effectiveness of the diabetes education and self-management for ongoing and newly diagnosed (DESMOND) intervention ( 14 ). The cost-utility analysis was undertaken using data from a 12-month, multicentre, cluster randomised controlled trial and the study resulted that the DESMOND intervention is considered to be cost effective compared with usual care, especially with respect to the real world cost of the intervention to primary care trusts, with reductions in Cardiovascular disease (CVD) risk especially reduction in weight and smoking ( 14 ).

According to a cohort study, conducted in 2005 by Diabetes UK, The cancer risk and mortality is progressively elevating in insulin treated diabetic individuals ( 15 ). This study involved 28900 UK resident patients with insulin-treated diabetes who were less than 50 years old at the diagnosis of diabetes. However, the results showed, risks of some cancers such as liver, pancreatic, endometrial, renal and colorectal cancer slightly are raising in patients with prime type 2 diabetes but some cancer incidence including gall bladder, breast cancers and non-Hodgkin lymphoma (NHL) have not changed or prostate cancer risk has been reduced ( 15 ).

Celiac disease, as a chronic immune mediated disorder, is triggered by gluten intake in predisposed patients ( 16 ). Type 1 diabetes is one of the diseases associated with celiac disease ( 18 ). Both diseases have a common genetic predisposition. In one Turkish study involving 100 diabetic patients (51 female, 49 male, mean age 26 ±9 years, and 80 control subjects - 40 female, 40 male, mean age 27 ± 8 years), it was estimated that the prevalence of celiac disease is more in diabetic patients than the general people and celiac disease in diabetic patients can only be diagnosed by screening tests for celiac disease as CD is mostly seen as asymptomatic in these patients. The most sensitive and specific test for the diagnosis of CD is the anti-endomysial IgA antibody (IgA-EMA) test with a sensitivity of more than 90% and a specificity about 100%. This is a screening method in patients at high risk for CD. Anti-endomysium IgA was tested by indirect immunofluorescence using sections of human umbilical cord for screening. Some investigators predicted that the complications of diabetes are increased in the presence of celiac disease and worsens the metabolic control in these diabetic patients ( 17 ).

High blood glucose level can lead to microvascular and macrovascular complications ( 18 ). For examining this, a prospective observational study (UKPDS 35) was conducted by Stratton et al ( 18 ). To report positive correlation between hyperglycaemia and macro/micro-vascular insults in type 2 diabetic patients. This study involved 23 hospital-based clinics in England, Scotland and Northern Ireland. About 4600 patients including white, Asian Indian and African-Caribbean patients were participated in incidence rates analysis. Risk factors related macro-vascular complication were noticed in about 3600 of the total patient. The results of the study indicated that there is a direct relation between hyperglycemia, micro-vascular and macro-vascular complications ( 18 ). This is also clear by examining a cohort study, conducted by Fuller et al to assess cardiovascular disease associated risk in type 1 diabetic patients in the United Kingdom ( 19 ). This study consisted of group of 7500 patients with type 1 diabetes and 5 age- and gender-matched controls per non-diabetic individuals comparison group (nearly 38200) selected from the General Practice Research Database (GPRD). The cardiovascular events in these two groups were apprehended between1992-1999. These high CVD risks were seen for strokes, acute coronary disorders, and for coronary revascularizations. Results showed that women having type 1 diabetes continue to experience greater relative risks of cardiovascular disease than men compared with those without diabetes ( 19 ). Hence, there is increased absolute and relative risk of mortality due to CVD in patients with type 1diabetes compared with those without diabetes in the United Kingdom ( 19 ).

Blood glucose awareness training and cognitive behavioural therapy have been able to balance blood glucose level in type 1 diabetic patients ( 20 ). To support this evidence, a systematic review was completed ( 20 ) in Oxford to assess fear of hypoglycaemia in the patients having diabetes. About 36 papers were reviewed. And it was implicated from the review that fear of hypoglycaemia can have negative impact on diabetes management and awareness training is needed to reduce this fear of hypoglycaemia. This was further supported by a randomised control trial, carried out ( 21 ) on 650 randomly selected diabetic patients from Bournemouth Diabetes and Endocrine Centre’s diabetes register to determine the relationship between numeracy skills and glycaemic control in type 1 diabetes. Out of 650 patients 112 patients completed the study. Forty-seven percent were the male patients and it was found that low numeracy skills were badly associated with glycaemic control in diabetes and literacy was also badly associated with glycaemic control in diabetes and also relationship between literacy and glycaemic control was found to be independent of the duration of diabetes and socio-economic status of the patients.

