Tag: Cardiometabolic health

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Does Mounjaro Lower Your Risk of Heart Attack and Stroke?

On By Dr. Scott RennieIn Weight Loss & Metabolic HealthLeave a comment

On August 28, 2026, the FDA approved a new use for Mounjaro (tirzepatide): lowering the risk of cardiovascular death, nonfatal heart attack, and nonfatal stroke in adults with type 2 diabetes who are at high risk for those events (1). That is a real change written into the drug’s FDA-approved label. The short version is this: tirzepatide matched, but did not beat, a diabetes drug that already had proven heart benefits of its own. Whether that counts as exciting news depends on what you were expecting going in.

What the Label Now Says

Mounjaro’s original approval covered blood sugar control in adults, later extended to children age 10 and up with type 2 diabetes in December 2025 (3). The new cardiovascular indication sits on top of that one. It reads, in the FDA’s language, as lowering the risk of major adverse cardiovascular events, meaning cardiovascular death, nonfatal heart attack, or nonfatal stroke, in adults with type 2 diabetes who are already at high risk for those events (1, 2). That population matters: this approval is specific to people with type 2 diabetes who already carry meaningful cardiovascular risk, largely established atherosclerotic disease.

An outcomes indication like this one is a different category of claim than glycemic control. It says the drug changed what happens to a person’s heart and vessels over years, something a lab value at three months cannot tell you on its own. That distinction is the entire reason a cardiovascular outcomes trial exists.

The Trial Behind It

The approval rests on SURPASS-CVOT, a randomized, double-blind trial that enrolled more than 13,000 adults with type 2 diabetes and established atherosclerotic cardiovascular disease across 640 sites in 30 countries (4). Participants were assigned to tirzepatide, titrated up to 15 mg weekly or their highest tolerated dose, or dulaglutide (Trulicity) 1.5 mg weekly, followed for a median of roughly four years. Dulaglutide was not a placebo. A drug with its own proven cardiovascular track record from the REWIND trial, chosen deliberately as a harder comparator than sugar water.

The primary outcome, a composite of cardiovascular death, heart attack, or stroke known as three-point MACE, occurred in 12.2 percent of the tirzepatide group and 13.1 percent of the dulaglutide group. That is a hazard ratio of 0.92, with a 95.3 percent confidence interval of 0.83 to 1.01 (4). Tirzepatide met the prespecified bar for noninferiority (p=0.003). It did not meet the bar for superiority (p=0.09). Read plainly: tirzepatide did not fall behind a drug already known to protect the heart, and it numerically edged ahead, but the trial cannot say with statistical confidence that it beat dulaglutide on this endpoint.

Two other numbers are worth knowing even though they sit outside the approved claim. All-cause mortality was 16 percent lower with tirzepatide than with dulaglutide, hazard ratio 0.84, 95 percent confidence interval 0.75 to 0.94, per Lilly’s topline results release (5). And the weight difference was large: about 11.6 percent body weight reduction with tirzepatide against 4.5 percent with dulaglutide (4), which tracks with everything already known about how the two drugs differ on that front. Neither of those numbers was the tested primary endpoint, so treat them as suggestive rather than proven.

I do not read this trial as evidence that tirzepatide is the better heart drug. I read it as evidence that choosing tirzepatide over an active cardioprotective comparator costs you nothing on the cardiovascular side, while it still outperforms on weight and blood sugar. That is a useful thing to know, and it is a smaller claim than the headlines will make it sound.

Where This Leaves Ozempic, Wegovy, and Zepbound

Semaglutide already has cardiovascular outcomes data of its own, built from different comparators and different populations, which matters when you start comparing hazard ratios across trials. SUSTAIN-6 tested injectable Ozempic against placebo in type 2 diabetes at high cardiovascular risk and found a hazard ratio of 0.74 (6). Ozempic tablets, oral semaglutide, picked up their own cardiovascular indication in October 2025 based on the SOUL trial, hazard ratio 0.86, in a population with type 2 diabetes and atherosclerotic disease, chronic kidney disease, or both, broader than “established cardiovascular disease” alone (7). Wegovy’s SELECT trial went further still: adults with overweight or obesity and established cardiovascular disease, no diabetes required at all, hazard ratio 0.80 against placebo (8).

