Healthy Lifestyle Plus GLP-1s Yields Bigger CV Reduction Than Drugs Alone

For patients with type 2 diabetes, a new study reinforces the importance of adhering to a healthy lifestyle even when taking a glucagon-like peptide-1 (GLP-1) receptor agonist.

Patients who combined a GLP-1 drug with low-risk lifestyle habits, such as eating a high-quality diet, being physically active, and getting sufficient sleep, had a significantly larger reduction in major adverse cardiovascular events when compared with those who took the medication alone.

“Individuals who use the GLP-1 and also adhered to six or more healthy habits, they had a 43% reduction in risk, which is quite remarkable,” senior researcher Frank B. Hu, MD PhD (Harvard T.H. Chan School of Public Health, Boston, MA), told TCTMD. “This is much greater than the 16% relative risk reduction associated with GLP-1s alone. It means that a healthy diet, even though you don’t have to be perfect, can amplify the effects of GLP-1 use in terms of cardiovascular disease [risk] reduction.”

For the analysis, which was published last week in the Lancet Diabetes & Endocrinology, researchers 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 investigated the combined impact of GLP-1 treatments with lifestyle interventions, aside from smaller, short-term studies showing that physical activity can help maintain weight loss, particularly if patients stop taking the medications. However, there’s limited long-term data because the randomized trials testing GLP-1s didn’t include lifestyle changes as part of the studies.   

With the Million Veteran Program, though, investigators have accumulated roughly 10 years of data on the use of GLP-1s 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 intake, stress management, social connection, and opioid drug addiction.

Lifestyle scores were tallied based on adherence to eight healthy habits (scored 0 to 8). High-quality diet was defined using the healthy plant-based index, for example, while sufficient physical activity was calculated based on intensity and frequency (eg, > 7.5 MET hours/week meeting the healthy threshold). Other scores were used to assess stress, social connection, 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 a GLP-1 receptor agonist. Compared with those who didn’t use the medications, 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 exactly the same as the risk reduction from SELECT, a large randomized, controlled trial,” said Hu. “It means that the observational analysis could replicate the finding, something that we were very happy about.”

After adjustment for multiple variables, including duration of diabetes and other cardiovascular risk factors, those who adhered to all eight healthy lifestyle habits had a 60% lower risk of MACE compared with those who adhered to just a single habit or none (score 0-1). However, as Hu noted, very few participants, just 1% of veterans in the study, were able to adopt all eight healthy habits.

Investigators observed a graded dose-response relationship among GLP-1 users with greater adherence to lifestyle: those who adopted to four, five and six healthy habits had respective 27%, 35%, and 42% lower relative risks of MACE when compared with those who had a 0-1 score.

Overall, individuals with type 2 diabetes taking a GLP-1 and adhering to six to eight lifestyle factors had a 43% lower risk of MACE compared with those not taking the medication and adhering to three or fewer healthy habits.

Both use of a GLP-1 and a healthy lifestyle—adopting six to eight low-risk habits—were independently associated with MACE: there was no evidence of a significant interaction.

Minimizing Side Effects, Maximizing Benefit

To TCTMD, Hu said the study was designed to reinforce the importance of lifestyle in the modern era of powerful weight-loss medications. Adopting a healthy diet and adhering to physical activity can be challenging for some people, but the study shows that abandoning those efforts is wrongheaded.  

“To think you can pop a pill [for] all your health problems, that, of course, is very naive,” said Hu, “because diet and lifestyle not only have independent effects on cardiovascular outcomes, but [lifestyle] can amplify effects and also reduce the side effects and complications associated with GLP-1 use.”

For example, diet and exercise can help attenuate the reported loss of muscle mass that can occur with GLP-1s, he said. Additionally, some people may experience side effects that lead to them stopping their medications. Adopting a high-quality diet, good sleep, and daily physical activity, among other lifestyle habits, can help reduce the weight gain that occurs if the drugs are stopped.

“Even though they’re very powerful drugs, they’re not a panacea for obesity and obesity-related chronic disease,” said Hu.

In an editorial, Stefano Del Prato, MD, PhD, and Anna Solini, MD, PhD (both from University of Pisa, Italy), write that the benefits of a healthy lifestyle in GLP-1 users is likely underestimated since participants in the study reported their habits at baseline. “Sustained maintenance over time can reasonably be expected to exert an even greater effect,” they write.

As the data accumulate, Hu said, they are planning on performing a similar analysis in people without type 2 diabetes.