Wegovy Shows Surprising Protective Effect Against COVID-19 Deaths

Large-scale study reveals that semaglutide reduces overall mortality and COVID-19 fatalities in high-risk patients

Recent headlines have highlighted an unexpected finding from a large-scale study on the medication semaglutide (Wegovy). While this drug is approved for weight management in certain individuals, researchers have discovered a potential additional benefit…a reduction in COVID-19 mortality among high-risk patients with cardiovascular disease. This finding, which emerged from a trial not initially designed to study COVID-19 outcomes, has sparked considerable interest in the medical community. It raises some questions about the complex relationships between metabolic health, cardiovascular function, and immune response. Shall we dig in?

Brief refresher

Wegovy is a brand name for semaglutide used specifically for weight management. It is approved for use in adults with a body mass index (BMI) of 30 or greater (obesity) or a BMI of 27 or greater (overweight) who have at least one weight-related condition, such as cardiovascular disease, but it is not exclusively for those with cardiovascular disease.

While Wegovy can be used in individuals with established cardiovascular disease, its primary focus is on weight management. Wegovy is also designed for individuals who do not necessarily have type 2 diabetes, though it has demonstrated cardiovascular benefits in patients with type 2 diabetes.

The Study

The SELECT trial (NCT03574597), a multicenter, randomized, double-blind, placebo-controlled, event-driven Phase 3 trial, has revealed that semaglutide not only aids in weight loss but also reduces all-cause mortality, CV death, and non-CV deaths (including infectious diseases particularly COVID-19)— talk about a happy surprise!

The trial involved over 17,600 participants aged 45 and older with a BMI ≥27 kg/m2, established cardiovascular disease, but without diabetes. Participants received either weekly injections of Wegovy (2.4 mg) or a placebo and were followed for an average of 3.3 years. Importantly, the trial overlapped with the most severe period of the COVID-19 pandemic (March 2020-March 2022), significantly influencing the results.

Key findings from the study include:

1. All-Cause Mortality: Semaglutide reduced overall death rates compared to placebo (4.3% vs. 5.2%; HR: 0.81; 95% CI: 0.71-0.93).

2. Cardiovascular Deaths: There was a trend towards fewer cardiovascular deaths with Wegovy, though not statistically significant (2.5% vs. 3.0%; HR: 0.85; 95% CI: 0.71-1.01).

3. Non-Cardiovascular Deaths†: Semaglutide significantly reduced non-cardiovascular deaths (1.7% vs. 2.2%; HR: 0.77; 95% CI: 0.62-0.95; p=0.02), primarily due to a decrease in deaths from infectious diseases.

4. Infectious Deaths†: These were the most common cause of non-cardiovascular death, with fewer occurrences in the semaglutide group (62 vs 87; HR: 0.71; 95% CI: 0.51-0.98; p=0.04).

5. COVID-19 Impact: While semaglutide did not prevent COVID-19 infections, it was associated with lower mortality among those who contracted the virus. There were fewer serious COVID-19-related adverse events in the semaglutide group (2.6% vs. 3.1%). Among those who developed COVID-19, fewer deaths were directly related to COVID-19 in the semaglutide arm (43 vs 65; HR: 0.66; 95% CI: 0.44-0.96).

†According to the prespecified testing hierarchy, all comparisons following CV death should be treated as "hypothesis generating" because CV death did not meet the prespecified P value. Moreover, testing subgroups and different components of endpoints can result in underpowered analyses and chance findings.

These findings are particularly noteworthy because they suggest that semaglutide benefits extend far beyond its primary use as a medication to aid in weight management. The reduction in infectious disease deaths, especially from COVID-19, is a surprising and potentially game-changing discovery. This effect might be partly attributed to the greater weight loss (5 kg more) observed in the semaglutide group compared to the placebo group after one year.

Potential Mechanism of Action

How is this happening? The study suggests that the decreased risk of infectious deaths might be due to weight loss, reduced inflammation, or direct effects of GLP-1 receptor agonism. However, the exact mechanism remains to be fully elucidated.

GLP-1 receptor agonists are believed to have potential mechanisms of action against SARS-Cov2 infection:

1. Anti-inflammatory Effects: GLP-1 agonists can reduce inflammation by decreasing the levels of pro-inflammatory cytokines.

2. Improved Endothelial Function: They enhance endothelial function, which can help in reducing vascular complications associated with COVID-19.

3. Reduction of Oxidative Stress: These agonists can lower oxidative stress, which is beneficial in managing the oxidative damage caused by the virus.

4. Modulation of Immune Response: GLP-1 agonists can modulate the immune response, potentially reducing the severity of the infection.

5. Cardioprotective Effects: They offer cardioprotective benefits, which are crucial given the cardiovascular complications seen in COVID-19 patients.

6. Renal Protection: These agonists can protect against kidney damage, which is a common complication in severe COVID-19 cases.

7. Metabolic Benefits: They improve metabolic parameters, which can help in managing the metabolic disturbances caused by the virus.

8. Reduction of Thrombosis: GLP-1 agonists can reduce the risk of thrombosis, a significant concern in COVID-19 patients.