Four trials went into these numbers, each built around its own comparator and its own patient population. Lining the hazard ratios up side by side and picking a winner overstates what any single number can tell you. SURPASS-CVOT is the only one of the four tested against an active drug with its own proven benefit, a harder bar to clear even when the resulting number looks smaller.

Zepbound carries no such indication yet. Zepbound and Mounjaro are the same molecule, tirzepatide, at the same doses. The difference is entirely regulatory. Mounjaro is approved for type 2 diabetes, and its new cardiovascular claim comes from a trial that specifically enrolled people with diabetes. Zepbound is approved for obesity and, separately, moderate to severe obstructive sleep apnea. Its own cardiovascular outcomes trial, SURMOUNT-MMO, is still enrolling, expected to include roughly 15,000 adults with obesity who do not have diabetes, and has not reported results (9). Tirzepatide’s heart benefit currently exists on the books only under the Mounjaro name, for a population that has diabetes.

For Patients

If you have type 2 diabetes and known heart disease and you are already doing well on dulaglutide, this trial should reassure you. Superiority was not shown, so nothing in the data requires a change if your current regimen is working. If your blood sugar or weight has been harder to manage, this approval gives your clinician a documented, FDA-recognized reason to discuss tirzepatide.

Coverage is worth asking about directly. An outcomes-based indication sometimes changes how an insurer’s prior authorization process treats a drug, because it can be framed as reducing a documented risk of death rather than only managing a lab value. That is not guaranteed, and formularies vary by plan. Ask specifically whether this new indication affects your prior authorization, rather than assuming it automatically will.

Patients on my video visits do ask about switching from semaglutide to tirzepatide after news like this. I tell them to stay on semaglutide if it’s working. Superiority was not shown here, so a regimen that is already working has no data forcing a change.

The Practical Question for Prescribers

For a patient with type 2 diabetes and established cardiovascular disease, tirzepatide’s larger effect on weight and A1c, paired with a trial showing it keeps pace on cardiovascular safety against an already-protective drug, makes a reasonable case for choosing it first. That is my opinion, and it deserves the caveat the superiority test earned: the point estimate favored tirzepatide, but the confidence interval did not exclude the possibility of no difference at all.

The active-comparator design is also worth sitting with. Because there was no placebo arm, SURPASS-CVOT cannot independently quantify tirzepatide’s benefit against doing nothing. It borrows dulaglutide’s REWIND-established benefit and shows tirzepatide keeps that benefit intact. Proving a brand new benefit from scratch would have required a placebo arm, and this trial did not have one.

When type 2 diabetes is the indication, I prescribe Mounjaro.

The Bottom Line

Tirzepatide gives up nothing on heart safety when measured against a drug that already protects the heart, and it does more for weight and A1c along the way. That is the real result of SURPASS-CVOT, even though the trial stopped short of proving superiority: the noninferiority bar was met (p=0.003), the superiority bar was not (p=0.09). If you have type 2 diabetes and heart disease, ask your prescriber whether tirzepatide fits your regimen better than what you are on now, and ask whether this new indication changes what your insurer will approve. The August 28, 2026 approval gives that conversation a documented reason to happen (1).

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Scott Rennie, D.O.
Board Certified in Obesity Medicine and Family Medicine

This blog is for educational purposes only and does not constitute individual medical advice. Always consult your own physician before making changes to your health, medications, or treatment plan.

