Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin

Article Summary Assignment for

“Reduction in the Incidence of Type 2 Diabetes

with Lifestyle Intervention or Metformin”

N Engl J Med 2002 Feb 7;; 346:393-403 Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin Diabetes Prevention Program Research Group.

Type 2 Diabetes Mellitus (T2DM), a metabolic disorder diagnosed by hyperglycemia, insulin resistance and/or insufficient insulin production occurring in 8% of US adults, is treated by lifestyle intervention or a first line drug,Metformin. The Diabetes Prevention Program Research Group’s investigated whether lifestyle intervention or Metformin would prevent or delay T2DM. The double-blind controlled study used (n=3,234) nondiabetic patients at risk for diabetes at 27 centers. Eligibility criteria included at least 25 years age, BMI of at least 24 (for Asians, at least 22), and blood glucose levels higher than normal but not within a diabetic range (a plasma glucose level of 95 to 125 mg per deciliter in fasting state and 140 to 199 mg per deciliter two hours after a 75 g oral glucose load). 45% of participants were from minority groups, African Americans, Hispanic Americans, Asian Americans and Pacific Islanders, and American Indians. In addition, the study recruited participants with high risks of T2DM, such as subjects age 60 and older, women with a history of gestational diabetes, and people who have a first-degree relative with T2DM. A four-step screening process determined participant eligibility. Participants were randomly assigned one of three approaches. The first included an intensive lifestyle change to reduce weight by 7% with a low-fat diet and increased physical activity (maintaining physical activity at least 150 minutes weekly with exercise such as biking or walking). The second approach included standard advice on diet and exercise plus treatment with metformin (850 mg twice daily). The third group received standard advice on diet and exercise regimen with placebo pills instead of metformin. The group receiving lifestyle intervention obtained instructions on dieting, exercise and behaviour modification to induce weight loss. Case managers individually met with participants within the first 24 weeks for at least 16 sessions; every other month, case managers met participants individually or in groups. Participants were requested to lower their fat to less than 25% of calories consumed. If these participants did not experience fat loss, then case managers set a calorie goal. Outcomes were to diagnose T2DM, based on an annual oral glucose tolerance test (126 mg per deciliter or higher) or a semiannual fasting plasma glucose test (200 mg per deciliter or higher), or higher two hours after a 75 g oral glucose load. If patient symptoms suggested T2DM development, then fasting plasma glucose was measured. For T2DM diagnosis, a second test within six weeks was used. If diagnosed with T2DM, patient and physician were informed; fasting plasma glucose measurements monitored blood glucose every six months and the assignment continued. If fasting blood glucose reached or exceeded 140 mg per deciliter, then study medication stopped and the physician decided treatment. Participants and investigators were unaware of results unless test values exceeded specific thresholds. To measure physical activity levels, self reports were annually assessed in the Modifiable Activity Questionnaire. Activity level was calculated according to the duration and frequency of each activity (hours/week) weighted by the activity's estimated caloric expenditure, and totalled for all performed activities. The average metabolic equivalent of the activities performed weekly was evaluated for the entire year. Participant’s daily calorie intake was assessed at baseline and at one year with a block food frequency questionnaire. Results were stratified according to the treatment center and assignment to Metformin and placebo were double-blinded. Blinded treatment phase ended a year early because it did not possess a significant p value (less that 0.159). A Bonferroni-adjusted criterion of P<0.0167 compared outcomes. The study showed a 90% power to detect a 33% reduction from 6.5/100 cases of T2DM with an annual 10% loss to follow-up. Life-table methods were used with modified product-limit curves for the cumulative incidence of T2DM occurring to the log-rank test. The number of patients requiring treatment to prevent one case of confirmed T2DM over a three year span at a 95% confidence interval estimated the cumulative incidence of T2DM at three years and the standard of error (Greenwood estimate). Proportional hazards regression assessed the reduction of risk, heterogenous data and interactions between assignments. To measure differences over time in body weight, plasma glucose levels and glycosylated hemoglobin valued, fixed effects models were used. DPP results show high risk individuals can prevent or delay developing T2DM through weight loss by regular physical activity and a low fat and caloric diet. Metformin can also help delay T2DM onset. Participants, regardless of ethnic or gender group, reduced developing T2DM by 58% in the lifestyle intervention group receiving intensive individual counseling, motivational support and diet, exercise and behavior. Lifestyle changes for participants 60 years and older reduced their risk for T2DM by 71%. During the study, around 5% of lifestyle intervention group developed T2DM, in comparison with 11% of placebo group. Metformin receiving participants, men and women, decreased their rate by 31%. However, Metformin proved to be most effective in 25-44 year olds with a BMI of 35 or higher. Approximately 7.8% of the Metformin group developed T2DM every year of the study, in comparison to 11% of the placebo group. The study’s conclusions indicate that lifestyle intervention prevented/delayed T2DM in all genders and ethnicities with high risk of the disease. Systematic lifestyle intervention included individualized counseling but the study was not intended to assess the relative contributions of dietary changes; increased physical activity and weight loss reduction reduced T2DM risk by 58; 41% with Metformin. The higher T2DM risk in the placebo group (11%) than anticipated may have been due to the higher frequency of glucose testing or selecting high risk patients. Study implications indicate that Metformin treatment and lifestyle modification are highly effective in delaying and preventing T2DM. A strength of this study can be its large population at various geographic locations and racial backgrounds, making results applicable to a large cross section of the population. A weakness could include subjective self-reports measuring physical activity and daily caloric intake. Furthermore, the weekly and annual averaging of activity may not be a strong determinator in comparing other individuals’ physical activities, an important consideration as physical activity levels were a main component of the lifestyle intervention plan. Similarly, daily caloric intake based on a Block food-frequency questionnaire for the previous year, may not accurately represent consumption. At the time of the study, nearly 10 million people in the US had similar age, BMI and glucose concentrations to the study participants. Future research may want to further examine the findings’ effect on T2DM prevention, such as assessing the relative contributions of dietary changes, increased physical activity and weight loss reduction to the risk of T2DM. Future directions may examine whether glucose concentrations can be maintained at levels lower than T2DM diagnosis, and if these lower levels can prove improved health outcomes. Such research could follow-up on participants and analysis of the secondary outcomes of the study, such as reductions in risk of developing CVD, atherosclerosis.