SELECT, STEP, SURPASS & FLOW: What the Landmark Semaglutide and Tirzepatide Trials Actually Prove (2026)

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By Dr. Frank Yap, MD  |  Medically reviewed by One Day MD Review Team  |  Last updated: August 2026

Quick Answer

SELECT showed that semaglutide 2.4 mg cuts major cardiovascular events by 20% in people with overweight/obesity and existing heart disease who do not have diabetes. The STEP program (STEP 1–5, STEP 8, and the newer STEP UP trials) established semaglutide's weight-loss profile, with losses ranging from roughly 10% to over 20% of body weight depending on dose, population, and duration. The SURPASS program showed that tirzepatide — a dual GIP/GLP-1 agonist — produces larger HbA1c and weight reductions than semaglutide in type 2 diabetes, and the newly published SURPASS-CVOT (December 2025) confirmed tirzepatide is at least as cardioprotective as dulaglutide. FLOW showed semaglutide cuts major kidney disease events by 24% in people with type 2 diabetes and chronic kidney disease, which led the FDA to approve a dedicated kidney-protection indication for Ozempic in January 2025.

Why These Four Trial Programs Matter

Semaglutide (marketed as Ozempic, Wegovy, and Rybelsus) and tirzepatide (marketed as Mounjaro and Zepbound) began their clinical lives as glucose-lowering drugs for type 2 diabetes. Semaglutide is a selective GLP-1 (glucagon-like peptide-1) receptor agonist. Tirzepatide is a dual agonist that activates both the GIP (glucose-dependent insulinotropic polypeptide) receptor and the GLP-1 receptor, which is part of why it tends to produce larger reductions in HbA1c and body weight in head-to-head comparisons.

Four trial programs moved these drugs well beyond glycemic control:

  • SELECT asked whether semaglutide protects the heart in people who are overweight or living with obesity but do not have diabetes.
  • STEP is the phase 3 program that established semaglutide 2.4 mg (and now 7.2 mg) as a weight-management therapy in its own right.
  • SURPASS is tirzepatide's phase 3 diabetes program, culminating in SURPASS-CVOT, tirzepatide's first dedicated cardiovascular outcomes trial.
  • FLOW asked whether semaglutide slows the progression of chronic kidney disease (CKD) in type 2 diabetes — and led directly to a new FDA-approved kidney indication in 2025.

Together, these four programs are why clinicians increasingly describe GLP-1/GIP therapy as addressing cardiovascular-kidney-metabolic (CKM) syndrome as a whole, rather than treating blood sugar, weight, heart risk, and kidney risk as separate problems.

At-a-Glance Comparison Table

Trial Drug Population N Headline Result Published
SELECT Semaglutide 2.4 mg Overweight/obesity + CVD, no diabetes 17,604 20% ↓ MACE (HR 0.80) NEJM, Nov 2023
STEP 1 Semaglutide 2.4 mg Obesity/overweight, no diabetes 1,961 −14.9% vs −2.4% body weight NEJM, 2021
STEP 2 Semaglutide 2.4/1.0 mg Obesity/overweight + type 2 diabetes 1,210 −9.6% vs −3.4% body weight Lancet, 2021
STEP 3 Semaglutide 2.4 mg + IBT Obesity/overweight, no diabetes (US) 611 86.6% vs 47.6% achieved ≥5% loss JAMA, 2021
STEP 4 Semaglutide 2.4 mg (withdrawal design) Obesity/overweight, no diabetes 803 Continued loss vs regain after stopping JAMA, 2021
STEP 5 Semaglutide 2.4 mg Obesity/overweight, no diabetes 304 ~15% weight loss sustained at 104 weeks Nat Med, 2022
STEP 8 Semaglutide vs liraglutide Obesity/overweight, no diabetes 338 −15.8% vs −6.4% body weight JAMA, 2022
STEP UP Semaglutide 7.2 mg Obesity, ± type 2 diabetes ~1,900 + 512 (T2D arm) Up to ~20.7% weight loss ADA 2025 (pending full publication)
SURPASS-1 Tirzepatide (monotherapy) Type 2 diabetes 478 HbA1c −1.87% to −2.07% Lancet, 2021
SURPASS-2 Tirzepatide vs semaglutide 1 mg Type 2 diabetes 1,879 Superior A1C & weight loss vs semaglutide NEJM, 2021
SURPASS-3 Tirzepatide vs insulin degludec Type 2 diabetes 1,444 A1C −2.37%, weight −13.9% (15 mg) Lancet, 2021
SURPASS-4 Tirzepatide vs insulin glargine Type 2 diabetes, high CV risk 2,002 Favorable glycemic/MACE trend Lancet, 2021
SURPASS-5 Tirzepatide + insulin glargine Type 2 diabetes on basal insulin 475 (approx.) A1C −2.59%, weight −11.6% (15 mg) JAMA, 2022
SURPASS-CVOT Tirzepatide vs dulaglutide Type 2 diabetes + ASCVD 13,299 Noninferior MACE (HR 0.92); 16% ↓ mortality NEJM, Dec 2025
FLOW Semaglutide 1.0 mg Type 2 diabetes + CKD 3,533 24% ↓ major kidney events (HR 0.76) NEJM, July 2024

