Raising an insulin dose to hit an A1C target usually means more hypoglycemia and more weight gain. SURPASS-5 tested adding tirzepatide instead — here's what happened to blood sugar, weight, and hypoglycemia risk over 40 weeks.
Basal insulin like glargine is a common step in type 2 diabetes care once oral medications stop being enough. But pushing the dose higher to close the gap to target usually trades one problem for two others: a higher risk of hypoglycemia, and steady weight gain.
SURPASS-5 asked whether adding tirzepatide — Eli Lilly's dual GIP/GLP-1 agonist, sold as Mounjaro — to that regimen could close the gap without that trade-off. It was a 40-week, phase 3, randomized, double-blind, placebo-controlled trial run at 45 centers worldwide, registered as NCT04039503, with results published in JAMA in February 2022.
Researchers enrolled 475 adults with type 2 diabetes already on basal insulin glargine, with or without metformin, whose blood sugar remained inadequately controlled. Average age was 61, average BMI was 33.4, and participants had lived with diabetes for 13.3 years on average.
After a 4-week period to stabilize each patient's insulin dose, glargine was titrated throughout the study toward a fasting glucose target — the same as if no study drug were involved — while participants separately received tirzepatide or volume-matched placebo.
Every tirzepatide dose beat placebo by a wide margin, and the gap held regardless of which dose patients took — even the lowest, 5 mg, cut A1C more than double what placebo achieved. Weight moved in opposite directions entirely: tirzepatide patients lost up to 8.8 kg over 40 weeks, while the placebo-plus-insulin group gained 1.6 kg, the usual pattern when insulin doses climb alone.
Severe hypoglycemia — the safety concern that usually limits how aggressively insulin gets titrated — stayed rare: just three episodes total across all tirzepatide arms combined. Diarrhea, nausea, and vomiting were the most common side effects, and discontinuation for adverse events rose with dose (10% at 5 mg, up to 18% at 15 mg, versus 3% on placebo). No deaths occurred during the trial.
Adding tirzepatide to titrated insulin glargine cut A1C by up to 2.4 percentage points — nearly triple what placebo achieved — while patients on tirzepatide lost weight instead of gaining it, the usual cost of pushing insulin doses higher. Severe hypoglycemia stayed rare across all three doses tested.
Sources: Dahl D, Onishi Y, Norwood P, et al., "Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial," JAMA, published online February 8, 2022 (DOI 10.1001/jama.2022.0078). See AJMC summary and trial registration (ClinicalTrials.gov NCT04039503).
If you're already on basal insulin and still not at target — SURPASS-5 is the evidence your prescriber may be weighing when they suggest adding a GLP-1/GIP agent instead of simply raising the insulin dose again. It doesn't replace insulin; it's an add-on studied specifically alongside it.
If you're on both tirzepatide and insulin now — the trial is also a reminder that insulin needs usually go down as tirzepatide's effect kicks in, which is exactly why glargine doses stayed titrated (not fixed) throughout the study. Dose adjustments should always be managed by your prescriber, not self-directed.
The main tradeoff worth weighing going in: gastrointestinal side effects were common enough to push some patients off higher doses. That's consistent with every other tirzepatide trial in this series — worth discussing upfront rather than discovering mid-titration.
This article summarizes a published clinical trial for general education. It is not medical advice and does not replace guidance from your prescriber. Insulin and tirzepatide dosing should only be adjusted under medical supervision.