3 June 2014
Diabetes, the New Epidemic
Professor Paolo Pozzilli MD
Diabetes is spreading worldwide and it is rapidly becoming a new epidemic threat for the 3rd millennium. Its natural history is related to long-term complications that impact life quality (complications such as retinopathy, nephropathy, and neuropathy) and life expectancy (macrovascular disease) (1). Diabetes, therefore, imposes a large and growing burden on public health worldwide.
In 2007, over 246 million people were diagnosed with diabetes, and future projections indicate a significant increase in the next decades. It has been reported that by the 2035 there will be more than 470 million people with diabetes worldwide, with the highest rates of increase in the developing countries. In these regions, diabetes will affect over 228 million subjects, twice as many as in the western countries (1).
Why did type 2 diabetes become pandemic?
The prevalence of obesity, a known risk factor for type 2 diabetes, has dramatically increased over the years, especially among children and adolescents. The number of overweight children under the age of 5 years is estimated to be over 42 millions worldwide. Rates of childhood obesity have greatly increased between 1980 and 2010 (2). Currently, 10% of children worldwide are either overweight or obese (3). Childhood obesity is already epidemic in some areas and rising in others.The diabetic and obesity epidemics will be the major drains on healthcare budgets in 10 years from now and it is crucial to reverse this trend in childhood obesity.
Unfortunately, obesity is often neglected and still not fully recognized as a disease by the people. On the other hand, diabetes remains undiagnosed for years– according to the NHANES survey conducted in the United States, diabetes was undiagnosed in 30% of screened population (4); importantly, over 25% of patients newly diagnosed with diabetes showed already established diabetic retinopathy or microalbuminuria, a marker of kidney injury (5, 6).
Diabetes is preceded by intermediate subclinical stages, commonly defined as prediabetes, comprising the categories of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT). Pre-diabetes stages represent abnormal metabolic states, conferring a high risk to progress to diabetes or its complications (7, 8). Clinical intervention studies have shown that prediabetic status is reversible and an early intervention may delay the final deterioration of glucose homeostasis. Therefore its early detection is crucial to reduce the risk to develop the disease (9).
Can type 2 diabetes be prevented or delayed?
Effect of lifestyle changes
Weight gain and sedentary lifestyle are two main pathophysiological elements linked to diabetes development. Both conditions may alter glucose homeostasis by impairing insulin production and/or action on target tissues. Several trials have shown that lifestyle changes based on weight loss and physical activity may reduce the risk of type 2 diabetes (table 1).
In the Diabetes Prevention Program (DPP), carried out on 3,234 subjects at risk for diabetes (overweight with IGT), a lifestyle-modification program with the goals of at least a 7 % weight loss and at least 150 minutes of physical activity per week reduced the risk of type 2 diabetes by 58% (10).
In the Finnish Diabetes Prevention Study (DPS), 522 middle-age overweight subjects with IGT were randomly assigned to either control or intervention program consisting in receiving individualized counseling aimed at reducing weight, total intake of fat, and intake of saturated fats and increasing intake of fiber and physical activity. During the study, diabetes risk was reduced by 58 % in the intervention group and directly associated with changes in lifestyle (11).
The China Da Quing Diabetes Prevention Study (CDQDPS) compared the efficacy of different lifestyle changes approaches (diet and physical activity alone, or combined). After six years, the intervention strategies reduced significantly the risk of type 2 diabetes compared with the control group (by 48% in diet group, 41% in the physical activity group, 46% in the combined approach) (12). These results confirmed the efficacy of lifestyle changes even in individuals with clinical and ethnic features different from those in the DPP and DPS.
Effect of pharmacological intervention
Pharmacological intervention may prevent type 2 diabetes (table 2). However, their use as an alternative strategy to lifestyle changes is limited due to the lack of long-term sustained effect, as well as by the higher costs and the increased risk of adverse events compared to non-pharmacological intervention.
Metformin. Metformin acts as an insulin-sensitizer and it is the only drug approved for type 2 diabetes prevention in subjects with prediabetes. The DPP showed that treatment with metformin (850 mg twice daily) reduced diabetes incidence by 31 % compared with the control group. However, the same trial also showed that lifestyle was more effective than metformin (10). In the Indian Diabetes Prevention Program (IDPP), carried out on 531 subjects of Indian ethnicity with IGT, a lower dose of 500 mg daily was equally effective in reducing diabetes risk but no synergistic effect was evident for combined treatment with metformin and lifestyle (13).
Alpha-glucosidase inhibitors (AGI). AGIs lower blood glucose by reducing carbohydrate processing in the bowel and therefore glucose absorption. The STOP-NIDDM trial on 1,419 subjects with IGT has shown that acarbose reduced significantly the risk of type 2 diabetes by 25% compared with the placebo control group (14). Moreover, hypertension and cardiovascular events were reduced by 34% and 49%, respectively (15). Similar efficacy was obtained by voglibose with a 40.5% risk reduction over three years of treatment (16).