Diabetic patients can develop hyperglycaemia and hypoglycaemia in the critical care setting while hospitalized due to various factors including infection, poor diet, and drugs ( 22 ). Hospitalized patients can develop hyperglycaemia even in the absence of family history of diabetes ( 22 ). The blood glucose level range of 100–200 mg/dl is the target of glycaemic control in the hospitalized patients. Insulin infusion is done in hospitalized patients having type 1 diabetes and in type 2 diabetic patients, oral drugs are stopped and insulin is started for glycaemic control ( 22 ).

Educational and psychosocial interventions are able to approximately improve diabetes management. ( 23 , 24 ). A systematic review was completed by Hampson et al ( 23 ) to investigate the educational and psychosocial intervention efficacy on improvement of diabetes management in adolescents type 1 diabetes patients. About 60 articles were reviewed. This systematic review gave the result that educational and psychosocial interventions have beneficial impacts on various diabetes management consequences. Similarly a systematic review was conducted by Norris et al ( 24 ) to assess the effectiveness of self-management education on glycosylated hemoglobin in adults having type 2 diabetes. Total 31 articles on randomized control trials were reviewed and it was found that DSME improves glycated hemoglobin levels at immediate follow-up by 0.76%, that long-lasting interventions may be needed to maintain the improved glycaemic control brought about by DSME programs as the more contact time between patient and educator enhances the efficacy of the result and that the improvement in glycosylated hemoglobin level drops 1–3 months after the intervention ceases ( 24 ). Further supporting this, another systematic review was conducted by Hawthorne et al ( 25 ) to determine the efficacy of various diabetic diet advice on balancing blood glucose level and weight in type 2 diabetic individuals. Only randomized controlled trials of 6 months or longer, were selected for the review and total 36 articles were reviewed. In this review study, some parameters such as weight, mortality, maximal exercise capacity and compliance various lipoproteins levels and blood pressure were measured. The review indicated that dietary advice is effective in the glycaemic control in type 2 diabetes mellitus ( 25 ) further supported all these reviews by conducting a systematic review to assess the effectiveness of culturally appropriate diabetes health education on type 2 diabetes mellitus as prevalence of type 2 diabetes mellitus is higher in ethnic minorities in the developed countries like the United Kingdom ( 25 ). Eleven randomised control trials of culturally appropriate diabetes health education on people having type 2 diabetes over 15 years from defined ethnic minority groups of developed countries were reviewed. The trials indicated both glycaemic control as well as improvement in knowledge after culturally appropriate diabetes education interventions. It was suggested from the review that culturally appropriate diabetes health education is effective in glycaemic control in type 2 diabetes and improving the knowledge score and changing the lifestyles and attitudes of the people.

Various diabetes education courses are being carried out in the United Kingdom, including DAFNE, DESMOND and X-PERT in order to increase awareness and knowledge of diabetes among people. These diabetes courses are designed to empower diabetic patients to manage their own condition effectively. Various factors like cost, distance, shortage of enough educators or centres, lack of appropriate services affect many people with diabetes to get access to diabetes knowledge. Educating the patients regarding diabetes have a key role in encouraging and supporting them to assume active responsibility for the day to day control of their situation. The review depicts that illiteracy and lack of knowledge poses a great challenge to effective health education. The review demonstrates that south Asian patients face problems regarding diet aspect and show poor level of knowledge about diabetes and also are discouraged to join educational sessions. The review indicates that impaired awareness of the diabetes increases the chances to develop complications of diabetes as the severe hypoglycaemia is becoming more common in insulin treated type 2 diabetes than previously recognized and with increased duration of insulin therapy may increase to meet that observed in type 1 diabetes. The risk of severe hypoglycaemia increases with having impaired awareness of hypoglycaemia. The authors has concluded that diabetes associated complications and psychological insults is usual in diabetic individuals. The study indicates that many providers involved in the study are aware of the diabetes related psychological problems but lack confidence in their ability to evaluate these problems and to support these patients. So, there is a need for manipulating models of care that provide essential psychosocial services. There is also need of integrating mental health professionals into the diabetes care team. This study will help the government to implement the diabetes education programmes that are cost effective and attractive to the public, easy to get access. Any diabetes service should provide highly structured diabetes education programme. In spite of the advanced medications and their delivery systems there is less improvement in control of diabetes in children and young people in UK in last decade. Better diabetic education and knowledge to control and treat diabetes at right time can reduce the risk factors and minimize the chances to develop complications of diabetes and thus reduce morbidity and mortality in diabetics.

Authors’ contribution

CMJN completed the article, MS and MMB reviewed the article, and JM completed the draft.

Conflicts of interest

The authors declared no competing interests.

Ethical considerations

Ethical issues (including plagiarism, data fabrication, double publication) have been completely observed by the authors.

Funding/Support

Please cite this paper as: Nazar CMJ, Bojerenu MM, Safdar M, Marwat J. Effectiveness of diabetes education and awareness of diabetes mellitus in combating diabetes in the United Kigdom; a literature review. J Nephropharmacol. 2016;5(2):110-115.