Evolving epidemiology and the transition of patients with type 2 diabetes



by S. Del Prato, Italy

Marit Eika JØRGENSEN,
Professor, MD, PhD123
1Steno Diabetes Center
2National Institute of Public Health,
Southern Denmark University
3Greenland University,
Ilisimatusarfiq, Greenland
DENMARK

Type 2 diabetes is one of the most rapidly increasing chronic conditions in the world due to the increasing number of new cases in combination with aging populations. Prevalence has increased in all regions of the world, which is most disconcerting due to the excess risk of subsequent micro- and macrovascular complications. Over the last decades, a multifactorial approach to managing type 2 diabetes has been employed in most countries, which has convincingly reduced the incidence of all vascular complications. However, improvements in care and outcomes have been observed primarily in older adults, while the mortality relative to the background population is markedly higher among young people with type 2 diabetes. Low socioeconomic status is also associated with a higher diabetes-associated morbidity, and some ethnic groups have a higher risk of late diabetes complications. The increase in the number of years spent with the condition means that people with diagnosed diabetes will have more years of exposure and a greater cumulative risk of developing diabetes complications. Furthermore, with more people surviving traditional micro- and macrovascular late diabetic complications, new nonvascular complications are emerging, such as cancer, infectious diseases, lung disease, and mental diseases, which could have implications for future prevention and care.

Diabetes is one of the most rapidly increasing chronic and frequent conditions in the world. Moreover, type 2 diabetes causes 5 million deaths per year, primarily from cardiovascular diseases, and, by 2030, type 2 diabetes is expected to become the seventh leading cause of death worldwide.1 Knowledge about the incidence, prevalence, and mortality from diabetes is crucial for health care planning, preventive efforts, and managing the disease and its complications. The following article summarizes the global evidence on epidemiology and demography of diabetes and its comorbidities.

Demography of diabetes: prevalence, incidence, and mortality

♦ Global prevalence estimates of diabetes
Type 2 diabetes has reached endemic proportions, affecting around 415 million people worldwide, which corresponds to a prevalence rate of 9%.2 The International Diabetes Federation (IDF) predicts that 642 million people will have diabetes in 2040 and more than 90% of these people will have type 2 diabetes. As a result, type 2 diabetes is currently more frequent among people of Asian, Hispanic-American, or African origin than among Europeans, which is partly due to economic development and globalization. The prevalence has particularly increased in populations that have experienced an epidemiological transition from a traditional to a wealthy lifestyle. The rapid development of diabetes in previously undernourished populations became known as the “thrifty gene” hypothesis,3 suggesting that genes predisposing people to diabetes might be advantageous when food is in short supply; however, this hypothesis has never been confirmed. In genetically predisposed individuals, obesity and physical inactivity are often described as the sole risk factors responsible for type 2 diabetes, although this ignores that fact that aging is probably the more important risk factor for diabetes.

♦ The contribution of incidence and mortality to the change in diabetes prevalence
The extent to which the increase in diabetes prevalence is explained primarily by an increase in incidence or a decrease in mortality is unknown. A recent calculation based on the Danish Diabetes Registry showed that, while the decline in mortality, particularly among elderly people with diabetes, has had some impact on the increasing prevalence of diabetes over the past decades, the major driving factor has been the increase in diabetes incidence, particularly in younger people. Consequently, incidence contributes to more cases than mortality removes.4

♦ Changing incidence
Environmental changes related to urbanization, obesity, and aging are known to play a major role in the increasing incidence of diabetes. Historically, in Western countries, the prevalence of diabetes shifted from the more affluent population to the poorer population. Parallel to this, increasing affluence and a movement toward a Western lifestyle has produced a rapid increase in type 2 diabetes within low-income countries where it was previously rare.5 Studies of populations exposed to similar environmental conditions consistently show that some ethnic groups are disproportionately affected by diabetes.6-10 This difference in diabetes risk presumably depends on an interaction between environmental factors, lifestyle, and genetic factors. However, most knowledge about the epidemiology of diabetes and its risk factors is based on cross-sectional studies, since longitudinal incidence studies are lacking. Furthermore, it is not completely clear whether the observed increase in diabetes incidence is due to a true increase in incidence reflecting an increase in underlying risk factors, such as obesity and sedentary behavior, or whether it reflects improvements in diagnostic activity. The latter would imply a higher number of patients diagnosed at an earlier (and often asymptomatic) stage.