MACE = major adverse cardiovascular events (a composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke). IBT = intensive behavioral therapy. All weight-loss figures are placebo-adjusted or head-to-head estimated treatment differences unless noted; see each trial's section below for the exact estimand used.

The SELECT Trial: Semaglutide and Cardiovascular Risk Without Diabetes

SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) is the trial that moved semaglutide from a weight-loss drug into a cardiovascular-protection drug. Published in the New England Journal of Medicine in November 2023 (Lincoff et al.), it enrolled 17,604 adults across 804 sites in 41 countries — all at least 45 years old, with a BMI of 27 or higher, established cardiovascular disease, and no diagnosis of diabetes. Participants were randomized 1:1 to once-weekly subcutaneous semaglutide 2.4 mg or placebo, both added to standard of care, and followed for a mean of 39.8 months.

What SELECT found

  • Primary outcome (3-point MACE — cardiovascular death, nonfatal MI, or nonfatal stroke): 6.5% with semaglutide vs 8.0% with placebo — a hazard ratio of 0.80 (95% CI, 0.72–0.90), a 20% relative risk reduction.
  • Incident type 2 diabetes: reduced by roughly 73% in participants with prediabetes at baseline, a striking secondary finding given that two-thirds of the trial population had dysglycemia going in.
  • Weight loss: a mean reduction of 10.2% of body weight at 208 weeks (4 years) versus 1.5% with placebo — and, notably, subgroup analyses found the cardiovascular benefit held across baseline weight and waist-circumference categories, suggesting the heart protection isn't purely a function of how much weight was lost.
  • Kidney outcomes (prespecified secondary analysis): a composite kidney endpoint — kidney disease death, dialysis initiation, sustained eGFR under 15, or a sustained ≥50% eGFR decline — occurred in 1.8% of the semaglutide group versus 2.2% of placebo (HR 0.78, 95% CI 0.63–0.96, P = 0.02), roughly a 22% relative risk reduction. This finding foreshadowed the dedicated FLOW trial discussed later in this guide.
  • Heart failure subgroup: in participants who had heart failure at baseline (about a fifth of the trial), semaglutide reduced both MACE (HR 0.72) and a composite heart-failure outcome (HR 0.79), with consistent benefit regardless of heart failure subtype.

Clinically, SELECT is what led the FDA to approve Wegovy (semaglutide 2.4 mg) in March 2024 for reducing the risk of cardiovascular death, heart attack, and stroke in adults with established cardiovascular disease and either obesity or overweight — independent of a diabetes diagnosis. It was also the first GLP-1 cardiovascular outcomes trial conducted specifically in a non-diabetic population, which matters because earlier CV benefit data for this drug class (SUSTAIN-6, LEADER, REWIND) came from people who already had diabetes.

The STEP Trials: Semaglutide and Weight Management

The STEP (Semaglutide Treatment Effect in People with Obesity) program is the phase 3 body of evidence that got semaglutide 2.4 mg approved for chronic weight management in 2021, and it's still growing with the newer STEP UP trials testing a 7.2 mg dose. All STEP trials use once-weekly subcutaneous semaglutide added to lifestyle intervention, with a gradual 16-week dose-escalation schedule to reduce gastrointestinal side effects.

