SURPASS data: ‘Impressive’ tirzepatide could change goals for diabetes treatment
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Data from the SURPASS clinical trial program suggest the dual incretin agonist tirzepatide could be a game-changing new therapy for adults with type 2 diabetes, many of whom experienced substantial weight loss and achieved normoglycemia.
Tirzepatide (Eli Lilly), an investigational glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, was shown across multiple SURPASS studies to lead to marked improvements in glycemic response and significant reductions in body weight, with no increased risk for hypoglycemia and an adverse event profile similar to other agents in the GLP-1 class.
“At first glance, this is very impressive data,” Daniel J. Drucker, MD, senior scientist at the Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital and professor of medicine at the University of Toronto, said during the SURPASS symposium at the American Diabetes Association Scientific Sessions. “This is among the most impressive phase 3 clinical trial data we have seen as a community for the treatment of type 2 diabetes. In fact, when one sees the data for the number of people getting to [HbA1c] goal — whether it is 7% or even lower than 6% — it is quite remarkable. A substantial proportion of people are having their glucose control normalized on this therapy.”
More exciting, Drucker said, was the degree of weight loss observed across all tirzepatide doses in each of the SURPASS studies.
“This is something we have not appreciated before,” Francesco Giorgino, MD, PhD, of the University of Bari Aldo Moro in Bari, Italy, said during the presentation. “These data have brought attention to this very ambitious target in a way that was never considered earlier. This could be the premise for trying to rethink the goals we should pursue in a person with type 2 diabetes. The consequences in the midterm or longer term of keeping a person at an HbA1c of less than 5.7% might be quite significant.”
Overview of trials
For the first phase 3 trial in the program, SURPASS-1, researchers analyzed data from 478 adults with type 2 diabetes naive to injectable diabetes medications and a BMI of at least 23 kg/m² (mean age, 54 years; 48.3% women; mean diabetes duration, 4.7 years; mean HbA1c, 7.94%; mean BMI, 31.9 kg/m²). Researchers assigned participants tirzepatide 5 mg (n = 121), 10 mg (n = 121), 15 mg (n = 121) or placebo (n = 115) for 40 weeks. Primary outcome was change in HbA1c from baseline to 40 weeks.
In the treatment-regimen estimand, mean HbA1c reductions across the three doses were –1.75% (5 mg), –1.71% (10 mg) and –1.69% (15 mg), compared with 0.09% in the placebo arm. Mean body weight reductions across the three doses were –6.3 kg (5 mg), –7 kg (10 mg) and –7.8 kg (15 mg), compared with –1 kg in the placebo arm.
The percentage of participants achieving an HbA1c of less than 7% was 81.8% (5 mg), 84.5% (10 mg), 78.3% (15 mg) and 23% (placebo). The percentage of participants achieving an HbA1c of less than 5.7% was 30.9% (5 mg), 26.8% (10 mg), 38.4% (15 mg) and 1.4% (placebo). Top-line data on the SURPASS-1 findings were previously reported by Healio.
“At 40 weeks, statistically significant and clinically meaningful reductions in HbA1c and body weight were achieved with all three doses of tirzepatide; 31% to 52% of participants taking tirzepatide achieved normoglycemia, defied as an HbA1c of less than 5.7%, and 13% to 27% achieved body weight loss of at least 15%,” Carol Wysham, MD, president of the Endocrine Society, clinical professor of medicine at the University of Washington and an Endocrine Today Editorial Board Member, said during the presentation.
For SURPASS-2, researchers analyzed data from 1,879 adults with type 2 diabetes inadequately controlled with metformin therapy of at least 1,500 mg daily (mean age, 57 years; mean baseline HbA1c, 8.28%; mean baseline weight, 93.7 kg). Researchers randomly assigned participants 5 mg, 10 mg or 15 mg tirzepatide or 1 mg semaglutide (Ozempic, Novo Nordisk) for 40 weeks, followed by a 4-week safety follow-up period. Primary endpoint was change in HbA1c from baseline to 40 weeks.
