The study emphasizes the importance of vigilance with diet and exercise, among other things, to reduce CV risk in type 2 diabetes.
For patients with type 2 diabetes, a new study reinforces the importance of following a healthy lifestyle even when taking glucagon-like peptide-1 (GLP-1) receptor agonists.
Patients who combined the GLP-1 drug with low-risk lifestyle habits, such as eating a high-quality diet, being physically active and getting enough sleep, had a significantly reduced number of major adverse cardiovascular events compared with those who took the drug alone.
Senior researcher Frank B. “Individuals who used GLP-1 and followed six or more healthy habits had a 43% reduction in risk, which is quite remarkable,” Hu, MD PhD (Harvard TH Chan School of Public Health, Boston, MA) told TCTMD. “This is much greater than the 16% relative risk reduction associated with GLP-1 alone. This means that a healthy diet, even if you don’t have to be perfect, can enhance the effect of GLP-1 use in terms of heart disease (risk) reduction.”
For analysis, which was published in the last week Lancet Diabetes and EndocrinologyResearchers included 98,261 US veterans (5.5% women) with type 2 diabetes enrolled in the Department of Veterans Affairs’ Million Veteran Program between 2011 and 2023.
To date, Hu said, few studies have examined the combined effect of GLP-1 treatment with lifestyle interventions, with small, short-term studies suggesting that physical activity may help maintain weight loss, especially if patients stop taking medications. However, long-term data is limited because the randomized trials that tested GLP-1 did not include lifestyle changes as part of the study.
However, with the Million Veterans Program, investigators have accumulated approximately 10 years of data on the use of GLP-1 in patients with type 2 diabetes. In addition, the research program includes detailed, self-reported surveys on lifestyle, including eating habits, physical activity, smoking status, sleep, alcohol consumption, stress management, social relationships, and opioid drug addiction.
Lifestyle scores were tallied based on adherence to eight healthy habits (score 0 to 8). For example, high-quality diet was defined using a healthy plant-based index, while adequate physical activity was calculated based on intensity and frequency (for example, 7.5 MET hours/week meeting the healthy threshold). Other scores were used to assess stress, social relationships, sleep, and the absence of heavy drinking and/or opioid addiction. During follow-up, 10,443 participants with type 2 diabetes developed MACE, a composite endpoint that included MI, stroke, or cardiovascular death over 632,543 person-years of follow-up.
Of the participants, 13,394 reported using GLP-1 receptor agonists. Compared with those who did not use the drugs, GLP-1 use was associated with a 16% lower risk of MACE (HR 0.84; 95% CI 0.76–0.92).
The relative reduction in MACE risk among GLP-1 users “is the same as the risk reduction chooseA large randomized, controlled trial,” Hu said. “This means that the observational analysis could replicate the findings, something we were very happy with.”
After adjusting for several variables, including duration of diabetes and other cardiovascular risk factors, people who followed all eight healthy lifestyle habits had a 60% lower risk of MACE compared with those who followed only one habit or did not follow any habits (score 0-1). However, as Hu said, very few participants, only 1% of the veterans in the study, were able to adopt all eight healthy habits.
The investigators observed a graded dose-response relationship among GLP-1 users with higher lifestyle adherence: those who adopted four, five and six healthy habits had 27%, 35% and 42% lower relative risks of MACE compared with those with a 0-1 score, respectively.
Overall, people with type 2 diabetes taking GLP-1 and following six to eight lifestyle factors had a 43% lower risk of MACE compared with people not taking the drug and following three or fewer healthy habits.
GLP-1 use and a healthy lifestyle – adopting six to eight low-risk habits – were both independently associated with MACE: there was no evidence of any significant interaction.
Minimizing Side Effects, Maximizing Benefits
According to TCTMD, Hu said the study was designed to reinforce the importance of lifestyle in the modern age of powerful weight-loss drugs. Adopting a healthy diet and maintaining physical activity may be challenging for some people, but studies show that it is wrong to abandon those efforts.
“To think that you can pop a pill for all your health problems is certainly very foolish,” Hu said, “because diet and lifestyle not only have independent effects on cardiovascular outcomes, but can also amplify (lifestyle) effects and reduce side effects and complications associated with GLP-1 use.”
For example, diet and exercise may help reduce the muscle loss that occurs with GLP-1s, he said. Additionally, some people may experience side effects that may cause them to discontinue their medications. Adopting a high-quality diet, good sleep, and daily physical activity, among other lifestyle habits, may help reduce the weight gain after stopping the medication.
“Even though they are very powerful drugs, they are not a panacea for obesity and obesity-related chronic disease,” Hu said.
In an editorial, Stefano Del Prato, MD, PhD, and Anna Solini, MD, PhD (both from the University of Pisa, Italy), write that the benefits of healthy lifestyle in GLP-1 users may have been underestimated because participants in the study reported their habits at baseline. “Continued maintenance over time can be expected to have an even greater impact,” they write.
As data accumulates, Hu said, they plan to conduct a similar analysis in people without type 2 diabetes.
