Most tirzepatide trials compare it to a placebo or another injectable. SURPASS-4 compared it to daily insulin, in patients already at high risk for a heart attack or stroke — the population doctors worry about most.
SURPASS-4 enrolled 2,002 adults with type 2 diabetes who already had, or were at high risk for, cardiovascular disease, and whose blood sugar wasn't controlled on one to three oral medications. That's a sicker, older population than most weight-loss-focused tirzepatide trials — the average participant had known heart disease or several major risk factors going in.
Instead of comparing tirzepatide to a placebo, researchers compared three tirzepatide doses (5 mg, 10 mg, 15 mg) against titrated insulin glargine — a standard basal insulin regimen and one of the most common next steps when oral medications stop working. The open-label trial ran 52 weeks for the main results, with safety follow-up continuing longer to capture cardiovascular events.
At the highest dose, tirzepatide lowered A1C by 2.58 percentage points and body weight by 11.7 kg (about 13.0%) over 52 weeks. Insulin glargine, by comparison, lowered A1C by 1.44 points — and patients gained an average of 1.9 kg, which is typical for basal insulin therapy.
Hypoglycemia was also lower with tirzepatide. Clinically significant low blood sugar occurred in roughly 6–9% of tirzepatide patients versus 19% on glargine overall — and the gap widened further in patients not also taking a sulfonylurea, where tirzepatide's rate dropped to as low as 1–3% against glargine's 16%. Basal insulin's biggest practical downside is the constant risk of going too low; this trial suggests tirzepatide avoids that trade-off.
Tirzepatide was not associated with excess cardiovascular risk in this high-risk group. The hazard ratio for major adverse cardiovascular events (heart attack, stroke, or cardiovascular death) was 0.74, with a confidence interval spanning 0.51 to 1.08 — numerically favoring tirzepatide over insulin, though not a formal outcomes trial built to prove superiority.
Sources: Del Prato et al., The Lancet 2021 (SURPASS-4, PMID 34672967) · Eli Lilly investor release on Lancet publication. See SURPASS-4 on PubMed.
Tirzepatide's downside in this trial was the same one seen everywhere else: gastrointestinal side effects. Nausea (12–23%), diarrhea (13–22%), decreased appetite (9–11%), and vomiting (5–9%) were all substantially more common than with insulin glargine (nausea 2%, diarrhea 4%, appetite loss under 1%, vomiting 2%). Most cases were mild to moderate and clustered in the dose-escalation weeks — the same pattern seen in tirzepatide's other trials.
SURPASS-4 wasn't designed as a dedicated cardiovascular outcomes trial — that role went to the later, purpose-built SURPASS-CVOT, which compared tirzepatide directly to another GLP-1 drug rather than insulin. But for anyone weighing tirzepatide against the more traditional path of adding daily insulin, SURPASS-4 is the trial that shows what that specific choice actually looks like: better blood sugar control, meaningful weight loss instead of weight gain, less hypoglycemia, and no signal of added heart risk — against more GI side effects and, unlike an insulin pen, a weekly rather than daily injection.
This article summarizes findings from a published, peer-reviewed clinical trial and manufacturer safety data for general education. It is not medical advice. Decisions about diabetes medication, insulin, or tirzepatide should be made with your prescriber based on your own health history.