The many clinical trials of semaglutide

11th October 2025, A/Prof Chee L Khoo

Injectable semaglutide

Weekly semaglutide injectable has been around for some years now. Even with my special interest in diabetes and obesity, I am getting confused with all the clinical trials involving semaglutide in patients with obesity with or without diabetes. They all have very innovative acronyms most of them starting with “S” which makes them hard to keep track of. I thought it’s probably time to have a summary of what clinical trials involving weekly semaglutide injections that have been published thus far.

All the extra non-glucose benefits from the SGLT2 inhibitors and GLP1/GIP were discovered when the regulatory authorities mandated that in treating hyperglycaemia, the glucose lowering agents do not cause harm. Specifically, cardiovascular harms. For the GLP1-RA class, exenatide demonstrated safety but there were no CV benefits (1). With semaglutide, it was the SUSTAIN series of trials that demonstrated cardiovascular safety (and benefits).

SUSTAIN series

  • SUSTAIN 1: Focused on drug-naïve patients, showing significant reductions in HbA1c and body weight compared to placebo.
  • SUSTAIN 2: Compared semaglutide to sitagliptin, revealing greater HbA1c reductions and weight loss with semaglutide.
  • SUSTAIN 3: Compared semaglutide to exenatide, with semaglutide showing superior efficacy in lowering HbA1c and body weight.
  • SUSTAIN 4: Evaluated semaglutide against insulin, demonstrating non-inferiority and better HbA1c reductions.
  • SUSTAIN 6: Focused on cardiovascular outcomes, showing a significant reduction in major adverse cardiovascular events (MACE) among patients treated with semaglutide (2).
  • SUSTAIN 7: Compared semaglutide to dulaglutide, with semaglutide providing better glycemic control and weight loss.
  • SUSTAIN 8: Compared semaglutide to canagliflozin, showing superior HbA1c reductions and weight loss.

Now, most of the trials in the SUSTAIN series were to compare semaglutide with various other glucose lowering agents – exenatide, sitagliptin, insulin, dulaglutide and canaglifloxin in HbA1c efficacy. Except for SUSTAIN 6 which was to look at cardiovascular outcomes. Indeed, SUSTAIN 6 showed that semaglutide 1mg significantly reduced composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. That was the beginning of the chase for cardiovascular benefits.

There are more than just the 8 SUSTAIN trials:

  • SUSTAIN 9 (semaglutide plus SGLT-2 inhibitor vs placebo) – better glycaemic control and better weight loss
  • SUSTAIN 10 (semaglutide vs liraglutide) – better glycaemic control and better weight loss
  • SUSTAIN 11 (adding semaglutide to basal insulin vs adding prandial insulin) – better glycaemic control and better weight loss
  • SUSTAIN FORTE (semaglutide 2.0mg vs semaglutide 1.0mg) – better glycaemic control and better weight loss
  • SUSTAIN – CHINA MRCT (similar to SUSTAIN 2 – semaglutide vs sitagliptin in Asian (but not Japanes) participants) – better glycaemic control and better weight loss as in SUSTAIN 2
  • SUSTAIN (Japan) (Semaglutide vs any other glucose lowering agents) – better glycaemic control and better weight loss
  • SUSTAIN (Japan, sitagliptin) (semaglutide vs sitagliptin in Japanese participants)

The (next) STEP

Of course, we now know that semaglutide is more efficacious than sitagliptin and can replace prandial insulin with additional bonus of modest weight loss. Well, since 1.0 mg semaglutide was very efficacious in weight reduction, what about higher dose of semaglutide? That was the basis of the Semaglutide Treatment Effect in People with obesity (STEP) program. Once again there were a series of 9 STEP trials all exploring the efficacy of semaglutide 2.4mg in participants who were obese.

  • STEP 1 was 68 weeks of semaglutide 2.4 mg vs placebo
  • STEP 2 was 68 weeks of semaglutide 2.4 mg vs placebo vs semaglutide 1mg in participants with obesity and T2D
  • STEP 3 was 68 weeks of semaglutide 2.4 mg plus intensive behavioural therapy (IBT) vs placebo
  • STEP 4 was semaglutide 2.4mg for 20 weeks then randomised to ongoing semaglutide vs ongoing placebo (3)
  • STEP 5 was 104 weeks of semaglutide 2.4mg vs placebo
  • STEP 6 was semaglutide 2.4mg vs 1.7mg vs placebo in east Asians
  • STEP 8 was semaglutide 2.4mg vs liraglutide 3.0mg vs placebo
  • STEP Teens was semaglutide 2.4mg vs placebo in adolescents

Apart from STEP 3 which has intensive behavioural therapy (IBT), all participants in the other STEP trials had standard lifestyle intervention. The weight loss achieved overall ranged from 9.6% to 17.4% loss in the semaglutide 2.4mg group. Interestingly, in STEP 2 and 6 which include participants with T2D, the average weight loss was less than the other STEP trials (9.6%and 13.2% respectively). In the STEP 3 trials, the addition of IBT, the weight loss was higher at 16%. Further, expectedly so, in the STEP 4 trials, the weight loss was about 11kg at the 20 week mark and if semaglutide was continued, there was a further 6kg loss to week 68 while there was a 6kg regain in the group that stopped the semaglutide after 20 weeks.

