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Prevention of Diabetes and Metabolic Syndrome: Lessons Learned from the DPP and DPPOS Trials

Prevention of Diabetes and Metabolic Syndrome: Lessons Learned from the DPP and DPPOS Trials

Prediabetes is a high-risk state for developing diabetes, and currently, more than 84 million adults in the US have prediabetes.1 Diagnosing and managing prediabetes is essential, considering that it increases the annual risk for developing diabetes by 10%, and individuals with prediabetes have a 70% lifetime risk of progressing to diabetes.2 As with diabetes, prediabetes increases the risk of atherosclerotic cardiovascular disease (ASCVD), nephropathy, and retinopathy.3,4 The exponential rise in obesity has contributed to the overall impact of prediabetes; individuals with prediabetes that are also overweight or obese have an increased risk of progressing to diabetes.5
However, despite the increased morbidity and mortality, prediabetes is underdiagnosed and undertreated. It is estimated that 90% of individuals with prediabetes in the US are not aware that they have the condition.6 The treatment of prediabetes is a complex and controversial topic in the clinical community; many clinicians are reluctant to screen and manage patients with prediabetes.7 Studies have shown that clinicians rarely provide lifestyle modification counseling, refer eligible patients to an intensive behavioral lifestyle intervention modeled on the successful Diabetes Prevention Program (DPP), or prescribe metformin; all of which are recommended in the ADA guidelines for prediabetes.7-10
The reasons for undertreatment are multifactorial; clinicians may not view prediabetes as a disease state that warrants intervention or believe that treating prediabetes does not prevent diabetes or its complications, as well as a lack of FDA approved pharmacotherapies for prediabetes.7-9 However, several approaches to prevent or reduce diabetes progression in these individuals have been successful, including targeting overweight and obesity with intensive lifestyle interventions, pharmacotherapy, and bariatric surgery, as well as glycemic control with existing glucose-lowering medications.11
“Prediabetes occurs when fasting plasma glucose (FPG) levels or 2-hr plasma glucose (PG) levels following an oral glucose tolerance test (OGTT) lie between normal levels and the cut points for diagnosing diabetes. At present, fasting glucose levels of 100-125 mg/dL, or 2-hr PG levels following an OGTT between 140 – 199 mg/dL are considered to be prediabetic.12 However, the criterion mostly used in practice is the fasting glucose as most clinicians do not routinely do an OGTT” – mentioned Edward S. Horton, MD, Professor of Medicine at Harvard Medical School and Senior Investigator at the Joslin Diabetes Center in Boston.
Dr. Horton has played a pioneering role in several clinical trials that have looked at prevention of diabetes or diabetes complications with intensive lifestyle interventions or metformin, including the Diabetes Prevention Program (DPP), DPP Outcomes Study (DPPOS), and the Action for Health in Diabetes (LookAHEAD) Study. Some of the strongest evidence for lifestyle modification in the prevention of diabetes comes from the DPP program, which was established by the Centers for Disease Control and Prevention (CDC) to bring evidence-based lifestyle change programs to Americans at high-risk for type 2 diabetes.13
“At first, the DPP really looked at interventions to decrease progression from impaired glucose tolerance to diabetes, but as the study progressed, we began to look at prevention of cardiovascular disease and all of the longterm complications associated with diabetes, like retinopathy, nephropathy, and neuropathy. In this program, nondiabetic patients with impaired glucose tolerance or elevated FPG were randomized to metformin, intensive lifestyle modification, or placebo control. We chose metformin because along with effectiveness it conferred selective advantages such as low cost, long term safety data, and fewer adverse events compared to other potential candidates at the time which had also been shown to prevent type 2 diabetes, including troglitazone, rosiglitazone, pioglitazone, voglibose, and insulin glargine14-18” – mentioned Dr. Horton, further adding: “intensive lifestyle involved reducing dietary fat and overall calorie intake, increasing physical activity to at least 150 minutes a week of moderate-intensity exercise similar to brisk walking and to achieve and maintain at least a 7 percent reduction in their body weight. As reported13, the study was highly successful; the lifestyle intervention reduced the incidence of diabetes by 58% and metformin reduced the incidence by 31% compared to placebo. Furthermore, the incidence of metabolic syndrome (MetS) was reduced by 41% in the lifestyle group and by 17% in the metformin group compared to placebo. Quite remarkably, in people diagnosed with MetS at baseline, 18% in the placebo group, 23% in the metformin group, and 38% of the lifestyle group no longer had the syndrome at 4-years.19 Because the results of the study were so dramatic, it was stopped ahead of schedule, and we gave everyone an intensive lifestyle program including those in the original placebo and metformin groups. We asked the individuals to continue taking metformin in addition to lifestyle modification, which is what is known as the DPPOS, the long-term follow-up of the DPP study, which is still ongoing.”
Recent results from more than 11 years of follow- up in the DPPOS study have demonstrated the longer-term effectiveness of metformin, showing a 18% risk reduction for the development of diabetes, a 28% decreased risk for microvascular complications in patients who did not develop diabetes, as well as reduced risk for atherosclerosis in men.20,21 Indeed, the remarkable results of the DPP and DPPOS study call at least for a reflection about the powerful role of lifestyle modification in the prevention of diabetes and metabolic syndrome. However, we know that implementing and maintaining life style changes is difficult to say the least. Dr. Horton shared some of the approaches used in the DPP to give an idea of what it takes to achieve and sustain meaningful lifestyle changes: “All the participants across different centers in the DPP program had a very intense course in lifestyle modification. Besides physicians, we had trained dietitians, exercise physiologists, behavior modification specialists to deal with some of the psychological problems, and we used the team approach to really work with people to help them achieve the lifestyle changes.” Although most clinical practices do not have the resources to address all these factors, they should be at least be encouraging lifestyle changes or refer eligible patients to lifestyle specialists, nutritionists, or to a local DPP program in order to better address the rising impacts of type 2 diabetes and metabolic syndrome.


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    October 2019 | Vol. 2 Q4