9. Neuroprotective Effects: They offer neuroprotective benefits, potentially reducing the neurological complications associated with COVID-19.

Study Strengths and Limitations

The SELECT trial's long follow-up period and large sample size provide robust evidence for these effects (our data science brains are buzzing). This study ran from October 2018 through March 2021, with the last patient visit on June 29, 2023, thus overlapping with the most severe period of the COVID-19 pandemic (March 2020-March 2022).

However, it's important to recognize that the trial faced challenges in determining the causes of death during the COVID-19 pandemic. These challenges included difficulties in accurately attributing deaths to specific causes amidst the widespread impact of the pandemic. This uncertainty could have influenced the accuracy of the results, particularly in categorizing and interpreting the causes of death (although the investigators conservatively attributed unknown deaths to CV deaths to help overcome this limitation).

Additionally, it's worth noting that the study was not specifically designed to assess COVID-19 outcomes, and the findings related to COVID-19 were observational within the context of the larger trial. Despite these limitations, the trial's findings provide valuable insights into the potential benefits of semaglutide.

Safety of Semaglutide and Other GLP-1 Agonists

Of course, nothing comes without risks. In the SELECT study, there were adverse event (AE) trends noted that are also included on the US product label and the European Label. The most common side effects of GLP-1 agonists include:

1. Gastrointestinal Symptoms: Nausea, vomiting, diarrhea, and constipation are the most frequently reported side effects. These occur because GLP-1 agonists slow down gastric emptying, which can lead to these digestive issues.

2. Indigestion: This is another common gastrointestinal side effect, often linked to the delayed gastric emptying caused by these medications.

3. Dizziness: Some patients experience dizziness, which may be related to changes in blood sugar levels. In the SELECT study, it was noted that numerically there were more "falls" in semaglutide patients - 55 vs. 39 with those on placebo and vertigo in 18 semaglutide patients vs 8 in the placebo group.

4. Tachycardia (Increased Heart Rate): This can occur due to the effects of GLP-1 agonists on the cardiovascular system.

5. Hypoglycemia (Low Blood Sugar): Although less common, hypoglycemia can occur, especially when GLP-1 agonists are used in combination with other diabetes medications.

6. Pancreatitis: There have been reports of pancreatitis, a serious inflammation of the pancreas, associated with GLP-1 agonists.

7. Intestinal Blockage (Ileus): This is a more severe gastrointestinal complication that has been noted in some cases.

These events are not necessarily caused by semaglutide. However, it is important to carefully monitor vulnerable populations like the elderly, those with low blood pressure, and also those on many medications that may interact or have additive effects when initiating and adjusting therapy with GLP-1 agonists.

Also noted in the SELECT study was a numerically higher number of anemia-related events. This did not reach a significant threshold and is not included on the various product labels, but it is reasonable to consider that some patients may alter their diet drastically while taking semaglutide and should ensure they get foods rich in iron and B12. A great summary of this is provided by the BMI Doctors.

Ultimately, the primary cause of these side effects is the way GLP-1 agonists like semaglutide work. They mimic the GLP-1 hormone, which affects various bodily functions, including insulin release, glucagon suppression, and gastric emptying. These actions can lead to the side effects mentioned above.

Study Implications

This study highlights semaglutide's potential as a multifaceted therapeutic agent, offering benefits that go well beyond weight management and cardiovascular health. Its apparent protective effect against severe COVID-19 outcomes and overall mortality reduction in high-risk populations opens new avenues for research and treatment strategies in managing obesity-related health risks. The significant reduction in all-cause mortality and non-cardiovascular deaths, even if the reduction in cardiovascular deaths was not statistically significant, underscores the broad impact of semaglutide on weight loss and reduced systemic inflammation on overall health outcomes.

Future Directions

The unexpected findings from the SELECT trial will likely shape the future trajectory of research and clinical practice involving GLP-1 receptor agonists like semaglutide. While these results are promising, we should approach them with measured optimism. The study's outcomes will undoubtedly spur further studies on the broader potential benefits of these medications, particularly their impact on immune function and infectious disease outcomes.

Healthcare providers may factor these potential benefits into their decision-making process when considering treatment options for eligible patients. However, it's important to emphasize that any use should still align with current approved indications. Off-label use, while sometimes practiced, carries potential risks and legal considerations that providers must carefully weigh.

The results highlight the complex interplay between metabolic health, cardiovascular function, and immune response, suggesting a more holistic approach to treating obesity and its related comorbidities may be beneficial. As research progresses, we may see evolving guidelines and potentially expanded indications for these medications, but such changes would require rigorous clinical trials and regulatory approval processes, which is a lengthy process. In the meantime, these findings open up exciting new avenues for research and underscore the potential for unexpected benefits from existing therapies.

Bottom Line

Let’s all pause to snap for science. This is really promising stuff. But while the results are exciting and may influence future research and clinical practice, decisions about using Wegovy should still be made based on its current approved indications and in consultation with a healthcare provider. The potential for expanded use will likely be a subject of ongoing research and regulatory review.

xo,

Team Unbiased Science