Long-term Type 2 diabetes in persons with prediabetes could be delayed or prevented by adopting a lifestyle intervention program that included more exercise, a healthier diet, and a 7 percent or greater weight loss goal.
However, neither strategy decreased the risk of cardiovascular disease for study participants over the course of the 21-year study, according to the results of the multicenter Diabetes Prevention Program Outcomes Study (DPPOS), which were released today in the prestigious, peer-reviewed journal Circulation of the American Heart Association.
According to the U.S. Centers for Disease Control and Prevention’s 2020 National Diabetes Statistics Report, type 2 diabetes (T2D) affects more than 34 million Americans or nearly 11% of the country’s total population, and cardiovascular disease (CVD) is the main cause of death and disability among T2D patients.
When the pancreas is unable to create enough insulin and the body is unable to use the insulin it produces effectively, type 2 diabetes develops. Compared to people without T2D, adults with T2D have a twofold increased risk of dying from a CVD, such as a heart attack, stroke, or heart failure. Other cardiovascular disease risk factors, including as being overweight or obese, having high blood pressure, or having high cholesterol, are frequently present in people with T2D.
For the 3,234 adults who took part in the original, three-year Diabetes Prevention Program (DPP) study, the DPPOS analyzed 21 years of follow-up (through 2019). The goal of this DPPOS research was to see if the drug metformin or a change in lifestyle may lower the risk of cardiovascular disease or the frequency of serious cardiac events such as heart attacks, strokes, or cardiovascular disease-related death.
“The risk of cardiovascular disease in people with prediabetes is increased, and CVD risk further increases over time after Type 2 diabetes develops and progresses,” said Ronald B. Goldberg, M.D., chair of the writing group for the DPPOS and a 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’s Miller School of Medicine in Miami, Florida. “We were focused on assessing the impact of lifestyle or metformin interventions for the prevention of Type 2 diabetes in people with prediabetes to reduce cardiovascular disease.”
In order to determine how to stop or delay the onset of T2D in individuals with prediabetes, the landmark DPP experiment involved 27 centers across the United States from 1996 to 2001. A 2-hour glucose reading of 140–199 mg/dL on an oral glucose tolerance test, fasting glucose levels of 95–125 mg/dL, and a body mass index of 24 kg/m2 or greater were the initial requirements for study participants who were then accepted into the DPP.
3,234 adults from a range of racial backgrounds participated in the original DPP study, which lasted roughly three years. Nearly 70% of the participants were women, and the participants’ average age was 51 years.
The risk of cardiovascular disease in people with prediabetes is increased, and CVD risk further increases over time after Type 2 diabetes develops and progresses. We were focused on assessing the impact of lifestyle or metformin interventions for the prevention of Type 2 diabetes in people with prediabetes to reduce cardiovascular disease.
Ronald B. Goldberg
When compared to participants taking twice-daily doses of metformin, people in the intensive lifestyle intervention group (nutritional improvement and physical activity aimed at achieving a weight loss of 7 percent) had a reduced incidence of T2D of 31 percent as opposed to those in the placebo group who received standard care, which included information about effective treatment and management of T2D at the time of dialysis.
All participants in the initial DPP experiment were welcome to join the DPPOS, which started in 2002. To evaluate the long-term effects of the therapies on the onset of T2D and its consequences, the DPPOS included nearly 90% of the initial research participants for up to 25 years of follow-up.
Everyone in the trial was given the option to engage in the lifestyle intervention through a group format during a one-year bridge period due to the lifestyle intervention’s success. The metformin-using group from the initial DPP study was able to continue taking the drug throughout the DPPOS, and they were aware that they were not taking a placebo but metformin.
“From the beginning of the Diabetes Prevention Program, we were primarily interested in whether prevention of diabetes would lead to a reduction in the development of the complications that are caused by Type 2 diabetes cardiovascular disease, kidney disease, retinopathy, and neuropathy,” said Goldberg. “Managing blood glucose levels is important, and we encourage interventions to prevent the long-term complications of Type 2 diabetes.”