STEP 1 — the foundational trial

1,961 adults with obesity (or overweight plus a weight-related condition), without diabetes, were randomized 2:1 to semaglutide 2.4 mg or placebo for 68 weeks. Mean weight change was −14.9% with semaglutide versus −2.4% with placebo — an estimated treatment difference of −12.4 percentage points (95% CI, −13.4 to −11.5; P<0.0001). Eighty-six percent of the semaglutide group lost at least 5% of body weight. A follow-up extension study tracking participants for a year after stopping the drug found that roughly two-thirds of the lost weight was regained, and most cardiometabolic improvements reverted toward baseline — a finding that shaped how clinicians now frame obesity as a chronic condition requiring ongoing treatment rather than a course that ends.

STEP 2 — the type 2 diabetes population

1,210 adults with obesity/overweight and type 2 diabetes were randomized to semaglutide 2.4 mg, 1.0 mg, or placebo. Weight loss with type 2 diabetes is typically harder to achieve pharmacologically than in a non-diabetic population, and STEP 2 confirmed that pattern: −9.6% with the 2.4 mg dose versus −3.4% with placebo — smaller than STEP 1's effect size, but still clinically meaningful, alongside a 1.6-percentage-point greater HbA1c reduction than placebo.

STEP 3 — added intensive behavioral therapy

611 participants received semaglutide 2.4 mg or placebo on top of intensive behavioral therapy (30 counseling sessions) and an initial low-calorie, meal-replacement diet. This combination produced the program's largest response rates: 86.6% of the semaglutide group lost ≥5% of body weight (vs. 47.6% placebo), 75.3% lost ≥10% (vs. 27.0%), and 55.8% lost ≥15% (vs. 13.2%) — all P<0.001.

STEP 4 — what happens if you stop

803 participants who had already lost a mean 10.6% of body weight during a 20-week semaglutide run-in were then randomized to continue semaglutide 2.4 mg or switch to placebo for 48 more weeks. Those who continued kept losing weight; those switched to placebo regained a substantial portion — an early, controlled demonstration of the "STEP 1 extension" withdrawal finding above.

STEP 5 — two-year durability

304 participants were followed for 104 weeks (2 years), the longest placebo-controlled STEP trial. Weight loss was sustained through the full two years, at roughly 15% with semaglutide, reinforcing that STEP 1's results weren't a short-term effect that plateaus or reverses on-treatment.

STEP 8 — head-to-head against liraglutide

This 338-participant, open-label trial directly compared semaglutide 2.4 mg to liraglutide 3.0 mg (Saxenda), the previous-generation GLP-1 weight-management drug. Semaglutide produced significantly greater weight loss: −15.8% versus −6.4% at 68 weeks.

STEP UP and STEP UP T2D — the 7.2 mg dose (newest data)

Presented at the ADA Scientific Sessions in 2025 and still working through full peer-reviewed publication, STEP UP tested a higher 7.2 mg semaglutide dose against the currently approved 2.4 mg dose and placebo, in adults with obesity (STEP UP) and adults with obesity plus type 2 diabetes (STEP UP T2D, 512 participants). At 72 weeks, on-treatment weight loss reached 20.7% with 7.2 mg versus 17.5% with 2.4 mg and 2.4% with placebo; using the more conservative treatment-policy estimand (which counts everyone regardless of adherence), the figures were 18.7%, 15.6%, and 3.9% respectively. About a third of the 7.2 mg group lost 25% or more of body weight, versus roughly a sixth on 2.4 mg. Because this dose hasn't completed full peer review or regulatory review as of this writing, treat these as promising but not yet final numbers.

The SURPASS Trials: Tirzepatide and Type 2 Diabetes

The SURPASS program is tirzepatide's phase 3 registration package for type 2 diabetes, encompassing five global trials (SURPASS-1 through -5, over 6,200 participants combined) plus the newer, dedicated cardiovascular outcomes trial, SURPASS-CVOT. Because tirzepatide activates both the GIP and GLP-1 receptors, the SURPASS program consistently shows larger HbA1c and weight reductions than semaglutide's SUSTAIN/STEP data — a pattern confirmed directly in SURPASS-2's head-to-head design.

