# Tirzepatide Research: SURPASS, SURMOUNT, and Islet-Function Trials

> Tirzepatide research: the SURPASS T2D programme, SURMOUNT obesity trials, Heise 2022 clamp study, head-to-head vs semaglutide, and the 2024–2025 islet-sensitivity data.

## TL;DR

Tirzepatide research spans phase 1 through phase 3 trials enrolling tens of thousands of participants, plus dedicated studies measuring what happens inside pancreatic beta cells — the insulin-producing cells — when both incretin receptors are activated simultaneously. The short version: on blood sugar, tirzepatide outperforms every other incretin drug tested in large trials. On body weight, it produces the largest reductions measured in any phase 3 obesity trial to date. On pancreatic function, a clamp study showed it improves both insulin secretion and insulin sensitivity measurably more than the leading comparator. This page summarises the primary trial record.

## Discovery and phase 1: dual receptor engagement confirmed

Coskun et al. (2018) reported the discovery and proof-of-concept data for LY3298176 (tirzepatide) [1]. Key results:
- Activated both GIP and GLP-1 receptor signalling in vitro.
- Chronic administration to mice produced greater body-weight and food-intake reduction than a selective GLP-1 receptor agonist.
- Phase 1 programme (142 subjects — healthy volunteers and type 2 diabetes patients): once-weekly dosing supported by pharmacokinetics; reduced fasting glucose and body weight versus placebo.

Willard et al. (2020) characterised the receptor pharmacology [2]: tirzepatide is an imbalanced dual agonist (favours GIPR over GLP-1R) and shows biased GLP-1R signalling (cAMP > beta-arrestin). This biased agonism is proposed to sustain insulin secretion by reducing receptor desensitisation.

## SURPASS programme — glycaemic efficacy in T2D

SURPASS-2 (Frias et al., 2021) — the head-to-head glycaemic superiority trial [3]:
- Design: open-label, 40-week, phase 3 RCT, n=1,879 adults with type 2 diabetes.
- Doses: tirzepatide 5/10/15 mg once weekly versus active comparator 1 mg once weekly.
- HbA1c reduction: -2.01/-2.24/-2.30 pp (tirzepatide) vs -1.86 pp (comparator). Non-inferior and superior at all three doses.
- Weight: -7.6/-9.3/-11.2 kg (tirzepatide) vs -5.7 kg (comparator); treatment differences -1.9, -3.6, -5.5 kg.
- Most common adverse events: gastrointestinal, mostly mild to moderate.

**Tirzepatide vs semaglutide** was directly tested in SURPASS-2. Tirzepatide at all three doses produced superior HbA1c reduction. The 15 mg dose produced an additional -5.5 kg body-weight reduction compared with the 1 mg comparator dose — a large, clinically meaningful difference [3].

In a network meta-analysis of 38 phase 3/4 placebo-controlled RCTs (Kang et al., 2025; 16,660 T2DM participants, 104 arms), tirzepatide 15 mg produced the largest HbA1c reduction of all agents analysed (-1.79%). GI adverse-event odds ratios were similar across compounds regardless of efficacy level [11].

## SURMOUNT programme — weight management

SURMOUNT-1 (Jastreboff et al., 2022) — the landmark obesity trial [4]:
- Design: double-blind, phase 3 RCT, n=2,539 adults with obesity (BMI ≥30) or overweight (BMI ≥27 with a weight-related complication) without diabetes. 72 weeks.
- **Tirzepatide weight loss:** mean weight change -15.0% (5 mg), -19.5% (10 mg), **-20.9% (15 mg)** versus -3.1% placebo.
- Dose escalation: 20-week stepwise titration starting at 2.5 mg.
- GI adverse events mostly mild to moderate, most frequent during escalation.

**Tirzepatide weight loss** — the SURMOUNT-5 head-to-head comparison [5]:
- Design: open-label, phase 3b RCT, n=751 adults with obesity, no diabetes. 72 weeks. Tirzepatide maximum tolerated dose (10 or 15 mg) vs comparator maximum tolerated dose (1.7 or 2.4 mg).
- Result: -20.2% (tirzepatide) vs -13.7% (comparator), P<0.001.
- Greater reductions in waist circumference; higher proportions reaching ≥10/15/20/25% weight loss with tirzepatide.

## Islet function and insulin sensitivity: the clamp data

**Heise et al. (2022)** — phase 1 clamp RCT, n=117, 28 weeks [8]:
This is the strongest evidence for the beta-cell-insulin-sensitivity lens. Primary endpoint: clamp disposition index (CDI) — the product of insulin secretion rate and insulin sensitivity (M-value from hyperinsulinaemic-euglycaemic clamp).
- CDI ETD vs placebo: **+1.92** (95% CI 1.59–2.24; P<0.0001).
- CDI ETD vs comparator: **+0.84** (95% CI 0.46–1.21).
- Insulin sensitivity (M-value ETD vs comparator): **+1.52 mg/min/kg**.
- Insulin secretion rate ETD: **+102.09 pmol/min/m²**.
- Glucagon AUC reduced on meal testing.

**Mather et al. (2024)** — meal-test model, 28-week RCT [9]:
Greater reduction in fasting glucose and total glucose AUC vs comparator (P<0.01). Greater glucagon AUC suppression (P<0.01). Higher ISR at 7.2 mmol/L (beta-cell glucose sensitivity, P<0.05).

**Thomas et al. (2020)** — mechanistic substudy [10]:
Improved markers of beta-cell function and insulin sensitivity in people with type 2 diabetes on tirzepatide up to 15 mg.

**Yamaguchi et al. (2025)** — prospective Japanese clamp, n=16:
Glucose infusion rate rose from 3.21 to 5.16 mg/min/kg (P<0.001). HbA1c fell from 7.95% to 6.14%; weight fell 4.9 kg. No significant correlation found between the insulin-sensitivity gain and other measured variables, suggesting an early direct sensitising effect.

**Mather et al. (2025) — exploratory weight-normalised analysis:**
The correlation of insulin-sensitivity improvement with weight change was stronger for tirzepatide (R=-0.656) than for comparator (R=-0.268; P=0.0242 for between-drug difference). Regression slope of M-value change vs weight change differed between drugs (P=0.0461). The tirzepatide benefit on insulin sensitivity exceeds what weight loss alone predicts [9].

## Beyond-glycaemia trials (2024–2025)

**SUMMIT CMR substudy** — HFpEF (Kramer et al., 2025) [C3]:
In obesity-related heart failure with preserved ejection fraction, tirzepatide reduced LV mass by 11 g (95% CI -19 to -4 g; P=0.004) and paracardiac adipose tissue by 45 mL (95% CI -69 to -22 mL; P<0.001) versus placebo in 106 participants with paired CMR imaging. LV-mass change correlated with body-weight change (P<0.02).

**Gastrointestinal safety meta-analysis** (Safwan et al., 2025) — 13 RCTs, 26,894 obese participants without diabetes [13]:
Overall GI adverse event risk was elevated (RR 2.94 for tirzepatide vs 1.68 for semaglutide vs placebo), without a significant biliary or pancreatic signal for tirzepatide in this obesity population.

**Tirzepatide vs semaglutide** across programmes now includes the SURMOUNT-5 head-to-head weight comparison (-20.2% vs -13.7%) [5] and the SURPASS-2 glycaemic comparison (-2.30% vs -1.86% HbA1c) [3] — the most direct comparative data available.

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Trial figures read from primary sources. Not a clinic, not a dispenser, not a recommendation.