Tirzepatide shows broader heart-and-kidney edge over dulaglutide in diabetes trial analysis

Cardiologists crowded into a ballroom at the American College of Cardiology’s annual meeting in New Orleans on March 28 as new numbers flashed on the screen: 23.7% versus 27.4%. In a field where single‑digit differences can shift treatment guidelines and billions in drug spending, those two percentages—representing serious heart and kidney problems in patients on rival diabetes drugs—drew immediate attention.

The figures came from a secondary analysis of a large cardiovascular outcomes trial comparing tirzepatide, a newer “twin hormone” drug, with dulaglutide, a long‑used GLP‑1 receptor agonist, in more than 13,000 adults with type 2 diabetes and established heart disease. The analysis, published the same day in JAMA Cardiology, found that patients assigned to tirzepatide had a significantly lower rate of an expanded “cardiorenal” composite outcome than those on dulaglutide over roughly four years of follow‑up.

The trial’s main result, released last year in The New England Journal of Medicine, showed tirzepatide was as safe as dulaglutide for the classic trio of cardiovascular death, heart attack and stroke—but not clearly superior. The new report suggests that when researchers look more broadly at death, coronary procedures, heart‑failure hospitalizations and kidney decline, tirzepatide may offer an edge, underscoring a shift in how doctors assess diabetes drugs that increasingly act on multiple organs.

A head-to-head test in high-risk patients

The study, known as SURPASS‑CVOT, enrolled 13,165 adults with type 2 diabetes and documented atherosclerotic cardiovascular disease at more than 600 sites worldwide between 2020 and 2022. Participants’ average age was about 64, and most had lived with diabetes for around 15 years. Nearly nine in 10 had high blood pressure, and many had survived a heart attack or undergone coronary stenting or bypass surgery.

Volunteers were randomly assigned in a double‑blind fashion to once‑weekly injections of tirzepatide, titrated up to 15 milligrams, or dulaglutide at 1.5 milligrams. Both drugs are made by Eli Lilly and Co.; tirzepatide is marketed as Mounjaro for diabetes and Zepbound for obesity, while dulaglutide is sold as Trulicity.

Regulators required the primary endpoint to be a standard three‑point measure known as major adverse cardiovascular events (MACE)—cardiovascular death, nonfatal heart attack or nonfatal stroke. After a median of about four years, that endpoint occurred in 12.2% of patients on tirzepatide and 13.1% on dulaglutide. The hazard ratio was 0.92, with a confidence interval that crossed 1.0, meaning tirzepatide met the bar for noninferiority but not for formal superiority.

That result assured regulators that tirzepatide does not increase major heart risks compared with an established GLP‑1 drug with proven cardiovascular benefit. But it left open a question clinicians have been debating informally: in high‑risk patients who already qualify for an injectable incretin, is one of these drugs better than the other at preventing the full spectrum of complications they fear—not just heart attacks and strokes, but procedures, hospitalizations and kidney failure?

A broader “cardiorenal” lens

To probe that question, investigators led by Cleveland Clinic cardiologist Dr. Stephen Nissen conducted a post hoc analysis using a six‑component “major cardiorenal event” composite. The endpoint included all‑cause death, heart attack, stroke, coronary revascularization procedures, hospitalization for heart failure and a kidney composite that captured persistent severe albumin in the urine, a sustained doubling of serum creatinine with reduced kidney function, the need for chronic kidney replacement therapy or death attributed to kidney disease.

Over follow‑up, 1,559 of 6,586 participants in the tirzepatide arm (23.7%) experienced at least one of those events, compared with 1,803 of 6,579 (27.4%) in the dulaglutide arm. That translated to a 16% relative risk reduction with tirzepatide (hazard ratio 0.84; 95% confidence interval 0.79 to 0.90) and an absolute difference of 3.7 percentage points. The authors calculated that treating 27 patients with tirzepatide instead of dulaglutide for about four years would prevent one such major cardiorenal event.

A Cleveland Clinic news release announcing the findings said tirzepatide was “associated with lower risk of heart and kidney damage compared to dulaglutide” in patients with type 2 diabetes and cardiovascular disease. The release quoted Nissen as saying the team set out to examine “six major complications including heart attack, stroke, coronary procedures, heart failure, kidney failure and all causes of death.”

The analysis found advantages for tirzepatide across several individual outcomes. All‑cause mortality occurred in 8.6% of tirzepatide‑treated patients versus 10.2% of those given dulaglutide. The composite kidney endpoint was reported in 4.9% versus 6.1%, a 21% relative risk reduction. Rates of heart attack and coronary revascularization were also modestly lower with tirzepatide, while hospitalizations for heart failure were similar between groups.

Importantly, when the researchers re‑ran the composite excluding kidney events and heart‑failure hospitalizations, tirzepatide still reduced a four‑component cardiovascular outcome—all‑cause death, heart attack, stroke and revascularization—by about 14%.

