By Michael J. Critelli | MakeUsWell Newsletter, 

Six years ago this month, we were becoming aware of the SARS-Cov-2 virus, later described as the COVID-19 pandemic. It is usually remembered as a sudden viral catastrophe that demanded unprecedented emergency responses. 

With the benefit of hindsight, however, it is equally accurate to describe COVID-19 as a metabolic stress test, one that revealed how profoundly baseline health shaped vulnerability to an acute infectious threat. The virus did not strike populations randomly. It exploited long-standing physiological weaknesses that had accumulated quietly for decades.

Few developments illuminate this reality more clearly than the later emergence of GLP-1 receptor agonists as powerful therapies for obesity, insulin resistance, and related cardiometabolic conditions. These medications were not widely available during the pandemic’s early years, but their rise helps clarify what kind of resilience was missing in 2020, and why emergency medicine alone could not fully compensate for it.

From the earliest data, COVID outcomes followed a strikingly consistent pattern. Severe illness, hospitalization, and death clustered among individuals with obesity, type 2 diabetes, hypertension, cardiovascular disease, and chronic inflammatory states. Age mattered, but metabolic health often mattered nearly as much—and in some cases more than any single demographic variable. These gradients appeared across countries, health systems, and viral waves.

I recall research conducted at the time that challenged widely held assumptions. Despite the belief that COVID risk rose almost exclusively with age, risk models and large cohort studies showed that multimorbidity can meaningfully narrow the risk gap between younger and older adults, and in some scenarios, younger adults with multiple chronic conditions approached the risk of much older adults without those conditions.

Anecdotally, many of us observed something similar among friends and family. Individuals with multiple chronic conditions who did not take particularly good care of their health often contracted COVID multiple times within relatively short periods after receiving booster shots. A 2022 article summarizing a number of studies on the link between obesity and vaccination effectiveness, entitled “Impact of Obesity on Vaccination to SARS-CoV-2” and published in Frontiers in Endrochronology, concluded that “enhanced viral disease severity among COVID-19 patients with obesity have been noted amidst the SARS-CoV-2 pandemic.” Later studies have contained findings consistent with this observation.

The same pattern appears with influenza and other respiratory viruses. Vaccination clearly reduces severe outcomes, but it is not a “get out of jail free” card. Baseline health continued to shape susceptibility and recovery.

Public health responses understandably emphasized emergency countermeasures: lockdowns, masking, antivirals, and, most critically, vaccines. These tools were essential and saved millions of lives. But they largely focused on reducing exposure and, in the case of vaccines, priming the immune system, rather than addressing the underlying terrain on which the virus operated. COVID was treated primarily as an external invader to be blocked or neutralized, not as a challenge that revealed how compromised metabolic systems amplify biological shocks.

GLP-1 therapies underscore this distinction. These medications improve glycemic control, reduce insulin resistance, promote substantial weight loss, and often improve blood pressure and lipid profiles. In other words, they directly target the very conditions that define COVID risk stratification. Observational studies conducted after vaccines became available suggest that individuals with diabetes who were already taking GLP-1 therapies experienced lower rates of severe COVID outcomes than similar patients who were not. While such studies cannot prove causality, they align with biological plausibility and clinical intuition.

What GLP-1s reveal most clearly is the difference between risk management and resilience building. Vaccines work by training the immune system to recognize a pathogen, but their effectiveness is not independent of the host. Chronic inflammation, insulin resistance, and metabolic dysfunction impair immune responsiveness, reduce the durability of protection, and increase residual risk even after vaccination. This helps explain why layered risk remained layered protection: vaccination compressed risk but did not equalize outcomes across metabolic strata.

GLP-1 therapies operate upstream of this problem. By improving metabolic health, they plausibly enhance immune competence, reduce inflammatory burden, and increase physiological reserve. If large numbers of high-risk individuals had entered the pandemic with better metabolic profiles, whether through GLP-1s or other effective interventions, the population-level impact of COVID would almost certainly have been less severe. Not eliminated, but meaningfully blunted.

Timing, however, is crucial. Medications that treat chronic disease are not emergency shields. Their most meaningful benefits accrue over weeks and months, not days. They could not have been deployed in March 2020 to rapidly alter hospitalization curves. Their hypothetical value lies in pre-pandemic preparedness, not acute crisis response. 

That said, it is worth noting that nearly a year elapsed between the identification of COVID as a virulent threat and the widespread availability of vaccines. More aggressive efforts to reduce chronic disease burden during that window could have reduced vulnerability while pharmaceutical countermeasures were still being developed.

This distinction exposes a structural blind spot in public health. Systems optimized for crisis response are poorly suited to long-term risk reduction, even when the latter determines who suffers most during crises. The rise of GLP-1s also helps explain why COVID risk stratification stopped short of risk modification. 

Identifying high-risk populations was analytically straightforward and operationally useful. Reducing risk would have required confronting obesity, food systems, prevention failures, and chronic disease management at scale, areas fraught with political, economic, and cultural resistance. Pharmaceutical solutions that fit existing regulatory pathways aligned more easily with institutional incentives than strategies aimed at metabolic repair.

Baseline health is not a background variable. It is a primary determinant of outcomes when systems are stressed.

COVID was not just a viral event; it was a mirror. It reflected decades of accumulated metabolic vulnerability and revealed how little resilience had been built into population health. GLP-1 therapies, arriving after the worst waves had passed, help articulate the lesson: emergency medicine can save lives in the moment, but it cannot substitute for sustained investment in metabolic resilience. 

Future pandemic preparedness will depend not only on faster vaccines and better antivirals, but on whether societies are willing to address the chronic conditions that turn biological threats into mass casualties.