SURPASS-1 through -5: the glycemic and weight evidence

  • SURPASS-1 (478 participants, monotherapy vs. placebo): HbA1c fell by 1.87%, 1.89%, and 2.07% at the 5 mg, 10 mg, and 15 mg doses respectively, versus a 0.04% increase with placebo. Weight fell 7–9.5 kg, and 81–86% of tirzepatide-treated participants reached an HbA1c of 6.5% or below.
  • SURPASS-2 (1,879 participants, head-to-head vs. semaglutide 1 mg over 40 weeks): all three tirzepatide doses produced statistically superior HbA1c and weight reductions compared with semaglutide 1 mg — the first phase 3 evidence that a GIP/GLP-1 dual agonist could outperform a best-in-class GLP-1-only drug.
  • SURPASS-3 (1,444 participants, vs. titrated insulin degludec over 52 weeks): the 15 mg dose reduced HbA1c by 2.37% and body weight by 12.9 kg (13.9%) — a notable result because insulin typically causes weight gain, not loss.
  • SURPASS-4 (2,002 participants, vs. titrated insulin glargine, high cardiovascular-risk population): tirzepatide again produced superior glycemic and weight outcomes versus glargine. The trial wasn't statistically powered for cardiovascular superiority, but exploratory analyses showed a favorable trend toward fewer MACE events with tirzepatide versus glargine — a signal that helped justify running the dedicated SURPASS-CVOT trial described below.
  • SURPASS-5 (tirzepatide added to titrated insulin glargine, 40 weeks): the 15 mg dose reduced HbA1c by 2.59% and body weight by 10.9 kg (11.6%), with more than 85% of participants across all three tirzepatide doses reaching an HbA1c below 7%.

Pooled across SURPASS-1 to -5, the proportion of participants who reached an HbA1c under 7% with at least 5% weight loss and without hypoglycemia — a demanding composite endpoint — ranged from 43% to 82% with tirzepatide, versus just 4–5% with placebo.

SURPASS-CVOT: tirzepatide's cardiovascular outcomes trial (new, December 2025)

For years, tirzepatide carried strong glycemic and weight data but lacked a dedicated cardiovascular outcomes trial — unlike semaglutide, which had SUSTAIN-6 and then SELECT. That gap closed with SURPASS-CVOT, published in the New England Journal of Medicine in December 2025 (Nicholls et al.). This was a head-to-head, active-comparator trial — not placebo-controlled — comparing tirzepatide (up to 15 mg) against dulaglutide 1.5 mg, a GLP-1 drug with its own established cardiovascular benefit (from the earlier REWIND trial), in 13,299 adults with type 2 diabetes and established atherosclerotic cardiovascular disease, followed for a median of about four years across 640 sites in 30 countries.

  • Primary outcome (3-point MACE): occurred in 12.2% of the tirzepatide group versus 13.1% of the dulaglutide group — HR 0.92 (95.3% CI, 0.83–1.01). This met the trial's prespecified noninferiority threshold (P = 0.003) but did not reach statistical significance for superiority (P = 0.09) — an important nuance discussed further below.
  • All-cause mortality: reduced by 16% with tirzepatide (HR 0.84, 95% CI 0.75–0.94, P = 0.002) — a prespecified secondary endpoint that did reach significance.
  • Post hoc cardiorenal composite analysis: after a median treatment duration of about 47 months, this broader composite occurred in 23.7% of the tirzepatide group versus 27.4% of the dulaglutide group (HR 0.84, 95% CI 0.79–0.90).
  • Tirzepatide also produced greater reductions in HbA1c, body weight, blood pressure, and lipids than dulaglutide, along with a favorable trend in eGFR slope — an early kidney-protection signal that mirrors what FLOW later confirmed for semaglutide.

Why "noninferior, not superior" still matters: Because SURPASS-CVOT compared tirzepatide against an already cardioprotective drug (dulaglutide) rather than placebo, "noninferiority" is a genuinely positive result — it means tirzepatide is at least as good at preventing heart attacks and strokes as a proven GLP-1 therapy, while also delivering better glycemic control, more weight loss, and lower all-cause mortality. It is not the same claim SELECT makes for semaglutide (superiority over placebo in a non-diabetic population), and the two trials shouldn't be read as directly comparable head-to-head evidence of "which drug protects the heart more." A separate placebo-controlled outcomes trial for tirzepatide in people without diabetes — SURMOUNT-MMO — is still ongoing (expected results in the coming years) and will be the more direct analogue to SELECT.