By comparing the results of each intervention group to the placebo group, the DPPOS evaluated cardiovascular disease outcomes to ascertain the effects of lifestyle and metformin interventions on participants’ risk of suffering a non-fatal heart attack, stroke, or passing away due to a cardiovascular occurrence. Researchers published their findings based on a median follow-up of 21 years, which included the original DPP trial’s average follow-up time of three years.
Following a futility analysis of the cardiovascular events, the trial was terminated before the intended 25-year follow-up period could be reached. Throughout the duration of the trial, participants underwent annual screenings that included electrocardiograms, assessments of their cardiovascular disease risk factors, such as smoking, cholesterol, and blood pressure levels, and measurements of their body mass index.
Over the course of the trial, the proportion of people who took blood pressure and cholesterol-lowering drugs climbed overall, albeit it was somewhat lower in the lifestyle group than in the other two.
The incidence of heart attacks, strokes, or cardiovascular deaths did not significantly differ between the three intervention groups after an average of 21 years of follow-up.
Specifically, the analysis found:
There was a continued reduction or delay in the development of T2D for up to 15 years.
Similar numbers of non-fatal heart attacks occurred in all three groups: 43 in the placebo group, 46 in the metformin group, and 35 in the lifestyle intervention group.
The number of non-fatal strokes also showed similarities, with 39 occurring in the lifestyle intervention group, 16 in the metformin-only group, and 28 in the placebo group.
Cardiovascular deaths during the initial DPP trial were rare, with only 37 occurring among individuals in the lifestyle intervention, 39 in the metformin group, and 27 among those who received a placebo.
“The fact that neither a lifestyle intervention program nor metformin led to a decrease in cardiovascular disease among people with prediabetes may mean that these interventions have limited or no effectiveness in preventing cardiovascular disease, even though they are highly effective in preventing or delaying the development of Type 2 diabetes,” said Goldberg.
“It’s important to note that most study participants also received treatment with cholesterol and blood pressure medications, which are known to reduce CVD risk. Therefore, the low rate of development of cardiovascular disease found overall may have been due to these medications, which would make it 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 to cardiovascular disease prevention in people with prediabetes and Type 2 diabetes.”
The study had a number of drawbacks. The results cannot be generalized to all individuals with prediabetes because the researchers only included a subgroup of individuals who satisfied the criteria for prediabetes.
After the initial DPP phase, the lifestyle intervention’s ferocity was lessened, and over the course of the study’s 21-year duration, participants in the metformin group gradually dropped their drug adherence. The usage of metformin outside of the trial by patients with Type 2 diabetes may have masked differences between the study groups.
Results could have been impacted by the participants’ primary care teams’ high prescription rates for blood pressure and cholesterol medications as well as the lifestyle group’s lower use of these drugs. Since some patients did not complete the full 21 years of follow-up, there may have also been some under-estimation of cardiovascular events.
“These long-term findings confirm the link between Type 2 diabetes and cardiovascular disease is complex and requires more research to understand it better,” said the American Heart Association’s Chief Medical Officer for Prevention Eduardo Sanchez, M.D., M.P.H., FAHA, FAAFP, and clinical lead for Know Diabetes by Heart, a collaborative initiative between the American Heart Association and the American Diabetes Association addressing the link between diabetes and cardiovascular disease.
“However, these important results also tell us that lifestyle intervention is incredibly effective to delay or prevent Type 2 diabetes, which, itself, reduces the risk for cardiovascular disease. The CDC estimates nearly 1 of every 3 adults in the U.S. has prediabetes, therefore, preventing or delaying Type 2 diabetes is a public health imperative to help extend and improve the lives of millions of people.”
The National Institute of Diabetes and Digestive and Kidney Diseases of the National funded the study through grants Institutes of Health. Additional funding was provided by several other divisions of the National Institutes of Health: the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart, Lung, and Blood Institute, the National Cancer Institute, and the National Institute on Minority Health and Health Disparities; as well as the U.S. Department of Health and Human Services’ Office of Research on Women’s Health; the U.S. Centers for Disease Control and Prevention; and the American Diabetes Association.