Figure 1. Life years lost to diabetes from 1995-2012.
Each line shows life years lost (years) for people with diabetes mellitus (DM) from 1995 to 2012
according to age for men (blue) and women (red). The upper line represents 1995; each line represents
the following years, and the lowest line represents 2012.
From reference 11: Bendix Carstensen. The Danish national diabetes register: life lost to DM.
bendixcarstensen.com/DMreg/demoYLL.pdf.

♦ Life years lost to diabetes
Mortality rates are higher in type 2 diabetes compared with the general population without diabetes, but the excess mortality varies according to age, sex, and diabetes duration. Generally, mortality has decreased over the last decades in most studied populations. Figure 1 shows life years lost to diabetes from 1995 to 2012 in Denmark for the total population with diabetes, according to age and sex.11 In 1995, women aged 30 years old, with or without diabetes, had a life expectancy of 37.7 and 49.2 years, respectively, and, in 2012, life expectancy was 46.6 and 53.1 years, respectively. Men with diabetes who were 50 years old in 1995 had a life expectancy of 17.8 vs 26.3 years in men without diabetes, and, in 2012, the life expectancy was 24.5 vs 30.6 years, respectively. Therefore, the life-shortening impact of diabetes decreases with age, but also with calendar time.

The changing pattern of diabetes complications

Life expectancy has improved for men and women with diabetes; however, the lower mortality has led to a 28.7% increase in the years lived with diabetes-related disabilities due to diabetic complications.12

♦ Epidemiology of microvascular complications
The risk of developing microvascular complications (retinopathy, neuropathy, and nephropathy) is elevated when glucose levels are not managed intensively.13-15 In 1977, the UKPDS study (UK Prospective Diabetes Study), a randomized, multicenter trial in patients with a new clinical diagnosis of type 2 diabetes, identified a clear beneficial effect of intensive glucose- lowering treatment on microvascular complications (ie, nephropathy and retinopathy), with a 24% risk reduction at the 10-year follow-up.16 In 2013, a meta-analysis14 concluded that intensive glycemic control reduced the risk of nephropathy (relative risk [RR], 0.75; 95% CI, 0.59-0.95), retinopathy (RR, 0.79; 95% CI, 0.68-0.92) and the composite outcome of microvascular diseases (RR, 0.88; 95% CI, 0.82-0.95) compared with conventional glycemic control. The Steno 2 study analyzed the effect of a multifactorial intensive intervention, and showed that multifactorial cardiovascular risk reduction during a 5.5-year period reduces the risk of nephropathy, retinopathy, and autonomic neuropathy in patients with established type 2 diabetes and microalbuminuria.17 After a 21-year follow-up, the progression of retinopathy, blindness, and autonomic neuropathy decreased by 33%, 53%, and 41%, respectively, in the intensive-treatment group,18 but there were no between-group differences in the progression of peripheral neuropathy.

The clinical management of diabetes has markedly improved over the past decades,19,20 but to which extent this has resulted in lower rates of microvascular complications has not been well studied. In the latest edition of the IDF Diabetes Atlas, estimates of complications were not included due to the lack of comparability of the available data. Furthermore, incidence data are generally lacking, which is—to some extent—due to the lack of systematic screening for microvascular complications in many countries.21

The annual incidence of micro- and macroalbuminuria in type 2 diabetes ranges from 7% to 9% with little variation across different countries.22-25 Time trends in nephropathy have been studied in the US, and the NHANES data (National Health and Nutrition Examination Survey) showed that the rates of end-stage renal disease decreased between 1990 and 2010 (–28.3%; 95% CI, –34.6 to –21.6).26 However, the decrease was smaller than for all other complications. Although the prognosis for people with diabetic nephropathy has improved, cardiovascular disease and overall mortality in type 2 diabetes are still largely related to nephropathy.27

Diabetic retinopathy is one of the most important causes of visual impairment globally, and, to be most effective, prevention of vision loss requires early screening and intervention.

