Diabetes medication may reduce mortality in obese people: study

Excess weight, especially abdominal obesity, is associated with a variety of health problems, including diabetes, high blood pressure, and cardiovascular disease. Over the years, many different methods for weight loss have been tried, but most have been ineffective in the long term.

Recently, drugs called GLP-1 agonists, originally used to treat diabetes, have been attracting attention for their role in weight loss. These drugs mimic the gastrointestinal hormone GLP-1, which promotes insulin secretion, slows digestion, and promotes satiety. Of these drugs, semaglutide has been used to treat diabetes since 2017. In high doses, it is currently used as a weight loss drug in Western countries. Journal of the American College of Cardiology Promising results have been seen when used in people without diabetes.

The SELECT trial, funded by the manufacturer of semaglutide, included 17,604 obese or overweight participants without diabetes but with cardiovascular disease. Participants were randomly assigned to receive weekly injections of either semaglutide or a placebo and were followed for three years. The drug is known to reduce weight, so the aim was to see a reduction in deaths, heart attacks and strokes. During the follow-up period, 833 people (4.7%) died. Compared to the placebo group, participants who received semaglutide had a lower risk of all-cause mortality, including cardiovascular, non-cardiovascular and COVID-19 deaths.

The main results of the SELECT study were: New England Journal of Medicine December 2023. A 19% reduction in cardiovascular deaths, heart attacks, and strokes was noted in the semaglutide group.

However, these results also raise questions. For example, why was an early reduction in mortality observed, even before participants had lost weight? Health benefits from weight loss usually take time to manifest. For example, the Swedish Bariatric Surgery Study by Sjöström et al. also demonstrated a reduction in mortality with weight loss, but with a mean follow-up of 10.9 years. After surgery, weight was reduced in the first year, but the reduction in mortality was seen much later.

Second, participants in the SELECT study were not diabetic, suggesting that the known antidiabetic effects of GLP-1 agonists could not explain the reduction in deaths. Finally, the number of deaths from COVID-19 was unexpectedly reduced. The paper did not mention the vaccination status of participants. Thus, the question of how GLP-1 agonists affect COVID-19 mortality remains open.

When a clinical trial reports an unexpected benefit in the treatment group compared to the placebo group, there are two possibilities: either the treatment is truly superior or participants in the placebo group were in poorer health at the start of the trial. The surprising result of this study was the faster-than-expected reduction in mortality and the apparent effect on COVID-19 mortality. This indicates that we should look more closely at whether the two groups had important differences at baseline.

A large randomized trial like SELECT can minimize such differences, so there were no significant baseline differences between the semaglutide and placebo groups in terms of age, sex, HbA1c, blood pressure, cholesterol levels, BMI, or waist circumference.

However, the supplementary tables comparing baseline parameters between those who died and those who survived show notable differences in terms of loop diuretic use. Only 11.7% of survivors were using loop diuretics at the start of the study, compared with 35.9% of those who later died from cardiovascular causes. Loop diuretics are commonly prescribed for advanced cardiac, hepatic, and renal pathologies, and their use may indirectly represent the severity of a participant's health condition. This suggests that many of the participants who died during the study may have had more advanced cardiac disease from the start.

Randomization generally ensures a balanced distribution of participants, but some imbalances may still occur. The total number of people with heart failure was similar in both groups with different severity. However, the paper does not specify whether a higher proportion of people in the placebo group were taking loop diuretics and their heart failure may have been more advanced. Such discrepancies may have contributed to the higher mortality rate during follow-up. This may explain the unexpected differences observed in COVID-19 deaths. Properties other than the reduction in GLP-1 agonist dose or diabetes control may be involved here.

Research is essential to the advancement of medical knowledge. Unexpected findings are not uncommon, but it is important to explore all possible explanations before drawing conclusions. Although GLP-1 agonists are already recommended for people with diabetes, this study suggests that they may also be beneficial in overweight and obese people without diabetes. These findings could have an impact on medical practice, especially if further studies confirm the results.

(Rajeev Jayadevan is the Chairman of the Laboratory, IMA, Kerala.)