An outcomes study conducted by the Diabetes Prevention Program (DPP) has examined the effects of lifestyle interventions and the popular diabetes drug metformin on all-cause mortality.
The original DPP was conducted at 27 centers in the United States from 1996 to 2001. Building upon this work, the Centers for Disease Control developed a national program in which people can currently participate. The National DPP focuses on lifestyle changes, with curriculum and goal setting centered around exercise, healthy eating, and behavioral changes. Its goal is to establish partnerships between public and private sectors in order to offer cost-effective and evidence-based interventions that help to decrease and delay type 2 diabetes in communities across the United States.
To qualify for the National DPP, participants need to be diagnosed with prediabetes, be at high risk for prediabetes, or have a history of gestational diabetes and must be at least 18 years old. A high BMI is also required. The CDC offers an explanation of this program on its website.
Open access secondary data analysis
Between 1996 and 1999, 3,234 adults who were at least 25 years old and at high risk for type 2 diabetes were assigned to either receive intensive lifestyle intervention or be part of a placebo-controlled metformin study. The intensive lifestyle intervention group was focused on achieving at least 150 minutes of weekly physical activity. The purpose of the ongoing DPP Outcomes Study (DPPOS), which enrolled 2,779 of the participants of the original DPP, is to monitor the progression of diabetes, cancer, and cardiovascular diseases. This secondary data analysis uses data from the 20-year results of the DPPOS.
In this cohort, metformin did not decrease mortality
Demographics of the three groups did not vary at the start of the study; however, by December 2019, the prevalence of diabetes was statistically different between the groups, with 53% of the intensive lifestyle group, 55% of the metformin group, and 60% of the placebo group becoming diagnosed.
In this same cohort, metformin was shown to decrease major risk factors for mortality by reducing weight and improving cardiovascular risk factors [1,2]. However, in this 20-year follow-up study, it did not decrease all-cause nor cause-specific mortality.
Cancer was the leading cause of mortality among adults at high risk for type 2 diabetes. Although metformin and lifestyle modification prevented diabetes, neither strategy reduced all-cause, cancer, or cardiovascular mortality rates.
Most professionals and enthusiasts in the aging field have heard about specific compounds that may have the potential to improve healthy human lifespan, such as metformin and rapamycin. However, this has not yet been confirmed with large randomized control trials in humans, which is the purpose of the Targeting Aging with Metformin (TAME) trial and our own Participatory Evaluation of Aging with Rapamycin for Longevity (PEARL) trial. In the meantime, a wealth of data supports the idea that lifestyle factors are critical in maintaining and improving human health.
The authors of this study provide robust discussion of the current cohort research in this arena. They mention the possibility that a decrease in mortality was not seen in this study due to possible or prior use of metformin in the other treatment groups, which was not fully controlled. Since this study has spanned over 20 years, individuals in the non-metformin groups might have been prescribed metformin by their healthcare providers, as it typically is for newly diagnosed type 2 diabetes.
Another limitation the authors mention is that due to the strict inclusion criteria for participation, this cohort is in better health and its results cannot be generalized to sick populations, which may be why this study did not report the mortality results seen in other cohort studies.
Additionally, heart disease was not the leading cause of death in this study, which was suggested to be partly due to advances in medicine that improve cardiovascular risk factors.
The authors end with a call to action to continue to move cancer prevention efforts forward:
Because cancer was found to be the leading cause of death among participants at high risk of type 2 diabetes and others have shown that adults with prediabetes have an increased risk for cancer mortality, dedicated research efforts are needed to better understand how to prevent excess morbidity and mortality from cancer in this population.
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 Knowler, W. C., Barrett-Connor, E., Fowler, S. E., Hamman, R. F., Lachin, J. M., Walker, E. A., Nathan, D. M., & Diabetes Prevention Program Research Group (2002). Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England journal of medicine, 346(6), 393–403. https://doi.org/10.1056/NEJMoa012512
 The Diabetes Prevention Program Research Group (1999). The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes care, 22(4), 623–634. https://doi.org/10.2337/diacare.22.4.623