Diabetic retinopathy estimates decreased between 1990 and 2010; it was responsible for 4.8% of global blindness in 2002, 3.9% in 2004, and 1% in 2010.28 The NHANES study showed that, although the number of adults with diagnosed diabetes reporting visual impairment increased, the percentage of adults with diagnosed diabetes who reported visual impairment decreased significantly from 23.7% in 1997 to 17.6% in 2011 (Figure 2).29 Macular edema needs to by systematically detected because it is the main cause of referable eye disease,30 and novel intraocular injections have substantially decreased the visual impairment caused by macular edema.

Figure 2. Crude and age-adjusted percentage of adults aged 18 years or
older with diagnosed diabetes reporting visual impairment in the US between
1997 and 2011.
From reference 29: Centers for Disease Control and Prevention. Crude and age-adjusted
percentage of adults aged 18 years or older with diagnosed diabetes reporting visual impairment,
United States, 1997–2011. http://www.cdc.gov/diabetes/statistics/visual/fig2.htm.
© 2012, Centers for Disease Control and Prevention.

Recently, it has been demonstrated that deep neural networks can be trained to identify both diabetic retinopathy and macular edema from retinal fundus photos with high sensitivity and specificity.31 This automated system for the detection of diabetic eye diseases offers several advantages, and it has a huge potential to reduce blindness from diabetic retinopathy if applied to populations with poor ophthalmological services.

♦ Epidemiology of macrovascular complications
As for microvascular complications, the incidence of cardiovascular events continues to fall in Western countries,32,33 but people with diabetes still have elevated cardiovascular risk compared with the general population at all ages.34 Glucose control has a lower effect on arterial disease, the leading cause of years lost to type 2 diabetes, than on small vessel complications. Therefore, careful attention to other cardiovascular risk factors is needed. The Steno 2 study addressed this in a trial on patients with type 2 diabetes and microalbuminuria. After a 5.5-year follow-up, 7.8 years of intensified multifactorial target-driven care was associated with a 57% reduction in the primary composite cardiovascular end point compared with standard care.17 At the 21.2-year follow-up, the intensive treatment group had gained 7.9 years of life.18 The increase in lifespan corresponded to time free from incident cardiovascular disease.

Figure 3. Adjusted hazard ratios for coronary heart disease according to migrant
group and sex in Denmark between 2005 and 2013.
From reference 39: Andersen GS, Jørgensen ME, Søberg S. Ethnicity, Migration and T2DM.
https://www.diapedia.org/type-2-diabetes-mellitus/3104465162/ethnicity-migration-and-t2dm

This approach to treating diabetes has been implemented in most guidelines during the last 10 to 15 years, and epidemiological studies of the general type 2 diabetic population have convincingly demonstrated a significant decline in cardiovascular disease. In the US, the NHANES data showed that the rates of all diabetes complications decreased between 1990 and 2010, with the largest relative decreases in acute myocardial infarctions (–67.8%; 95% CI, –76.2 to –59.3), followed by strokes and amputations, which each declined by approximately 50% (–52.7% and –51.4%, respectively).26 Similar time trends have been seen in other Western populations, and, in particular, some studies have shown a >50% decline in major amputation rates over a decade.

However, there are social and ethnic inequalities in diabetes associated cardiovascular disease.35-38 Nationwide register studies from Scotland and Sweden have shown a higher incidence of cardiovascular disease among type 2 diabetes patients with low income and educational levels, even after taking diabetes duration, comorbidity, and cardiometabolic risk factors into account. In Denmark, a higher incidence of coronary heart disease has been found among migrants from the Middle East and Asia compared with Danish-born individuals with type 2 diabetes (Figure 3),39 irrespective of diabetes duration, BMI, smoking, and cardiometabolic risk factors. Importantly—and not reflected in the previous study—quality of care, comorbidity, and socioeconomic factors rather than migrant status itself may explain the observed rates of complications and mortality. A review showed that 15 studies have looked into ethnic differences in quality of care, all of which were performed in the US,40 and one major factor contributing to these ethnic differences was the frequency of screening procedures for complications. In five studies, the quality of care was higher for ethnic minorities, but eight studies reported an overall lower quality of care for ethnic minorities.

