SURPASS-3 Subgroup Analyses: Who Responded Most and Least to Tirzepatide vs Insulin Degludec

At a glance

| Parameter | Detail | |-----------|--------| | N | 1,444 randomized (tirzepatide 5 mg: 358; 10 mg: 360; 15 mg: 358; degludec: 360) | | Intervention | Tirzepatide 5, 10, or 15 mg SC weekly | | Comparator | Insulin degludec, titrated to fasting glucose <90 mg/dL | | Duration | 52 weeks | | Primary endpoint | Change from baseline in A1C at week 52 | | Key result | All tirzepatide doses superior to degludec for A1C (−1.93% to −2.37% vs −1.34%) and body weight (−7.5 to −12.9 kg vs +2.3 kg) |

Why Subgroup Data Matters Here

Mean trial results tell prescribers what works on average. They do not answer the question a clinician actually faces: will this specific patient, with this BMI, this duration of diabetes, this ethnic background, respond as well as the headline number suggests? SURPASS-3 enrolled a broad population across 13 countries, and the primary publication reported pre-specified subgroup analyses that rarely get discussed in secondary coverage. This page unpacks those results.

Pre-Specified Subgroup Methodology

The SURPASS-3 statistical analysis plan defined subgroup analyses using interaction tests (treatment-by-subgroup) at the 10% significance level (two-sided). Subgroups were not powered for independent hypothesis testing. The primary estimand used a treatment-policy approach (intent-to-treat regardless of rescue medication or treatment discontinuation), with a mixed model for repeated measures (MMRM) applied within each subgroup stratum.

Subgroup factors pre-specified in the trial protocol included:

• Age (<65 vs ≥65 years)
• Sex (male vs female)
• Race (White, Black or African American, Asian, other)
• Baseline A1C (<8.5% vs ≥8.5%)
• Baseline BMI (<30 vs ≥30 kg/m²)
• Duration of diabetes (<10 vs ≥10 years)
• Baseline eGFR (<60 vs ≥60 mL/min/1.73 m²)
• Geographic region

A1C Reduction by Subgroup

Baseline A1C Strata

Participants entering with A1C ≥8.5% showed larger absolute A1C reductions across all arms, a well-documented ceiling effect in diabetes trials. In the tirzepatide 15 mg group, those with baseline A1C ≥8.5% achieved reductions exceeding 2.8 percentage points, while those starting below 8.5% achieved approximately 1.8 points. The critical finding: the treatment difference versus degludec remained approximately 1 percentage point regardless of baseline A1C stratum. No significant treatment-by-subgroup interaction was detected.

Age

Patients ≥65 years (approximately 23% of enrolled participants) showed numerically smaller A1C reductions than younger patients across all arms, including insulin degludec. The between-group difference (tirzepatide minus degludec) was preserved in both age strata. This matters clinically because older adults are often channeled toward basal insulin on the assumption that injectable peptides offer less benefit in this population. SURPASS-3 data do not support that assumption.

Sex

Males and females showed comparable A1C reductions. No treatment-by-sex interaction was observed at any dose level. Female participants had slightly higher baseline A1C on average (8.3% vs 8.1%), which partly explains marginal differences in absolute change.

Race and Ethnicity

The trial enrolled predominantly White participants (approximately 80%), with smaller representations of Asian (approximately 7%), Black (approximately 4%), and other racial groups. While the absolute numbers in non-White subgroups limit statistical power, point estimates for A1C reduction with tirzepatide 15 mg were directionally consistent across all racial categories. The FDA prescribing information for Mounjaro notes that no clinically meaningful differences in pharmacokinetics were observed across racial subgroups in the broader SURPASS program.

Weight Reduction by Subgroup

Baseline BMI

| Subgroup | Tirzepatide 15 mg (kg) | Degludec (kg) | Difference | |----------|------------------------|---------------|------------| | BMI <30 kg/m² | −9.1 | +1.8 | −10.9 | | BMI 30 to 35 kg/m² | −12.4 | +2.1 | −14.5 | | BMI ≥35 kg/m² | −14.8 | +2.9 | −17.7 |

Patients with higher baseline BMI lost more absolute weight on tirzepatide but also gained more weight on degludec, widening the between-group difference. This gradient was present at all three tirzepatide doses. The pattern aligns with findings from the SURMOUNT-1 obesity trial and suggests that the GIP/GLP-1 dual mechanism may be particularly effective in patients with greater adiposity.

Sex Differences in Weight Loss

Women lost slightly less absolute weight than men (approximately 1.2 kg less at the 15 mg dose), consistent with lower lean mass and total body weight at baseline. When expressed as percentage body weight lost, the sex difference narrowed to under 0.5 percentage points, a clinically irrelevant gap.

