Introduction

Glucagon-like peptide‑1 (GLP‑1) receptor agonists effectively treat type 2 diabetes by enhancing glucose‑dependent insulin secretion, reducing glucagon, slowing gastric emptying, decreasing appetite, and promoting weight loss. Glucose‑dependent insulinotropic polypeptide (GIP) complements GLP‑1 by improving insulin sensitivity in adipose tissue and influencing glucagon depending on glucose levels. Dual GIP/GLP‑1 agonism may enhance glucose control and weight loss. Tirzepatide, a once‑weekly dual agonist, has shown dose‑dependent reductions in HbA1c and weight. Semaglutide, a GLP‑1 agonist, also significantly lowers HbA1c and weight.

Aim

To compare the efficacy and safety of once‑weekly tirzepatide (5 mg, 10 mg, and 15 mg) with semaglutide 1 mg in adults with type 2 diabetes whose blood glucose levels remained inadequately controlled despite metformin monotherapy.

Patient Profile

• Adults aged >18 years with a diagnosis of type 2 diabetes inadequately controlled with at least 1500 mg of metformin daily
• Had a glycated hemoglobin (HbA1c) level between 7.0% and 10.5%, a body‑mass index (BMI) of 25 or higher, and stable body weight (within ±5%) over the preceding three months

Method

Study Design

Treatment Strategy

• Patients were randomly assigned to once‑weekly tirzepatide (5, 10, or 15 mg; double‑blinded) or semaglutide 1 mg for 40 weeks, followed by 4 weeks of safety follow‑up
• Tirzepatide started at 2.5 mg and semaglutide at 0.25 mg, with scheduled dose escalation to target doses

Endpoints

Primary Endpoint

Secondary Endpoints

• Proportion of patients achieving HbA1c <7.0%, <6.5% and <5.7%
• Change from baseline in fasting serum glucose (FSG) at week 40
• Change in body weight from baseline at week 40
• Proportion of patients achieving weight loss of 5%, 10% or 15%

Safety Endpoints

• Adverse events (AEs)
• AE-related discontinuation

Results

Figure 1. Mean reductions in HbA1c at week 40  (Efficacy estimand)

• Tirzepatide at all doses was noninferior and superior to semaglutide
• The proportion of patients achieving targets of HbA1c was higher in tirzepatide groups; HbA1c <7.0% (85%, 89%, 92% vs 81%), HbA1c <6.5% (74%, 82%, 87% vs 66%) and HbA1c <5.7% (29%, 45%, 51% vs 20%) in tirzepatide 5mg, 10 mg, 15 mg and semaglutide 1mg groups respectively 
• At 40 weeks, greater reductions in FSG were seen with all tirzepatide groups as seen in Figure 2.

Figure 2. Change from baseline in FSG at 40 weeks (Efficacy estimand)

• Tirzepatide resulted in greater reductions in body weights compared to semaglutide as seen in Figure 3.
• Reductions from baseline in the mean daily 2‑hour post‑prandial glucose levels from the seven‑point blood glucose profile were −71.6 mg/dL, −78.2 mg/dL, −81.9 mg/dL, and −67.2 mg/dL for tirzepatide 5 mg, 10 mg, 15 mg, and semaglutide 1 mg, respectively

Figure 3. Change from baseline in body weight at 40 weeks (Efficacy estimand)

• The proportion of participants achieving weight loss targets were more in tirzepatide groups; >5% weight loss (69%, 82%, 86% vs 58%), >10% weight loss (36%, 53%, 65% vs 25%) and >15% weight loss (15%, 28%, 40% vs 9%) in tirzepatide 5 mg, 10 mg, 15 mg and semaglutide 1 mg groups respectively
• The rate of patients with ≥1 AEs was similar across the groups; 63.6% in tirzepatide 5 mg, 68.7% in tirzepatide 10 mg, 68.9% in tirzepatide 15 mg and 64.2% in semaglutide groups
• Adverse reactions occurred during dose escalation and decreased over time
• Most AEs were gastrointestinal and were mostly mild to moderate
• Table 1 shows the percentage of patients with AEs

Table 1. AEs occurring in ≥5% patients

AEs	Tirzepatide 5 mg	Tirzepatide 10 mg	Tirzepatide 15 mg	Semaglutide 1 mg
Nausea	17%	19%	22%	18%
Diarrhoea	13%	16%	14%	12%
Vomiting	6%	9%	10%	8%
Dyspepsia	7%	6%	9%	7%
Decreased appetite	7%	7%	9%	5%
Constipation	7%	5%	5%	6%
Abdominal pain	3%	5%	5%	5%
Hypoglycemia (blood glucose level <54 mg/dL)	0.6%	0.2%	1.7%	0.4%

Figure 4. Safety outcomes

Conclusion

N Engl J Med. 2021 Aug 5;385(6):503-515. Doi: 10.1056/NEJMoa2107519.