The FLOW Trial: Semaglutide and Kidney Protection

FLOW (Evaluate Renal Function with Semaglutide Once Weekly) is the dedicated kidney-outcomes trial that SELECT's secondary renal findings pointed toward. Published in the New England Journal of Medicine in July 2024 (Perkovic et al.), FLOW enrolled 3,533 adults with type 2 diabetes and chronic kidney disease — specifically, an eGFR of 50–75 mL/min/1.73m² with a urinary albumin-to-creatinine ratio (UACR) of 300–5,000 mg/g, or an eGFR of 25–50 with a UACR of 100–5,000 — all already on a renin-angiotensin system inhibitor. Participants were randomized to once-weekly semaglutide 1.0 mg or placebo, both added to standard of care, across 387 sites in 28 countries.

FLOW was stopped early — at a prespecified interim analysis, after a median follow-up of 3.4 years — because the efficacy signal was already clear enough to make continuing placebo treatment unjustifiable.

What FLOW found

  • Primary outcome (a composite of kidney failure, sustained ≥50% eGFR reduction, kidney-related death, or cardiovascular death): 331 events with semaglutide versus 410 with placebo — HR 0.76 (95% CI, 0.66–0.88; P = 0.0003), a 24% relative risk reduction, with an absolute risk reduction of about 4.9% at 3 years.
  • Kidney-specific components alone (excluding cardiovascular death from the composite): still a 21% relative risk reduction (HR 0.79, 95% CI 0.66–0.94).
  • Major cardiovascular events: 18% lower with semaglutide (HR 0.82, 95% CI 0.68–0.98, P = 0.029).
  • All-cause mortality: 20% lower with semaglutide (HR 0.80, 95% CI 0.67–0.95, P = 0.01).
  • Rate of kidney function decline: eGFR fell more slowly with semaglutide, by 1.16 mL/min/1.73m² per year (P<0.001).
  • Albuminuria: UACR was reduced 38% more with semaglutide than placebo at 104 weeks.
  • Weight: a modest additional 4.1 kg mean loss with semaglutide versus placebo — smaller than the STEP program's numbers, consistent with the lower 1.0 mg dose used and this population's higher average age and comorbidity burden.
  • Safety: serious adverse events were actually less frequent with semaglutide than placebo (49.6% vs. 53.8%), though treatment discontinuation was slightly more common (13.2% vs. 11.9%), mainly from gastrointestinal side effects.

Subsequent subgroup analyses confirmed the kidney benefit held consistently across the full spectrum of baseline CKD severity represented in the trial, including more advanced disease, and that the benefit was directionally consistent whether or not participants were also taking an SGLT2 inhibitor at baseline — though only about 16% of the trial population was on an SGLT2i, so head-to-head evidence of combined benefit is still limited.

The regulatory consequence was fast: on January 28, 2025, the FDA approved a new Ozempic indication specifically to reduce the risk of worsening kidney disease, kidney failure, and cardiovascular death in adults with type 2 diabetes and CKD — making semaglutide the first and, as of this writing, only GLP-1 receptor agonist with all three indications: glycemic control, cardiovascular risk reduction, and kidney risk reduction.

Putting It All Together: Cross-Trial Synthesis

Reading these four programs side by side, a few patterns stand out:

1. Semaglutide's evidence base is now genuinely "whole-body"

SELECT (heart, non-diabetic), STEP (weight), and FLOW (kidney, diabetic) collectively give semaglutide placebo-controlled, hard-outcome evidence across three organ systems — a breadth of data that, at the time of writing, no other single molecule in this class matches.

2. Tirzepatide's glycemic and weight efficacy is consistently larger — its cardiovascular case is catching up

Across every SURPASS trial that included a semaglutide, insulin, or placebo comparator, tirzepatide produced numerically larger HbA1c and weight reductions. What tirzepatide lacked until December 2025 was a dedicated cardiovascular outcomes trial. SURPASS-CVOT closed that gap by demonstrating noninferiority to an already cardioprotective comparator (dulaglutide) plus a significant mortality benefit — a meaningfully positive result, even though it isn't the placebo-controlled superiority claim SELECT makes. The more direct comparison to SELECT — a placebo-controlled tirzepatide outcomes trial in people without diabetes — is SURMOUNT-MMO, still enrolling/following participants as of this writing.

3. Dose matters more than people often assume

SELECT and FLOW both used lower semaglutide doses (2.4 mg and 1.0 mg respectively) than the newest STEP UP weight-loss data (7.2 mg). It's tempting to assume the organ-protective benefits seen at lower doses would simply scale up at higher doses, but that hasn't been directly tested in dedicated outcomes trials — it's an extrapolation, not a proven fact.