Sources

1. FDA approves Lilly’s Mounjaro (tirzepatide) to reduce cardiovascular risk in adults with type 2 diabetes. Eli Lilly and Company, August 28, 2026. https://investor.lilly.com/news-releases/news-release-details/fda-approves-lillys-mounjaro-tirzepatide-reduce-cardiovascular

2. FDA Expands Tirzepatide Label to Reduce Cardiovascular Risk in Type 2 Diabetes. AJMC. https://www.ajmc.com/view/fda-expands-tirzepatide-label-to-reduce-cardiovascular-risk-in-t2d

3. FDA approval letter, supplement 215866/S-039 (pediatric type 2 diabetes indication, age 10 and older). U.S. Food and Drug Administration, December 19, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/215866Orig1s039ltr.pdf

4. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (SURPASS-CVOT). New England Journal of Medicine, December 2025. PMID 41406444. https://pubmed.ncbi.nlm.nih.gov/41406444/

5. Lilly’s Mounjaro (tirzepatide), a GIP/GLP-1 dual agonist, demonstrated cardiovascular protection in landmark head-to-head trial. Eli Lilly and Company, July 31, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-mounjaro-tirzepatide-gipglp-1-dual-agonist-demonstrated

6. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes (SUSTAIN-6). N Engl J Med. 2016;375:1834-1844. https://www.nejm.org/doi/full/10.1056/NEJMoa1607141

7. McGuire DK, Marx N, Mulvagh SL, et al. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes (SOUL). N Engl J Med. 2025. https://www.nejm.org/doi/full/10.1056/NEJMoa2501006

8. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). N Engl J Med. 2023;389:2221-2232. PMID 37952131. https://pubmed.ncbi.nlm.nih.gov/37952131/

9. Tirzepatide for Reduction of Morbidity and Mortality in Adults with Obesity (SURMOUNT-MMO). ClinicalTrials.gov, NCT05556512. https://clinicaltrials.gov/study/NCT05556512

Does Fasting Slow Aging? What the Science Says

On By Dr. Scott RennieIn Longevity & Healthy AgingLeave a comment

Aging cannot be stopped. The pace of it may be influenced by what and when we eat, and that idea is old rather than new. Since the 1930s, animal studies have shown that cutting calories without causing malnutrition extends lifespan. Rodents held at a 30 percent reduction lived longer with less cancer and less heart disease.

The proposed mechanisms are lower oxidative stress, better mitochondrial function, and less inflammation. Less fuel in, less metabolic wear.

Then you move from mice to people and it gets complicated.

The CALERIE trials brought calorie restriction into human research. CALERIE II found that cutting roughly 15 percent of calories for two years improved blood pressure, cholesterol, and markers of oxidative stress, and those benefits appeared without major weight loss (Kraus et al., 2019). The obstacle is adherence. Sustained restriction is hard on mood, on social life, and on nutritional balance, and most people will not hold it.

Which is how fasting patterns entered the conversation. Intermittent fasting covers several approaches. Some people fast on alternate days. Others follow 5:2, eating normally five days a week and restricting on two. Time-restricted feeding, which confines eating to an 8 to 10 hour window, has drawn the most recent attention.

Alternate-day fasting does produce fat and weight loss, but hunger is a serious barrier and dropout rates run high. Modified versions have not clearly outperformed standard calorie restriction (Trepanowski et al., 2017).

Time-restricted feeding looks more workable. Sutton and colleagues tested an early schedule with all meals between 7 a.m. and 3 p.m. Participants did not lose weight, but insulin sensitivity, blood pressure, and oxidative stress markers all improved, and they reported less hunger through the evening (Sutton et al., 2018). Other short-term work points the same direction, particularly on appetite control and metabolic flexibility (Hatori et al., 2012; Varady et al., 2022).

What does that mean in practice? Calorie restriction has the strongest animal data and some genuinely promising human results, and almost nobody sustains it. Alternate-day fasting rarely survives contact with real life. Time-restricted feeding is the one most patients can actually keep, and even moving to a 10 hour window and dropping late-night meals is a defensible starting point.

When I talk this through with patients, I usually suggest starting at a 12 hour window and tightening it only if they tolerate the change well. What goes in the window still matters more than the window does, and nutrient density should not get lost in the enthusiasm about timing.