♦ Nonvascular complications
Several studies have shown a higher diabetes related morbidity and mortality from mental diseases, suicides, cancer, lung diseases, and infectious diseases, which may be due to the aging population, more patients surviving traditional long term complications, and partly due to more patients being diagnosed early and obesity. Except for infectious diseases, obesity has been suggested to be a common underlying risk factor for both diabetes and these nontraditional complications in most studies. The demography and epidemiology of cancer and tuberculosis in type 2 diabetes are summarized in the following section as examples of emerging nonvascular diabetes complications.

♦ Cancer and diabetes
Substantial evidence suggests that type 2 diabetes is associated with an increased risk for several types of cancers (eg, pancreas, liver, endometrium, kidney, and gastrointestinal).41 These associations may be due to some direct and indirect mechanisms. The risk of cancer among people with diabetes is higher with the advanced stages of the disease. It is not clear whether this increased risk is a result of the disease processes associated with diabetes or, if latent, whether cancer contributes to the deterioration of the diabetic status of the patients. While there is an approximate 20% to 50% higher risk for pancreas and liver cancer, there is no excess risk for other types of cancer among people with diabetes.42 Overall, about 35% of a Western population will be diagnosed with diabetes in their lifetime, 40% with cancer, and 15% with both cancer and diabetes. However, cancer patients with preexisting diabetes experience higher mortality than cancer patients without diabetes.43 Higher comorbidity at the time of cancer diagnosis, worse treatment outcomes, and cancer diagnosis at a more advanced stage may influence the cancer prognosis in patients with diabetes.

♦ Tuberculosis and diabetes
In low-income countries where the incidence of tuberculosis is high, the potential role of diabetes in tuberculosis incidence and prognosis is important. The association between diabetes and the incidence of tuberculosis is well established in cross sectional studies; however, some controversy over the directionality of the association remains due to observations that tuberculosis induces hyperglycemia. The few longitudinal studies on diabetes and tuberculosis have found an increased risk of tuberculosis among diabetic patients than among nondiabetic patients with RRs ranging from 1.3 to 1.9, generally decreasing with calendar time.44 In India, the fraction of tuberculosis attributable to diabetes is estimated to be 15% to 25%.45 Epidemiological studies have shown poor treatment outcomes for patients with tuberculosis and diabetes. Although not supported by interventional studies, the WHO recommends screening for diabetes in all patients with tuberculosis, followed by intensive glycemic control to attempt to improve the outcome for tuberculosis patients.46 Patients with tuberculosis are often vulnerable, with a high number of comorbidities; therefore, they are at a high risk for adverse effects of intensive glucose control. Controlled interventional studies on the effect of a glucose-lowering treatment on tuberculosis outcomes are clearly warranted to justify screening for, and tight control of, diabetes.

Conclusion

Type 2 diabetes occurrence has increased rapidly over a generation, and it is now one of the most frequent chronic conditions worldwide. The decline in diabetes-related mortality is encouraging, although the resulting increase in diabetes prevalence obviously challenges the health care system. A larger absolute number of older people will survive with diabetes complications with increased costs of diabetes treatment and costs related to screening for and treatment of the complications. The observed increase in diabetes incidence calls for intensified preventive strategies in nondiabetic individuals. Thus, the increasing diabetes prevalence has different public health consequences according to the contributing prevalence components. Stronger attention needs to be given to the management of diabetes and its associated risks in high-risk individuals (ie, people diagnosed with type 2 diabetes at a young age, people with a low socioeconomic status, and some ethnic groups) to reduce the burden of micro- and macrovascular complications. Finally, with more people surviving vascular diabetes complications, new diabetes-related morbidities are emerging, and, in the future, diabetes care should focus on screening and treating nontraditional complications.■

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Keywords: amputation; cancer; cardiovascular disease; epidemiology; infectious disease; microvascular complication; tuberculosis; type 2 diabetes