GLP-1s and the new longevity math: pills, risk, reality

The week longevity math got real

A decade ago, calling a weight loss drug a longevity therapy sounded like hype. This week at EASD 2025 it looked pragmatic. A large Medicare real world analysis presented at the meeting reported that older adults on semaglutide had a 23 percent lower combined risk of heart attack, stroke, or death compared with dulaglutide. Novo Nordisk highlighted the result in its REACH head-to-head analysis drawn from nearly 60,000 beneficiaries. That is not a vanity endpoint, that is survival. You can read the top line details in Novo's REACH head-to-head summary.

On the same stage, the field pivoted toward pills. Phase 3 readouts for oral GLP-1s suggested what patients have asked for all along. Novo's oral semaglutide for obesity delivered roughly 16.6 percent mean weight loss. Lilly's once daily orforglipron produced about 12.4 percent over 72 weeks. The message is simple. If you turn a weekly injection into a pill with similar metabolic power, uptake expands and adherence improves. For a deeper dive on population effects, see our breakdown of decoding Swiss Re's mortality forecast.

Call this the convergence moment. Biology that links adiposity to cardiometabolic events is meeting delivery formats that most people will actually use, and spreadsheet models are beginning to reflect it.

What a 23 percent reduction really means

Relative risk reductions sound big. The part that changes budgets and lives is absolute risk.

Consider a typical older adult on Medicare with type 2 diabetes and obesity. Annual risk for a major cardiovascular event or death can be around 3 percent per year depending on comorbidities.
A 23 percent relative reduction would lower that to about 2.31 percent per year. That is an absolute drop of 0.69 percentage points per year.
Over three years, on rough arithmetic, that is about a 2 percentage point absolute reduction. The number needed to treat would be in the ballpark of 50 to prevent one event across that time horizon.

These are back of the envelope estimates, not individualized risk calculations. The direction is clear. When relative reductions of this size land in populations with elevated baseline risk, absolute gains stack up in a way actuaries can model and payers can price.

Why GLP-1s move mortality rather than just weight

Weight loss gets the headlines because it is easy to visualize. The mortality signal emerges from a web of changes that happen together.

Adiposity and ectopic fat. GLP-1 agonism reduces visceral adipose tissue and liver fat. Less liver fat means better insulin sensitivity and reduced hepatic glucose output. That reduces glucotoxicity and lipotoxicity, two drivers of vascular damage.
Inflammation. Obesity and insulin resistance stoke low grade inflammation. GLP-1s reduce inflammatory signaling, often in lockstep with weight loss and improved glycemia. Lower inflammation helps plaques become less rupture prone.
Blood pressure and lipids. Modest drops in systolic blood pressure and improvements in triglycerides ride along with weight loss and glycemic control. Small shifts across millions of people equal many prevented events.
Heart failure and kidney disease. GLP-1s are not SGLT2 inhibitors, yet they appear to reduce heart failure admissions in some cohorts and slow kidney decline in diabetes. Better glycemia, less weight, lower blood pressure, and less inflammation create a friendlier milieu for both organs.
Sleep apnea and arrhythmia burden. Weight loss ameliorates obstructive sleep apnea. Better nocturnal oxygenation and less sympathetic drive can lower atrial fibrillation burden and downstream stroke risk.

Stack these changes and the composite endpoint moves. It is not magic. It is risk factor geometry shifting in the right direction at the same time.

The oral era will change behavior

Injections are a psychological and logistical hurdle. People juggling multiple pills and glucose checks do not cheer for needles. Oral GLP-1s will not be perfect substitutes. Some require fasting windows and careful timing. But a once daily pill removes training visits and refrigeration questions, and it smooths pharmacy fulfillment.

Expect three behavior shifts if oral GLP-1s roll out at scale.

Access expands. Primary care physicians can initiate a pill inside routine visits without device teaching or sample kits. Pharmacies can carry higher volumes without cold chain concerns.
Adherence improves. Even people comfortable with injections miss doses while traveling or during holidays. A pill in the weekly pillbox is easier to remember. Better persistence means physiologic effects accumulate.
Earlier starts. Patients who are injection hesitant may agree to start when offered a pill, especially if weight is already hurting mobility or sleep. Earlier starts add more months of risk reduction before the first event happens.

If you are modeling outcomes, the curve is simple. Injections work when taken. Oral versions increase the fraction of people who start and the fraction who stay on. Multiply those fractions by the drug effect that is already proven. You get more risk reduction at the population level without changing the molecule.

Cost, coverage, and the Medicare lever

Medicare is the fulcrum in the United States. The program already pays for GLP-1s labeled for diabetes under Part D. Coverage for obesity without diabetes is moving in fits and starts. Payers lean on prior authorization, step therapy, and caps because upfront drug costs are high and budget rules do not yet capture long run savings from avoided events.

Two forces will push coverage looser over the next few years.

Actuarial math that includes mortality. When credible real world data show fewer heart attacks, strokes, and deaths in Medicare aged cohorts, the long run cost curve bends. If the reductions described in decoding Swiss Re's mortality forecast hold, the return on drug spending looks better in five year windows, not just in ten.
Pills shift site of care. Oral drugs that run through standard pharmacy benefit channels are easier to manage than specialty injectables. More competition inside the oral class can nudge net prices down, and the logistics are simpler.