Fasting is one tool among several, and which one fits depends on the person, their health, and what they can hold onto for longer than a month.

Related Reading

Longevity Medicine: What Actually Works, and What Doesn’t Does Intermittent Fasting Work? A Doctor Explains Does Meal Timing Affect Your Metabolism and Health? Does Menopause Cause Weight Gain, or Is It Just Aging?

Scott Rennie, D.O.

References

Ravussin E, Redman LM et al. 2015.

Kraus WE et al. Lancet Diabetes Endocrinol. 2019.

Sutton EF et al. Cell Metab. 2018.

Trepanowski JF et al. JAMA Intern Med. 2017.

Heilbronn LK et al. 2005.

Spadaro PA et al. 2022.

Hatori M et al. Cell Metab. 2012.

Varady KA et al. 2022.

Board Certified in Obesity Medicine and Family Medicine

This blog is for educational purposes only and does not constitute individual medical advice. Always consult your own physician before making changes to your health, medications, or treatment plan.

An older couple walking together along a path

How Does Aging Change Your Metabolism? What Research Shows

On By Dr. Scott RennieIn Weight Loss & Metabolic HealthLeave a comment

Obesity, diabetes, cardiovascular disease, and frailty get treated as though they were the price of getting older. Work from researchers like Luigi Fontana points somewhere else. Decades of metabolic strain do most of this damage, and diet, activity, and the choices stacked on top of them shape how much strain accumulates.

The scale is hard to ignore. Chronic disease accounts for close to 90% of U.S. healthcare spending, most of it aimed at managing complications rather than preventing them (Martin et al., Health Affairs, 2021). Life expectancy in this country fell by more than two years between 2019 and 2021. Obesity now affects 40.3% of adults aged 20 and older, with 9.7% in the severe range (1). Excess adiposity drives hypertension, diabetes, fatty liver disease, and several cancers.

The biology is familiar. Oxidative stress, inflammation, and insulin resistance sit underneath most of these conditions (Fontana & Partridge, Cell, 2015). Abdominal fat is active tissue rather than storage. It fuels insulin resistance and chronic inflammation, and it also activates bone marrow. In the PESA cohort of 745 apparently healthy adults imaged with FDG-PET, bone marrow activation tracked with every component of metabolic syndrome, and the activated group carried metabolic syndrome at 22.2% versus 6.7% (Devesa et al., Eur Heart J, 2022). Obesity changes the terrain of the body long before symptoms show up.

Calorie restriction without malnutrition is the clearest intervention we have. The animal data are strong. In rhesus monkeys, long-term restriction slowed age-related brain atrophy (Colman et al., Science, 2009), preserved muscle and function (Colman et al., J Gerontol, 2008), and lowered frailty and chronic disease burden (Yamada et al., J Gerontol, 2018).

This literature gets oversold, and the primate data are where it happens. The 2017 joint reanalysis of the two big studies found a survival benefit in the Wisconsin animals and no significant survival effect in the National Institute on Aging cohort (Mattison et al., Nat Commun, 2017). Health measures improved in both. Lifespan did not reliably follow. That is a more honest summary than the one usually quoted.

Human data are thinner but point the same direction. CALERIE tested roughly a 25% calorie reduction over two years and found improvements in blood pressure, cholesterol, glucose, inflammatory markers, heart rate variability, and insulin sensitivity (Meydani et al., Aging, 2016; Stein et al., Aging Cell, 2012; Weiss et al., Am J Clin Nutr, 2006). Even the more realistic reduction people actually achieved, closer to 12%, produced meaningful metabolic change (Kraus et al., Lancet Diabetes Endocrinol, 2019).

Calories are one variable. Nutrient quality and timing matter too. Studies in mice suggest high-protein diets may shorten lifespan, while restricting methionine or branched-chain amino acids improves metabolic health and longevity markers (Solon-Biet et al., Cell Metab, 2014). A trial in men with prostate cancer found that a single month of protein restriction lowered fat mass, cholesterol, and insulin (Fontana et al., Cell Rep, 2016). Protein source appears to matter as well, with plant-based sources holding an advantage over animal-based ones.