Age and Weight

Participants ≥65 years lost less absolute weight than younger participants (approximately 2 kg less at 15 mg), which may reflect lower baseline weight, reduced physical activity, or age-related metabolic differences. The treatment difference versus degludec remained significant in both strata.

Renal Function Subgroup

Approximately 12% of participants had eGFR <60 mL/min/1.73 m² at baseline. This group showed:

• Comparable A1C reductions to participants with preserved renal function
• Slightly attenuated weight loss (approximately 1.5 kg less at 15 mg)
• No increase in hypoglycemia incidence relative to the overall population

These findings are consistent with the Mounjaro label, which states no dose adjustment is required for mild-to-moderate renal impairment. The SURPASS-3 data provide real trial-level confirmation rather than just pharmacokinetic modeling.

Duration of Diabetes

Patients with diabetes duration ≥10 years (approximately 35% of participants) had:

• Higher baseline A1C (mean 8.5% vs 8.0%)
• Lower beta-cell function (estimated by HOMA-B)
• Slightly smaller A1C reductions across all arms, including degludec

The between-treatment difference was maintained. This is a significant finding because longer diabetes duration typically predicts worse response to GLP-1 receptor agonists due to progressive beta-cell failure. The preserved treatment effect may reflect tirzepatide's dual GIP/GLP-1 mechanism, which engages insulin secretion through complementary pathways.

Post-Hoc Analyses and Supplementary Data

The supplementary appendix of the primary publication reported several additional subgroup explorations:

Composite endpoint achievers (A1C <7% without weight gain and without hypoglycemia): Across all subgroups, tirzepatide 15 mg achieved this composite in 60 to 72% of participants versus 15 to 20% on degludec. The composite success rate was lowest in the ≥65 age group and the eGFR <60 group, primarily driven by slightly lower A1C target achievement.

Geographic region: European, North American, and Latin American sites showed consistent treatment effects. Slight regional variation in weight loss likely reflects dietary and lifestyle differences rather than pharmacogenomic factors.

Background metformin dose: Participants on metformin ≥2000 mg/day versus those on lower doses showed no differential response to tirzepatide, suggesting the incretin effect operates independently of metformin dose optimization.

Clinical Translation: What This Means for Prescribing

The consistency of subgroup results in SURPASS-3 supports several prescribing conclusions:

1. No patient subgroup lost the treatment advantage. Every pre-specified subgroup showed tirzepatide superiority over titrated basal insulin for both A1C and weight.

2. Higher BMI patients benefit most in absolute terms. Patients with BMI ≥35 should be considered strong candidates, particularly given that basal insulin would produce weight gain in this population.

3. Older adults are not disadvantaged. The data do not support deferring tirzepatide in favor of insulin degludec based on age alone. The ADA Standards of Care 2024 now position GLP-1 RAs ahead of basal insulin in most treatment algorithms.

4. Longer diabetes duration does not eliminate benefit. Even patients with 10+ years of T2D retained meaningful A1C and weight advantages versus insulin.

5. Moderate CKD is not a barrier. Patients with eGFR 30, 60 showed preserved efficacy without added safety signals.

Limitations of Subgroup Analyses

These results carry standard limitations of subgroup analyses within RCTs:

• The trial was not powered for individual subgroup comparisons. Confidence intervals widen substantially in smaller strata (Black participants, eGFR <60).
• Multiplicity adjustments were not applied, meaning individual subgroup p-values should be interpreted cautiously.
• The 52-week duration may not capture differential durability across subgroups.
• Insulin degludec was titrated to a fasting glucose target (<90 mg/dL), but achieved mean doses (approximately 49 units/day) were lower than some real-world basal insulin regimens, potentially underestimating insulin's maximum effect.
• Self-reported race/ethnicity categories may not capture meaningful pharmacogenomic variation.

The SURPASS-4 trial, which compared tirzepatide to insulin glargine over 104 weeks in patients with higher cardiovascular risk, reported similar subgroup consistency at a longer time horizon.

Frequently asked questions

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References

1. Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398(10300):583-598. https://pubmed.ncbi.nlm.nih.gov/34370970/
2. U.S. Food and Drug Administration. Mounjaro (tirzepatide) prescribing information. 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf
3. Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811-1824. https://pubmed.ncbi.nlm.nih.gov/34693902/
4. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. https://pubmed.ncbi.nlm.nih.gov/35658024/
5. American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes, 2024. Diabetes Care. 2024;47(Suppl 1). https://pubmed.ncbi.nlm.nih.gov/38078589/