4. Benefit doesn't appear to be purely about weight loss

SELECT's subgroup analyses found cardiovascular benefit was fairly consistent regardless of how much weight a given participant lost, and FLOW's kidney benefit exceeded what would be expected from the relatively modest 4.1 kg weight difference alone. This supports the idea that GLP-1/GIP agonists have direct anti-inflammatory, hemodynamic, and metabolic effects on the heart and kidneys — not just an indirect benefit mediated through weight loss.

5. None of this changes the basics of who should — or shouldn't — take these drugs

These are prescription medications with real gastrointestinal side effects, a discontinuation rate that isn't trivial, and a well-documented pattern of weight regain after stopping (STEP 1 extension, STEP 4). Trial eligibility criteria were also specific — SELECT required established cardiovascular disease, FLOW required diagnosed CKD with a defined albuminuria/eGFR range. None of these trials answer whether a healthy-weight person with no cardiometabolic risk factors should take these drugs, because that population wasn't studied.

Monitoring Your Health on GLP-1/GIP Therapy

Because these trials show meaningful effects on weight, blood pressure, kidney function, and (per FLOW's weight sub-analysis and STEP data) lean mass alongside fat mass, clinicians increasingly recommend simple home monitoring alongside routine lab work — not as a substitute for physician-ordered eGFR, UACR, and HbA1c testing, but as a useful adjunct between visits.

  • Home blood pressure monitor: useful given the consistent systolic BP reductions seen across SURPASS and FLOW. Browse validated upper-arm monitors on Amazon (affiliate link).
  • Body composition scale: because rapid weight loss on these drugs includes some lean mass loss, a scale that tracks trends in muscle mass — not just total weight — is worth considering. Browse body composition scales on Amazon (affiliate link).
  • Protein and micronutrient support: given reduced appetite and intake on these therapies, many clinicians recommend prioritizing protein intake to help preserve lean mass.

None of the above is a substitute for the lab monitoring your prescribing physician orders — including periodic eGFR, UACR, HbA1c, and lipid panels, which is exactly what the FLOW and SURPASS-CVOT protocols themselves relied on to generate the outcomes described in this article.

Evidence Tier Reference (CEBM)

Following the Oxford Centre for Evidence-Based Medicine (CEBM) framework, here is how the findings in this article are graded:

Finding CEBM Tier Notes
SELECT primary MACE outcome 1b Large, prespecified, placebo-controlled RCT
STEP 1–5, 8, UP primary weight outcomes 1b STEP UP pending full peer review — treat as provisional 1b
SURPASS-1–5 primary glycemic/weight outcomes 1b Individual RCTs, mostly open-label vs. active comparator
SURPASS-CVOT primary MACE outcome 1b Active-comparator (not placebo) noninferiority RCT
SURPASS-CVOT post hoc cardiorenal analysis 2b Post hoc, hypothesis-generating
FLOW primary kidney outcome 1b Prespecified, placebo-controlled, stopped early for efficacy
SELECT kidney sub-study, SURPASS-4 CV trend 2b Prespecified secondary/exploratory, not the trial's primary powered endpoint

1b = individual randomized controlled trial with narrow confidence intervals. 2b = individual cohort study or low-quality/underpowered RCT, including post hoc and exploratory subgroup analyses of an otherwise 1b trial. Post hoc findings are hypothesis-generating, not confirmatory.

Using AI Tools to Personalize This Data

This article covers population-level trial results — averages across thousands of people. If you want help thinking through how it might apply to your own situation (never as a substitute for your physician), AI assistants can be useful for organizing your questions before an appointment. A few starting prompts:

Claude

"Based on the SELECT, STEP, SURPASS, and FLOW trial data, I have [your relevant history — e.g., type 2 diabetes, an eGFR of X, no history of heart disease]. Help me write a list of questions to ask my doctor about whether semaglutide or tirzepatide's kidney/heart benefits might apply to me."

ChatGPT

"Compare the SURPASS-CVOT and SELECT trial eligibility criteria against my profile: [age, BMI, diabetes status, cardiovascular history]. Would I likely have qualified for either trial, and what does that suggest about how directly the results apply to me?"

Gemini

"Summarize how the FLOW trial's CKD entry criteria (eGFR and UACR ranges) compare to my most recent lab results: [insert your eGFR and UACR]. Explain in plain language what category of kidney function I'm in."