Thiazolidinediones (TZD). TZDs increase insulin action on target tissues by enhancing activity of their receptor PPAR-γ. The DREAM study (17)showed that rosiglitazone (8 mg daily) reduced type 2 diabetes incidence by 62% over three years; however, this effect was not durable and the concern on cardiovascular safety raised by observational and post-hoc analysis (18, 19)has led the EMA to rosiglitazone withdrawal. Also the other TZD, pioglitazone, has shown to be effective in reducing diabetes incidence in 600 subjects with IGT, but adverse events such as weight gain and oedema were higher in the intervention group compared with the placebo (20).
Insulin.Recently, the ORIGIN study carried out on more than 12,000 people evaluated the effect of insulin glargine on diabetes risk. Treatment with glargin reduced type 2 diabetes by 20% but it was associated with increased risk of hypoglycaemic events and weight gain compared with the control group (21).
Do prevention interventions have sustained effects?
According to a follow-up analysis of the DPP, lifestyle may have sustained effect on diabetes prevention for a period as long as ten years; in this study, people previously on lifestyle changes had a sustained 34% reduction of type 2 diabetes, despite 5 kg body weight re-gain (22). In the seven years post-trial of the DPS a sustained effect of lifestyle was also evident– 21% risk reduction of developing type 2 diabetes (23). The benefit of lifestyle was durable for 14 years in the CDQDPS (24). On the contrary, among the pharmacological interventions, only metformin induces a sustained effect on diabetes prevention, while other drugs failed.
Can diabetes prevention be feasible?
Although clinical trials have shown that diabetes can be prevented or delayed, the number of people diagnosed with this disease is increasing worldwide, suggesting the difficulty to deliver prevention strategies in real life setting. Indeed, a recent analysis on the Italian population revealed that only 2% of people perceive diabetes as a serious disease eventually leading to death.
Data from the Food and Agriculture Organization of the United Nations show that caloric intake pro capite has grown by 30% in the last 40 years and that this is mainly related to increased intake of fat-enriched food. In parallel, price of food has significantly reduced over time. In particular, price of added sugars has dropped significantly more than the price of healthful foods (25).
It is well known that price is an important determinant of food choices and diet, suggesting that increasing the price of unhealthy foods, by taxation, should reduce consumption of the taxed foods. In the past years, several countries such as Denmark, France, Hungary and Peru have introduced taxes for unhealthy food items, and others countries are considering such taxes. Some of these taxes are small excise taxes levied on sugar sweetened beverages or either goods and services taxes, levied on junk food (26). A 20 years longitudinal study on 5,115 young adults has shown that 10% taxes on sugar soda and
pizza was able to reduce caloric intake by 7 and 10%, respectively; importantly, this was associated with significant weight loss and reduced insulin levels during the 20 years after the introduction of food taxes
(27). However additional evidence is needed to evaluate the cost-effectiveness of this strategy on obesity and type 2 diabetes risk.
Moreover, a recent trial has shown that the use of economic incentives produced significant weight loss (more than the control group) during a 16 weeks intervention (28). Another study showed similar results but it highlighted higher efficacy in terms of body weight changes for group-based incentives rather than individual incentives (29).However, such benefits were not fully sustained after study ending, suggesting that further studies are needed to evaluate this strategy in diabetes and obesity prevention.
Diabetes is a global issue. Intervention trials have shown that modest lifestyle changes can reduce significantly the rate of type 2 diabetes in patients at highest risk. Lifestyle changes have proven sustained effects over time, are safe, easy to deliver and less expensive than pharmacological approaches. However, barriers such as misconception of diabetes as serious disease by the people, reduced adherence to treatments and lack of community programs to support prevention –especially in developing countries– limit the feasibility of these approaches in real life settings.
Diabetes prevention requires social and political changes. Novel, additional and cost-effective strategies that can be easily delivered and accepted by the community are needed.
Table 1 – Lifestyle changes can prevent type 2 diabetes.
| Da Qing
|| 1. Diet
3. Diet & Exercise
| 0.66 (0.53-0.81)
|| Diet & Exercise
|| 0.42 (0.3-0.7)
|| 1. Diet & Exercise
| 0.42 (0.34-0.52)
|| 1. Diet & Exercise
3. Metformin + Diet & Exercise
| 0.72 (0.62-0.80)
DPS, Finnish Diabetes Prevention Study; DPP, Diabetes Prevention Program; IDPP, Indian Diabetes Prevention Program; RR, relative risk, CI, confidence interval
Tabella 2 – Pharmacological intervention for type 2 diabetes prevention.
(850 mg bid)
|| GI simptoms
(100 mg tid)
|| GI simptoms
(0.2 mg tid)
|| GI simptoms
|| IGT overweight
|| GI simptoms
* Odds Ratio; IGR, Impaired glucose regulation; GI, Gastro-intestinal; RR, relative risk; CI, confidence interval
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© Professor Paolo Pozzilli MD, 2014