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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.

    References:

    1. Centers for Disease Control and Prevention. “Prevalence of prediabetes.” February 19, 2018, available at https://www.cdc.gov/diabetes/data/statistics- report/prevalence.html, accessed December 20, 2018.
    2. Bowen, Michael E., et al. “Building Toward a Population- Based Approach to Diabetes Screening and Prevention for US Adults.” Current Diabetes Reports 18.11 (2018): 104.
    3. Ali, Mohammed K., et al. “Cardiovascular and renal burdens of prediabetes in the USA: analysis of data from serial cross-sectional surveys, 1988–2014.” The Lancet Diabetes & Endocrinology 6.5 (2018): 392-403.
    4. Grundy, Scott M. “Pre-diabetes, metabolic syndrome, and cardiovascular risk.” Journal of the American College of Cardiology 59.7 (2012): 635-643
    5. DeJesus, Ramona S., et al. “Incidence rate of prediabetes progression to diabetes: modeling an optimum target group for intervention.” Population Health Management 20.3 (2017): 216-22
    6. Centers for Disease Control and Prevention (CDC). “Awareness of prediabetes--United States, 2005- 2010.” MMWR. Morbidity and Mortality Weekly Report 62.11 (2013): 209.
    7. Mainous, Arch G., et al. “Prediabetes screening and treatment in diabetes prevention: the impact of physician attitudes.” The Journal of the American Board of Family Medicine 29.6 (2016): 663-671.
    8. Tseng, Eva, et al. “Survey of primary care providers’ knowledge of screening for, diagnosing and managing prediabetes.” Journal of General Internal Medicine 32.11 (2017): 1172-1178.
    9. Kandula, Namratha R., et al. “Preventing diabetes in primary care: providers’ perspectives about diagnosing and treating prediabetes.” Clinical Diabetes 36.1 (2018): 59-66.
    10. American Diabetes Association. “3. Prevention or delay of type 2 diabetes: standards of medical care in diabetes-2019.” Diabetes Care 42.Suppl 1 (2019): S29.
    11. Perreault, Leigh. “Prevention of type 2 diabetes.” Diabetes and Exercise. Humana Press, Cham, 2018. 17-29.
    12. American Diabetes Association. “2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2019.” Diabetes Care 42.Supplement 1 (2019): S13-S28.
    13. Knowler, William C., et al. “Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.” The New England Journal of Medicine 346.6 (2002): 393-403.
    14. Azen, Stanley P., et al. “TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebo- controlled trial of troglitazone in women with prior gestational diabetes mellitus.” Controlled Clinical Trials 19.2 (1998): 217-231.
    15. Scheen, A. J. “DREAM study: prevention of type 2 diabetes with ramipril and/or rosiglitazone in persons with dysglycaemia but no cardiovascular disease.” Revue Medicale de Liege 61.10 (2006): 728-732.
    16. DeFronzo, Ralph A., et al. “Actos Now for the prevention of diabetes (ACT NOW) study.” BMC Endocrine Disorders 9.1 (2009): 17.
    17. Kawamori, Ryuzo, et al. “Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance.” The Lancet 373.9675 (2009): 1607-1614.
    18. Origin Trial Investigators. “Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention).” American Heart Journal 155.1 (2008): 26-e1.
    19. Orchard, Trevor J., et al. “The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial.” Annals of Internal Medicine 142.8 (2005): 611-619.
    20. Aroda, Vanita R., et al. “Metformin for diabetes prevention: Insights gained from the diabetes prevention program/diabetes prevention program outcomes study.” Diabetologia 60.9 (2017): 1601- 1611.
    21. Diabetes Prevention Program Research Group. “Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study.” The Lancet Diabetes & Endocrinology 3.11 (2015): 866-875.

    Volume

    October 2019 | Vol. 2 Q4