Budget holders will still have to manage waste. Expect programs that pair GLP-1 coverage with lifestyle coaching, nutrition benefits, and strength training subsidies since lean mass preservation is a clinical and cost imperative in older adults.

The definition of a longevity therapy

For decades, longevity meant adding years at the tail of life or tinkering with biomarkers that might someday map to aging biology. The first mass market longevity therapies did not use that label. They were blood pressure medicines and statins. They saved lives by moving the distribution of risk in middle age and late life. GLP-1s emerging from a diabetes and obesity frame now deserve to be considered in the same lineage.

What qualifies a drug as a longevity therapy in a pragmatic sense?

It reduces clinically important events that drive mortality in the near term.
It works in large, real world populations outside trial bubbles.
It is feasible to deploy at scale using primary care.
It has a safety profile that allows years of continuous use for many.

By those criteria, GLP-1s are in the club. If you are tracking parallel plays in risk reduction, see how gene editing may cut lifetime LDL in edit once, lower for life and why a single intervention can shift decades of risk in a single edit to cholesterol.

The equity question

There is a real risk that longevity gains concentrate among those who already have more access. GLP-1s are expensive. Clinics in affluent zip codes activate coverage workarounds faster. Pharmacies in rural areas face supply squeezes first. If oral options open the funnel, the system still has to mind the gap.

Design choices that help:

Use simple eligibility rules that match trial and real world cohorts. Avoid labyrinthine paperwork that selects for free time and health literacy.
Build default nutrition and strength training support into coverage. Weight loss without muscle preservation invites frailty.
Track persistence and outcomes by race, income, and geography. Move resources to clinics that lag.

Longevity without equity is a mirage. A mortality curve that dips on average but not for everyone is not the victory it appears to be.

Safety, supply, and realistic guardrails

No drug that changes biology this much is free of tradeoffs.

Gastrointestinal effects are common. Nausea, vomiting, and diarrhea drive early discontinuation if dose titration is rushed.
Gallbladder issues can rise with rapid weight loss. Clinicians know to watch for biliary symptoms.
Lean mass and bone. Caloric deficits reduce muscle and bone if unopposed. Resistance training and adequate protein intake are not optional, especially for adults over 60.
Pancreatitis and thyroid warnings remain on labels. Absolute risks are low, and causality debates continue, but these signals require respect. Avoid in pregnancy and consider anesthesia planning due to delayed gastric emptying.
Rebound risk. Stopping therapy often leads to weight regain and the return of risk factors. That is a truth in chronic disease management, not a scandal.

Supply and manufacturing are still tight. If oral demand spikes, upstream peptide capacity and tableting lines will feel it. Predictable formularies and long term contracts can smooth the waves, but the first years of the oral era may still involve waitlists.

How the mortality modeling could reshape planning

Swiss Re's projection of a 2.3 to 6.4 percent reduction in United States mortality by 2045 is not a certainty. It is a scenario that assumes sustained uptake and persistence. Even the low end is a big number at the country scale. Life insurers will reprice, pension funds will revisit longevity risk, and public programs will rethink long run expenditure paths.

At a practical level, here is what may change if oral GLP-1s push adoption higher.

Life insurers adjust underwriting for cardiometabolic risk factors and medication status, and eventually price in population level improvements.
Health systems invest in multidisciplinary cardiometabolic clinics that combine GLP-1s, SGLT2 inhibitors, and lifestyle because combined management protects kidneys and hearts in parallel.
Employers stop treating these drugs as optional wellness perks and start treating them as core to workforce health, especially in physical jobs where weight loss improves safety.

What to watch in the next 12 to 24 months

Persistence curves. Real world adherence data for oral agents will tell us if the pill advantage is as large as expected.
Event driven endpoints beyond MACE. Heart failure admissions, kidney outcomes, and all cause mortality will matter for budgets.
Combination therapies. Oral GLP-1s paired with amylin analogs or small molecule co agonists could push weight loss higher at lower doses, which might improve tolerability.
Pricing and access. Net prices, not list prices, will determine how many people can stay on therapy long enough to benefit.
Resistance training at scale. Expect new benefit designs that bundle gym access or at home strength programs as part of GLP-1 coverage for older adults.

A simple decision framework for clinicians and payers

Identify high risk patients. Older adults with diabetes, obesity, and evidence of cardiovascular disease or chronic kidney disease derive the most absolute benefit.
Start with clear goals. Weight loss targets paired to blood pressure, A1c, and sleep apnea improvements keep expectations grounded.
Pair with muscle preservation. Strength programs and protein targets should start before the second dose titration.
Set a persistence plan. Talk through side effects in advance and agree on dose pacing to minimize early discontinuation.

Bottom line

The case for calling GLP-1s a real longevity therapy does not rest on wishful biomarkers. It rests on fewer heart attacks, fewer strokes, and fewer funerals in the very populations that drive Medicare spending. The arrival of potent oral options means more people will start and more will stay. If the early mortality math keeps holding, actuarial tables will bend, budgets will follow, and the definition of longevity therapy will become less mystical and more clinical. The next few years will tell us how far pills can push the curve. For now the signal is strong. The biology makes sense. The behavior change is real. The opportunity is to make it equitable, durable, and safe.