By Tim Drake, PharmD, MBA, BCPS

Assistant Professor of Pharmacy, College of Pharmacy, Roseman University of Health Sciences, South Jordan, UT

SYNOPSIS: In the SURPASS-2 trial, tirzepatide showed noninferiority and superiority vs. semaglutide in decreasing A1c levels in patients with type 2 diabetes.

SOURCE: Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021;385:503-515.

Metformin continues to be the drug of choice to treat patients with type 2 diabetes.1 Glucagon-like peptide 1 (GLP-1) agonists quickly gained favor and now are recommended second line after metformin because of their ability to cause weight loss, lower cardiovascular risk, and their low risk of causing hypoglycemia.2 Other agents to treat type 2 diabetes include sodium-glucose cotransporter-2 inhibitors, sulfonylureas, thiazolidinediones, and insulin.1 Important characteristics to consider when choosing a drug to treat diabetes include effectiveness at lowering blood sugar, cardiovascular and renal effects, weight loss or weight gain, and risk of hypoglycemia.3

Tirzepatide is a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 that is injected once weekly. GLP-1 agents work by stimulating insulin secretion in hyperglycemic states and reducing appetite by delaying gastric emptying. GIP works by stimulating insulin in hyperglycemic states and stimulating glucagon in hypoglycemic conditions.4 In theory, an agent that enhances both pathways should offer a better glucose-lowering benefit.

The authors of the SURPASS-2 trial compared the glucose-lowering effect of various doses of tirzepatide to semaglutide. This was an unblinded, parallel-group, randomized, active-controlled trial. Adult patients who had not achieved a glycosylated hemoglobin (A1c) level < 7% on metformin alone were randomly assigned to inject tirzepatide 5 mg, 10 mg, 15 mg, or semaglutide 1 mg on a weekly basis for 40 weeks. The primary endpoint was the change in A1c. Secondary endpoints included body weight change and achieving an A1c level < 7% and < 5.7%.

The authors included 1,878 patients in the results. Baseline characteristics were similar among the four groups. The starting mean A1c was 8.28% and the average weight was 93.7 kg. At the end of the study, the 5 mg tirzepatide group lowered A1c by 2.01%, the 10 mg group by 2.24%, and the 15 mg group by 2.30%. The A1c was lowered by 1.86% in the semaglutide group. The tirzepatide was superior to semaglutide for A1c-lowering for all three groups (P = 0.02 for 5 mg, P < 0.001 for 10 mg and 15 mg).

Tirzepatide was superior to semaglutide for weight loss, with mean body weight reductions for 5 mg, 10 mg, and 15 mg tirzepatide groups of 7.6 kg, 9.3 kg, and 11.2 kg, respectively. The semaglutide group lost an average of 5.7 kg (P < 0.001 for all groups).

A total of 82% of patients in the 5 mg group met the < 7% target vs. 86% in the 10 mg and 15 mg groups and 79% in the semaglutide group. The 5 mg group was noninferior, and the 10 mg and 15 mg groups were superior to semaglutide treatment (P < 0.05). Twenty-seven percent of patients in the 5 mg group met the < 5.7% target vs. 40% in the 10 mg and 46% in the 15 mg group and 19% in the semaglutide group. The 5 mg group was noninferior, and the 10 mg and 15 mg groups were superior to semaglutide (P < 0.001).

The most common adverse event in all groups was gastrointestinal (17% to 22%). Most cases were mild to moderate and occurred during the dose escalation phase of the study. Clinically significant hypoglycemia was low, with three, one, and eight patients in the 5 mg, 10 mg, and 15 mg groups, respectively, compared with two patients in the semaglutide group. There was one case of severe hypoglycemia in the 5 mg group and one case in the 15 mg group. There were two cases of pancreatitis in the tirzepatide group and three cases in the semaglutide group. Overall, the discontinuation rate for tirzepatide was 8.5% vs. 4.1% for semaglutide.


A different group of researchers recently published the results of the SURPASS-3 trial. This investigation was set up similar to SURPASS-2, except the control group injected the basal insulin degludec instead of semaglutide. The results of SURPASS-3 showed similar results of blood glucose-lowering and weight loss as SURPASS-2.

The authors concluded tirzepatide was superior to insulin degludec for A1c-lowering and weight loss and caused minimal hypoglycemia.5

The dual GIP/GLP1 agonist tirzepatide showed impressive results in lowering A1c levels and promoting weight loss in patients with type 2 diabetes who were taking metformin. The dual mechanism could help alleviate the medication burden while delaying the need for insulin. Of note, 46% of patients who took the higher 15 mg dose reached near-normal levels of glycemia with a low risk of hypoglycemia.

It is somewhat expected that a medication with a dual mechanism of action would outperform another with just one mechanism. Additionally, A1c and weight loss do not tell the whole story of an antidiabetic agent. Outcomes showing a reduction in mortality, cardiovascular, renal, and other macro- and microvascular events will help determine if tirzepatide will become an attractive therapy for diabetes.


  1. Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018: A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020;63:221-228.
  2. Müller TD, Finan B, Bloom SR, et al. Glucagon-like peptide 1 (GLP-1). Mol Metab 2019;30:72-130.
  3. [No authors listed]. Introduction: Standards of medical care in diabetes — 2021. Diabetes Care 2021;44:S1-S2.
  4. Christensen M, Vedtofte L, Holst JJ, et al. Glucose-dependent insulinotropic polypeptide: A bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes 2011;60:3103-3109.
  5. 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;398:583-598.