Timing has drawn its own attention. Intermittent fasting, whether through time-restricted eating or alternate-day fasting, extends lifespan in animal studies and protects against age-related disease including diabetes and cancer (Mattson et al., PNAS, 2014). Human studies suggest benefits on body fat, insulin sensitivity, and metabolic markers (Tosti et al., Aging Biology, 2022).

The gut microbiome adds a layer underneath all of it. Diet shapes microbial diversity and function, which in turn shapes inflammation, immunity, and metabolism (Thorburn et al., Immunity, 2014; Griffin et al., Cell Host Microbe, 2017). Fiber, protein type, and eating pattern all shift that balance. Nutrition never acts alone. It works through microbial partners.

What Fontana and others argue is that the real challenge lies less in treating diseases once they appear and more in holding metabolic integrity across a lifespan. That means healthcare built around prevention rather than reaction. Whole-food, plant-predominant eating. Fewer excess calories. Less reliance on protein-heavy patterns. Fasting strategies where they fit the patient. Attention to gut and immune health.

Aging isn’t a disease. Metabolic dysfunction is. Treat it early and seriously, through diet, lifestyle, and the interventions that have evidence behind them, and the curve bends toward years worth having.

Related Reading

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Scott Rennie, D.O.

References:

1. National Center for Health Statistics. Prevalence of Overweight, Obesity, and Severe Obesity Among Adults Age 20 and Older: United States, 1960–1962 Through August 2021–August 2023. https://www.cdc.gov/nchs/data/hestat/obesity-adult-17-18/obesity-adult.htm

2. Martin AB, et al. Health Affairs. 2021.

3. Fontana L, Partridge L. Promoting health and longevity through diet: from model organisms to humans. Cell. 2015;161(1):106-118. https://pubmed.ncbi.nlm.nih.gov/25815989/

4. Fontana L, Kennedy BK, Longo VD, Seals D, Melov S. Medical research: treat ageing. Nature. 2014;511(7510):405-407. https://pubmed.ncbi.nlm.nih.gov/25056047/

5. Devesa A, et al. Bone marrow activation in response to metabolic syndrome and early atherosclerosis. Eur Heart J. 2022;43(19):1809-1828. https://pubmed.ncbi.nlm.nih.gov/35567559/

6. Colman RJ, et al. Science. 2009;325(5937):201-204.

7. Colman RJ, et al. J Gerontol A Biol Sci Med Sci. 2008;63(6):556-559.

8. Yamada Y, et al. J Gerontol A Biol Sci Med Sci. 2018;73(3):273-278.

9. Mattison JA, et al. Caloric restriction improves health and survival of rhesus monkeys. Nat Commun. 2017;8:14063. https://pubmed.ncbi.nlm.nih.gov/28094793/

10. Weiss EP, et al. Am J Clin Nutr. 2006;84(5):1033-1042.

11. Meydani SN, et al. Aging (Albany NY). 2016;8(7):1416-1431.

12. Stein PK, et al. Aging Cell. 2012;11(4):644-650.

13. Kraus WE, et al. Lancet Diabetes Endocrinol. 2019;7(9):673-683.

14. Solon-Biet SM, et al. Cell Metab. 2014;19(3):418-430.

15. Fontana L, et al. Cell Rep. 2016;16(2):520-530.

16. Mattson MP, et al. Proc Natl Acad Sci USA. 2014;111(47):16647-16653.

17. Tosti V, et al. Aging Biology. 2022.

18. Thorburn AN, et al. Immunity. 2014;40(6):833-842.

19. Griffin NW, et al. Cell Host Microbe. 2017;21(1):84-96.

Board Certified in Obesity Medicine and Family Medicine

This blog is for educational purposes only and does not constitute individual medical advice. Always consult your own physician before making changes to your health, medications, or treatment plan.