A lifestyle intervention program of increased physical activity, eating a healthy diet and aiming for a weight loss of 7% or more, or taking the medication metformin were effective long-term in delaying or preventing type 2 diabetes in adults with prediabetes. However, neither approach reduced cardiovascular disease risk for study participants over 21 years of the study, according to the findings of the multicenter Diabetes Prevention Program Outcomes Study (DPPOS), published today in the American Heart Association’s flagship, peer-reviewed journal Edition†
Type 2 diabetes (T2D) is the most common form of diabetes, affecting more than 34 million people in the US, representing nearly 11% of the US population, according to the 2020 National Diabetes Statistics Report from the US Centers for Disease Control and Prevention, and cardiovascular disease (CVD) is the leading cause of death and disability among people with T2D. Type 2 diabetes occurs when the body cannot use the insulin it makes efficiently and the pancreas is unable to make enough insulin. Adults with T2D are twice as likely to die from CVD, including a heart attack, stroke, or heart failure, compared to adults who don’t have T2D. People with T2D often have different risk factors for cardiovascular diseaseincluding being overweight or obese, high bloodpressure or high cholesterol.
The DPPOS evaluated the 21-year follow-up (through 2019) for the 3,234 adults who participated in the original, 3-year Diabetes Prevention Program (DPP) study. This analysis of the DPPOS aimed to determine whether the medication metformin or lifestyle intervention could reduce the risk of cardiovascular disease or the rate of serious heart disease such as heart attack, stroke or death due to cardiovascular disease.
“The risk of cardiovascular disease in people with prediabetes is increased, and the risk of cardiovascular disease continues to increase over time after type 2 diabetes develops and progresses,” says Ronald B. Goldberg, MD, chair of the writing group for the DPPOS and professor of medicine, biochemistry, and molecular biology in the division of diabetes, endocrinology, and metabolism, and senior faculty member and co-director of the Diabetes Research Institute Clinical Laboratory at the University of Miami Miller School of Medicine in Miami, Florida. “We aimed to assess the impact of lifestyle or metformin interventions for the prevention of type 2 diabetes in people with prediabetes to reduce cardiovascular disease.”
The DPP was a landmark, 27-center randomized trial in the US from 1996-2001 to assess how to prevent or delay the onset of T2D in people with prediabetes. Study participants were screened and accepted into the DPP based on these criteria: an initial 2-hour glucose reading of 140-199 mg/dL on an oral glucose tolerance test; fasting glucose levels from 95-125 mg/dL; and body mass index of 24 kg/m2 or higher.
A racially diverse group of 3,234 adults was studied in the original DPP for nearly three years. The participants were on average 51 years old and almost 70% of the participants were women. People in the intensive lifestyle intervention group (nutrition improvement and fysical activity targeting a 7% weight loss) reduced the incidence of developing T2D by 58%, and participants taking twice-daily doses of metformin had a 31% reduced incidence of T2D, compared with people in the placebo group receiving standard care, including information on effective treatment and management of T2D at the time of diagnosis.
The DPPOS started in 2002 and was open to all participants in the original DPP study. The DPPOS enrolled nearly 90% of the original study participants for a 25-year follow-up to assess the long-term impact of the interventions on the development of T2D and its complications. Due to the success of the lifestyle intervention, everyone in the study was offered in groups to participate in the lifestyle intervention for a bridging period of one year. The group taking metformin in the original DPP study were able to continue taking the medication during the DPPOS and they were aware that they were taking metformin and not the placebo. (The metformin and placebo groups were blinded in the original DPP, so participants didn’t know whether they were taking metformin or placebo during that time period.)
“From the beginning of the Diabetes Prevention Program, we were particularly interested in whether diabetes prevention would reduce the development of the complications caused by type 2 diabetes – cardiovascular disease, kidney disease, retinopathy and neuropathy, Goldberg said. “To manage” blood glucose levels is important and we encourage interventions to prevent the long-term complications of type 2 diabetes.”
The DPPOS assessed cardiovascular disease outcomes to determine the effects of lifestyle and metformin interventions on participants’ risk of a nonfatal heart attack, stroke, or death due to a cardiovascular event, by comparing the outcomes of each intervention group with the placebo group. Researchers reported results based on a median follow-up of 21 years, including the median three-year follow-up period of the original DPP study. The authors conducted a futility analysis of cardiovascular outcomes, which resulted in the study being terminated before the planned 25-year follow-up was completed.
Throughout the study, participants were screened annually with electrocardiogram tests; measures of their risk factors for cardiovascular disease, including smoking, cholesterol levels, and blood pressure levels; and body mass index measurements. The percentage of all participants taking blood pressure and cholesterol-lowering drugs increased over the duration of the study and was slightly lower in the participants in the lifestyle group than in the other two groups.
After an average of 21 years of follow-up, the researchers found no significant differences in the incidence of heart attacks, strokes or cardiovascular death between the three intervention groups. In particular, the analysis found:
- There was a continuous reduction or delay in the development of T2D up to 15 years.
- The number of nonfatal heart attacks in each group was similar: 35 heart attacks occurred in the lifestyle intervention group; 46 in the metformin group; and 43 in the placebo group.
- Similarities were also found in the number of non-fatal strokes: 39 strokes in the lifestyle intervention group; 16 in the metformin-only group; and 28 in the placebo group†
- The number of deaths from cardiovascular events was low: 37 deaths among the participants in the lifestyle intervention; 39 in the metformin group; and 27 in the participants who took the placebo during the original DPP study.
“The fact that neither a lifestyle intervention program nor metformin has led to a reduction in cardiovascular disease in people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, although they are highly effective in preventing cardiovascular disease.” preventing or slowing the development of Type 2 diabetes,” Goldberg said. “It is important to note that most study participants were also treated with cholesterol and blood pressure medications, which are known to reduce the risk of cardiovascular disease. Therefore, the low rate of development of cardiovascular disease generally found may Due to these drugs, it would be difficult to identify a beneficial effect of lifestyle or metformin intervention.Future research to identify higher risk subgroups is needed to develop a more targeted approach for the prevention of cardiovascular disease in people with prediabetes and type 2 diabetes.”
There were several limitations to the study. The researchers selected a subgroup of people who met the criteria for prediabetes, but these results are not generalizable to everyone with prediabetes. In addition, the intensity of the lifestyle intervention was reduced after the initial DPP phase, and over the 21-year study period, there was a gradual reduction in drug adherence by participants in the metformin group. There was also off-study use of metformin in patients diagnosed with type 2 diabetes, which may have narrowed the differences between the study groups. The high level of blood pressure and cholesterol medications prescribed by the participants’ primary care team, as well as the lower use of blood pressure medications in the lifestyle group, may have influenced the results. There may also have been some underestimation of cardiovascular events, as some participants did not complete the 21-year follow-up.
“These long-term findings confirm that the link between type 2 diabetes and cardiovascular disease is complex and that more research is needed to better understand it,” said Eduardo Sanchez, MD, MPH, FAHA, FAAFP, and clinical lead for Know Diabetes by Heart, a collaborative initiative between the American Heart Association and the American Diabetes Association to address the link between diabetes and cardiovascular disease. “However, these important results also tell us that: lifestyle intervention is incredibly effective at delaying or preventing type 2 diabetes, which in itself reduces the risk of cardiovascular disease. The CDC estimates that nearly 1 in 3 adults in the US have prediabetes, which is why preventing or delaying type 2 diabetes is a public health imperative to help extend and improve the lives of millions.”
Effects of Long-Term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Outcomes Study, Edition (2022). DOI: 10.1161/CIRCULATIONAHA.121.056756
American Heart Association
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