The cardiovascular outcome trials series

The next stage of the clinical trials was to explore the other non-glycaemic benefits of semaglutide. The SELECT trial which explore the effect of semaglutide on cardiovascular events in overweight or obese patients with established cardiovascular disease but without diabetes (4). After a mean follow up of 39 months, semaglutide 2.4mg led to a 20% reduction in the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The SELECT trial was followed by the STEP-HFpEF and STEP HFpEF DM in patients with HFpEF with or without T2D.

The SUSTAIN 6 and SELECT trials demonstrated significant cardiovascular benefits in patients with established cardiovascular disease. It was only natural for Novonordisk to explore the other benefits of semaglutide:

STEP-HFpEF – Semaglutide in patients with obesity and HFpEF but without diabetes (7)

  • In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo.

STEP-HFpEF DM – Semaglutide in patients with obesity and HFpEF but with diabetes (8)

  • Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure related symptoms and physical limitations and greater weight loss than placebo at 1 year.

ESSENCE – Semaglutide in patients with biopsy-defined MASH and fibrosis stage 2 or 3 (9)

  • In patients with MASH and moderate or advanced liver fibrosis, once-weekly semaglutide at a dose of 2.4 mg improved liver histologic results. A reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% of the patients in the semaglutide group and in 22.4% of those in the placebo group (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001).

FLOW  in patients with CKD (10)

  • In patients with T2D and chronic kidney disease (defined by eGFR of 50 to 75 ml/min/1.73 m2 and a uACR  of >30 and <500 or an eGFR of 25 to <50 ml/min/1.73 m2 and a uACR of >10 and <500), semaglutide 2.4mg led to a 24% reduction in composite renal outcomes or death from renal or cardiovascular causes. Semaglutide also decrease the slope of eGFR decline compared with placebo.

STEP UP trials

If semaglutide 2.4mg was efficacious, is more better?Just published a few months ago were the STEP UP trials (STEP UP and STEP UP T2D) where semaglutidedosage was stepped up to 7.2mg and compared with semaglutide 2.4mg and placebo in patient without T2D and with T2D. In the STEP UP trial, patients in the semaglutide 7.2 mg cohort experienced weight loss of 20.7% after 72 weeks, compared to 17.5% in the semaglutide 2.4 mg cohort and 2.4% in the placebo cohort (5). The STEP UP T2D trial demonstrated that semaglutide also led to weight loss in patients with T2D but the effect appears to be less than participants without T2D in the STEP UP trial (6). Compared with placebo, semaglutide 7·2 mg led to reductions in mean bodyweight −13·2%.

We have been talking about semaglutide weekly injections in its various doses. We have not talked about the oral version of semaglutide. We covered oral semaglutide 2 months ago at GPVoice here. Essentially, high dose (50mg) oral semaglutide can result in up to 15.1% weight loss. To top up the data. the SOUL trial (Semaglutide cardiOvascular oUtcomes trial) reported a 14% reduction in cardiovascular events with semaglutide (11).

In summary, semaglutide (oral or injectable) is efficacious in glucose control, weight reduction in patients who are overweight or obese with or without T2D. Increasing the dose of weekly semaglutide from 2.4mg to 7.2mg resulted in higher weight loss. In addition, semaglutide also have cardiovascular, renal and hepatic benefits.

References

  1. Holman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2017 Sep 28;377(13):1228-1239.
  2. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Nov 10;375(19):1834-1844.
  3. Rubino D, Abrahamsson N, Davies M, et al; STEP 4 Investigators. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021 Apr 13;325(14):1414-1425.
  4. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al; SELECT Trial Investigators. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med. 2023 Dec 14;389(24):2221-2232.
  5. Wharton S, Freitas P, Hjelmesæth J et al; STEP UP trial group. Once-weekly semaglutide 7·2 mg in adults with obesity (STEP UP): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025 Sep 14:S2213-8587(25)00226-8.
  6. Lingvay I, Bergenheim SJ, Buse JB, Freitas P, Garvey WT, Harder-Lauridsen NM, Rosenstock J, Sahu K, Wharton S; STEP UP T2D trial group. Once-weekly semaglutide 7·2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial. Lancet Diabetes Endocrinol. 2025 Sep 14:S2213-8587(25)00225-6.
  7. Kosiborod MN, Abildstrøm SZ, Borlaug Baet al; STEP-HFpEF Trial Committees and Investigators. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2023 Sep 21;389(12):1069-1084.
  8. Kosiborod MN, Petrie MC, Borlaug BA, et al; STEP-HFpEF DM Trial Committees and Investigators. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N Engl J Med. 2024 Apr 18;390(15):1394-1407.
  9. Sanyal AJ, Newsome PN, Kliers I, et al; ESSENCE Study Group. Phase 3 Trial of Semaglutide in Metabolic Dysfunction-Associated Steatohepatitis. N Engl J Med. 2025 Jun 5;392(21):2089-2099.
  10. Perkovic V, Tuttle KR, Rossing P, Mahaffey KW, Mann JFE, Bakris G, Baeres FMM, Idorn T, Bosch-Traberg H, Lausvig NL, Pratley R; FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients with Type 2 Diabetes. N Engl J Med. 2024 Jul 11;391(2):109-121.
  11. McGuire DK, Marx N, Mulvagh SL, et al; SOUL Study Group. Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes. N Engl J Med. 2025 May 29;392(20):2001-2012. doi: 10.1056/NEJMoa2501006. Epub 2025 Mar 29. PMID: 40162642.