Metformin and physical activity best prophylactic interventions for prevention.
During the past two decades, The Diabetes Prevention Program (DPP) and its follow-up, the Diabetes Prevention Program Outcomes Study (DPPOS), have confirmed the beneﬁcial effects of the antidiabetic medication metformin in lowering the risk of developing diabetes in high-risk patients.
The DPP conducted a large, randomized clinical trial to examine the effect of metformin and a lifestyle-intervention program as methods to modify the potentially reversible factors for type 2 diabetes, such as elevated fasting and post-meal glucose levels, obesity, and a sedentary lifestyle. This study included 3,234 adults who did not have diabetes in the United States, between 1996-1999, and who were considered to have too high of a risk for the development of type 2 diabetes. Inclusion criteria were defined as follows: minimum age of 25 years, BMI ≥ 24, fasting blood glucose (FBG) of 90 to125mg/dL, and 2-hour post-meal blood glucose (2hPBG) of 140 to 199 mg/dL. Additionally, any individuals who were on antidiabetic medications, or had illnesses that could seriously reduce their life expectancy, were excluded from this trial. Participants were randomly put into three study arms. Each study arm received either standard lifestyle recommendations plus a twice daily dose of metformin 85mg tablet, or standard lifestyle recommendations plus a twice daily dose of matching placebo, and lastly, an intensive lifestyle modification recommendation alone.
The primary outcome measure for this study included the incidence of type 2 diabetes, measured based on FBG or 2hPBG or HbA1c levels. The results from DPP showed that amongst all groups, the study groups who received metformin and lifestyle interventions had a lower cumulative prevalence of diabetes in comparison to placebo group (7.8 and 4.8 vs.11.0 cases per 100 person-years). Furthermore, a 58% reduction and a 31% reduction in incidence of diabetes were associated with the intensive lifestyle intervention and metformin treatment respectively, as compared with placebo. Investigators suggested that treatment with metformin and lifestyle modifications appeared to be two highly effective routes of risk reduction for type 2 diabetes. The lifestyle intervention was predominantly the most effective intervention (1 case prevented per 7 persons treated for 3 years).
Following the previous trial, all participants of DPP were offered a lifestyle modification training, to be followed up with DPPOS. A total of 88% (n= 2776) of surviving participants volunteered to partake in DPPOS. The main objective of this study was to assess if lifestyle intervention and metformin are able to reduce the risk of developing diabetes-associated microvascular complications.
Individuals who received placebo and metformin during DPP continued to receive metformin, except the metformin intervention was no longer blinded. Additionally, the intensive lifestyle intervention group was offered a semi-annual lifestyle reinforcement. Although in DPPOS the placebo was discontinued, all participants were analyzed based on their original DPP-assigned group. Incidence of diabetes and microvascular disease were the primary outcomes for this study. In order to measure the prevalence of microvascular disease, investigators used a composite microvascular outcome, which included nephropathy, retinopathy, and neuropathy.
The results of DPPOS indicated that throughout an average 15-year follow up, there was a 27% reduction in development of diabetes associated with lifestyle modification intervention (hazard ratio 0·73, 95% CI 0·65–0·83; p<0·0001). The diabetes occurrence was decreased by 18% in the metformin group (hazard ratio 0·82, 95% CI 0·72–0·93; p=0·0001) when compared to placebo. It was noted that the between-group differences were decreasing over time.
At the end of year 15, 55% of patients who received intervention by lifestyle modifications developed diabetes, versus 56% of patients on metformin therapy and 62% of placebo group. Data analysis showed no significant difference in combined microvascular outcomes between the treatment groups in the total cohort (placebo 12·4%, 95% CI 11·1–13·8; metformin 13·0%, 11·7–14·5; lifestyle intervention 11·3%, 10·1–12·7). Furthermore, the results suggest that lifestyle modification intervention leads to a lower incidence of diabetes in female participants (8·7%, 95% CI 7·4–10·2) in comparison to the placebo (11·0%, 9·6–12·6) and metformin (11·2%, 9·7–12·9). Individuals who did not develop diabetes had a 28% risk reduction in regard to microvascular disease when compared with participants who developed diabetes (relative risk 0·72, 95% CI 0·63–0·83; p<0·0001).
Recently, investigators assessed the results of DPP and DPPOS to figure out which subgroups of participants will benefit the most from the metformin after 15 years of follow-up. Results indicate that over the course of 15 years of post-randomization follow-up, the prevalence of diabetes was decreased by 17% with metformin therapy in comparison to placebo or by 36% based on HbA1c levels. Women with a previous history of gestational diabetes experienced a larger benefit from metformin (HR 0.59, RD −4.57 cases/100 person-years) versus women who had offspring without prior gestational diabetes (HR 0.94, RD −0.38 cases/100 person-years [interaction P = 0.03 for HR, P = 0.01 for RD]). Additionally, metformin appeared to be more effective by HR and RD, on higher baseline FBG levels. Finally, metformin was more effective in individuals with higher baseline HbA1c by RD [RD: −1.03 cases/100 person-years with baseline HbA1c <6.0% and −3.88 cases/100 person-years with HbA1c 6.0–6.4% (P = 0.0001)].
- A 58% reduction in incidence of diabetes was associated with the intensive lifestyle intervention.
- Lifestyle intervention or metformin significantly reduced diabetes development over 15 years.
- Subjects with higher baseline FBG or HbA1c and women with a history of GDM, benefited the most from metformin.
Knowler, William C et al. “Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin” New England journal of medicine vol. 346,6 (2002): 393-403.
Soon, W. H. K., et al. “Effect of Combining Pre‐Exercise Carbohydrate Intake and Repeated Short Sprints on the Blood Glucose Response to Moderate‐Intensity Exercise in Young Individuals with Type 1 Diabetes.” Diabetic Medicine, John Wiley & Sons, Ltd (10.1111), 13 Feb. 2019, onlinelibrary.wiley.com/doi/abs/10.1111/dme.13914.
Ghazal Blair, Pharm.D. Candidate 2019, LECOM School of Pharmacy