“These broader outcomes may better capture the totality of benefit for therapies that affect weight, blood pressure and kidney function in addition to glucose control,” the JAMA Cardiology paper stated.

Benefits and limits of a post hoc look

The new analysis aligns with a growing movement in cardiology and endocrinology to view diabetes as part of a “cardio‑kidney‑metabolic” syndrome, where obesity, high blood sugar, vascular disease and chronic kidney disease cluster and amplify one another. In an accompanying editorial, University of California, Los Angeles cardiologist Dr. Gregg Fonarow and University of Glasgow cardiologist Dr. John McMurray wrote that modern incretin therapies “have important effects that extend beyond traditional atherosclerotic cardiovascular events,” and argued that expanded outcomes “may be more clinically meaningful” for many patients.

At the same time, both the authors and outside experts caution that the six‑component endpoint was not the prespecified primary outcome of SURPASS‑CVOT. Post hoc analyses, by definition, are performed after researchers have seen the results of the main trial, raising a risk of overstating findings that could partly reflect chance.

“As with all post hoc analyses, these results should be interpreted cautiously,” the JAMA Cardiology authors wrote, noting that the composite was not adjusted for multiple comparisons and that the kidney components were not centrally adjudicated in the same way as heart attacks and strokes.

Statisticians not involved in the study have pointed out that once a trial misses superiority on its primary endpoint, subsequent composite endpoints—especially those that add softer or more frequent events—cannot substitute for that prespecified result in regulatory decision‑making. Instead, they are generally viewed as hypothesis‑generating.

How the findings could influence care

Even framed as hypothesis‑generating, the cardiorenal data may carry weight in clinics where physicians already face decisions between competing injectable therapies.

The American Diabetes Association’s Standards of Medical Care now recommend GLP‑1 receptor agonists and SGLT2 inhibitors as first‑line options for many patients with type 2 diabetes, particularly those with cardiovascular or kidney disease. The American Association of Clinical Endocrinology’s 2026 algorithm highlights tirzepatide as a key option for patients who require substantial weight loss and have high cardiovascular risk.

Dulaglutide earned a U.S. Food and Drug Administration indication for reducing major cardiovascular events after the REWIND trial showed fewer heart attacks and strokes compared with placebo. Tirzepatide’s noninferiority to dulaglutide on three‑point MACE in SURPASS‑CVOT reassures physicians about its cardiovascular safety. The new cardiorenal analysis could tilt preferences further toward tirzepatide among patients at very high risk, clinicians say, provided safety and access are acceptable.

Like other drugs in its class, tirzepatide is associated with gastrointestinal side effects—nausea, vomiting and diarrhea—which occurred more often than with dulaglutide in the trial. In the JAMA analysis, 42.5% of tirzepatide‑treated patients reported gastrointestinal adverse events, compared with 35.9% of those on dulaglutide. Overall serious adverse events were similar between groups.

Evidence meets the reality of access

Any shift in clinical preference plays out against a fraught policy backdrop. GLP‑1 and related drugs typically carry list prices above $1,000 a month in the United States. Coverage for diabetes indications is more common than for obesity, but prior authorization requirements and formulary restrictions are widespread.

The Centers for Medicare and Medicaid Services this year launched a “GLP‑1 Bridge” program that allows coverage of certain agents, including Zepbound and Wegovy, for specific cardiovascular and sleep apnea indications under Medicare drug plans. State Medicaid programs vary widely; some cover GLP‑1 drugs for obesity in addition to diabetes, while others exclude them except in narrow circumstances. Commercial insurers often require documentation of body mass index thresholds and previous attempts at diet and exercise for weight‑management uses.

In 2025, the World Health Organization recommended GLP‑1–based medicines, including tirzepatide, for treating obesity in certain adults, and added some of the drugs to its Model List of Essential Medicines for high‑risk diabetes populations. The designation signaled their importance but did not solve questions of affordability in low‑ and middle‑income countries.

For health systems and payers, evidence that a drug reduces not only blood sugar and weight but also death, heart procedures and kidney failure could strengthen arguments that higher up‑front spending may be offset by avoided hospitalizations and dialysis. Independent groups that assess value, including the Institute for Clinical and Economic Review, have noted that such projections remain uncertain, particularly over decades.

A turning point, with unanswered questions

SURPASS‑CVOT is one of the largest and longest studies of tirzepatide to date, and its main message—cardiovascular safety at least on par with dulaglutide—is unlikely to change. The JAMA Cardiology analysis adds a layer of nuance, suggesting that, in patients already at high cardiovascular risk, tirzepatide may better protect the heart and kidneys when a wider net of outcomes is considered.

Whether that signal reshapes practice will depend on how guideline panels, regulators and insurers weigh post hoc evidence, and on whether future trials confirm similar patterns with prespecified endpoints. For now, the findings give doctors more data to discuss with patients facing a choice of injections—and put renewed focus on whether those patients can obtain the drugs that may best safeguard their hearts and kidneys over the long haul.