Perplexity

"Search for the most recent SURMOUNT-MMO trial updates and tell me whether tirzepatide's dedicated cardiovascular outcomes data (placebo-controlled, non-diabetic population) has been published yet."

These tools can help you organize information and questions — they cannot review your chart, examine you, or prescribe. Always bring the output to your physician rather than acting on it directly.

Frequently Asked Questions

What is the SELECT trial in simple terms?

SELECT tested whether semaglutide 2.4 mg could reduce heart attacks, strokes, and cardiovascular death in 17,604 people who had overweight or obesity and existing heart disease but did not have diabetes. It found a 20% relative risk reduction in major cardiovascular events compared with placebo.

What are the STEP trials?

STEP is semaglutide's phase 3 weight-management trial program (STEP 1 through 8, plus the newer STEP UP trials), which established that semaglutide 2.4 mg produces roughly 10–17% placebo-adjusted weight loss depending on the population and duration, and that a newer 7.2 mg dose may push that higher still.

What is the difference between the STEP trials and SELECT?

STEP measured weight loss as the primary outcome in people with obesity/overweight. SELECT measured hard cardiovascular events (heart attack, stroke, cardiovascular death) as the primary outcome, specifically in people who already had established heart disease. They used the same drug and dose but answered different clinical questions.

What are the SURPASS trials?

SURPASS is tirzepatide's phase 3 registration program for type 2 diabetes (SURPASS-1 through -5), plus the newer SURPASS-CVOT cardiovascular outcomes trial. Across the program, tirzepatide consistently produced larger HbA1c and weight reductions than comparators, including semaglutide 1 mg in a direct head-to-head trial (SURPASS-2).

Did SURPASS-CVOT prove tirzepatide protects the heart?

It proved tirzepatide is at least as protective as dulaglutide, an already cardioprotective GLP-1 drug, meeting its prespecified noninferiority threshold, and showed a significant 16% reduction in all-cause mortality. It did not reach statistical significance for superiority over dulaglutide on the primary MACE outcome. This is a different (and somewhat less direct) type of evidence than SELECT's placebo-controlled superiority finding.

What did the FLOW trial show about kidney health?

FLOW showed that semaglutide 1.0 mg reduced the risk of major kidney disease events — including kidney failure and cardiovascular death — by 24% in people with type 2 diabetes and chronic kidney disease, compared with placebo. This led the FDA to approve a dedicated kidney-protection indication for Ozempic in January 2025.

Is tirzepatide better than semaglutide?

For HbA1c reduction and weight loss, head-to-head data (SURPASS-2) shows tirzepatide outperforms semaglutide 1 mg. For cardiovascular and kidney outcomes specifically, semaglutide currently has more mature, placebo-controlled outcomes evidence (SELECT and FLOW), while tirzepatide's comparable placebo-controlled cardiovascular trial in non-diabetic patients (SURMOUNT-MMO) is still ongoing. "Better" depends on which outcome matters most for a given person, which is a conversation to have with a physician.

Do these trials mean everyone with obesity should take these drugs?

No. Each trial enrolled a specific population — SELECT required established cardiovascular disease, FLOW required a specific range of kidney function and albuminuria, and the STEP trials had their own BMI and comorbidity criteria. These results don't directly generalize to people outside those criteria, such as someone with a normal BMI or no cardiometabolic risk factors.

What are the most common side effects seen across these trials?

Gastrointestinal side effects — nausea, vomiting, diarrhea, and constipation — were consistently the most common adverse events across SELECT, STEP, SURPASS, and FLOW, and were the leading cause of treatment discontinuation in most of these trials.

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  • Nicholls SJ, et al. Cardiovascular Outcomes with Tirzepatide versus Dulaglutide in Type 2 Diabetes (SURPASS-CVOT). N Engl J Med. 2025;393:2409-2420.
  • Perkovic V, et al. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes (FLOW). N Engl J Med. 2024;391:109-121.
  • Lam CSP, et al. Tirzepatide for reduction of morbidity and mortality in adults with obesity: rationale and design of SURMOUNT-MMO. Obesity. 2025.
Medical disclaimer: This article is for general educational and informational purposes only. It summarizes published clinical trial data and does not constitute medical advice, a treatment recommendation, or a substitute for consultation with a qualified physician. Semaglutide and tirzepatide are prescription medications with specific indications, contraindications, and risks. Do not start, stop, or change any medication based on this article — talk to your doctor about whether the evidence discussed here applies to your individual health situation.

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