“Semaglutide once-weekly 1 mg was used as the comparator, as this is the highest dose currently approved for the treatment of patients with type 2 diabetes, and in head-to-head trials it has shown superior glycemic and body weight control compared with dulaglutide (Trulicity, Eli Lilly) 1.5 mg and once-weekly exenatide (Bydureon, AstraZeneca) 2 mg,” Juan Pablo Frias, MD, FACE, medical director and a principal investigator of the National Research Institute in Los Angeles, said when presenting the SURPASS-2 data.
Researchers found the estimated mean change from baseline in the HbA1c level was –2.01 percentage points, –2.24 percentage points and –2.3 percentage points with the 5 mg, 10 mg and 15 mg doses of tirzepatide, respectively, and –1.86 percentage points with semaglutide. The estimated differences between the 5 mg, 10 mg and 15 mg tirzepatide groups and the semaglutide group were –0.15 percentage points (95% CI, –0.28 to –0.03), –0.39 percentage points (95% CI, –0.51 to –0.26) and –0.45 percentage points (95% CI, –0.57 to –0.32), respectively.
At all doses, tirzepatide was noninferior and superior to semaglutide. Reductions in body weight were greater with tirzepatide vs. semaglutide, with least-squares mean estimated treatment differences of 1.9 kg, 3.6 kg and 5.5 kg for the 5 mg, 10 mg and 15 mg doses, respectively (P < .001 for all). SURPASS-2 findings were published in The New England Journal of Medicine and previously reported by Healio.
“Tirzepatide 5 mg, 10 mg and 15 mg doses demonstrated superior improvements in HbA1c and body weight vs. semaglutide 1 mg,” Frias said. “An HbA1c in the normal range of less than 5.7% was achieved by anywhere from 29% to 51% of tirzepatide-treated patients compared to 20% of patients treated with semaglutide. Body weight loss of greater than or equal to 15% was achieved by 40% of participants treated with the highest tirzepatide dose compared to 9% of semaglutide-treated patients, and the safety profiles [for both agents] were consistent with the GLP-1 receptor agonist class.”
In the randomized, open-label SURPASS-3 study, researchers compared tirzepatide with titrated insulin degludec (Tresiba, Novo Nordisk) on glycemic response in participants with type 2 diabetes as an add-on to metformin therapy, with or without SGLT2 inhibitors (mean age, 57 years; 44.2% women; mean diabetes duration, 8.4 years; mean HbA1c, 8.17%; mean BMI, 33.5 kg/m²; 32% prescribed SGLT2 inhibitors). A cohort of 1,444 participants were assigned tirzepatide 5 mg (n = 359), 10 mg (n = 361) or 15 mg (n = 359), or insulin degludec (n = 365) for 52 weeks. The primary efficacy endpoint was mean change in HbA1c from baseline to week 52.
“SURPASS-3 is the first study comparing efficacy and safety of a dual GIP/GLP-1 receptor agonist with a basal insulin in patients failing treatment with metformin plus or minus an SGLT2 inhibitor,” Giorgino said during the presentation.
Researchers found that all tirzepatide doses were superior to insulin degludec for mean change from baseline in HbA1c and body weight, and in the proportion of patients achieving all HbA1c and body weight goals at week 52. Among patients assigned tirzepatide 15 mg, 48.4% achieved an HbA1c of less than 5.7% and 42.5% achieved at least 15% body weight loss. The findings were first presented in a late-breaking poster earlier in the meeting.
In SURPASS-5, researchers assessed efficacy of the three tirzepatide doses vs. placebo as an add-on to insulin glargine therapy with or without metformin in adults with type 2 diabetes.
“Glycemic control is suboptimal in many patients on basal insulin due to the lack of dose titration, often related to concerns about hypoglycemia and weight gain,” Michelle Welch, MD, FACE, founder and president of Diabetes and Metabolism Specialists in San Antonio, said during the presentation. “GLP-1 receptor agonists, when combined with basal insulin therapy, have demonstrated superior glycemic control without increasing risk for hypoglycemia or weight gain with up-titration of insulin dose.”
Researchers analyzed data from 475 adults with type 2 diabetes (mean age, 61 years; 44% women; mean diabetes duration, 13.3 years; mean HbA1c, 8.31%; mean BMI, 33.4 kg/m²) assigned 5 mg, 10 mg, or 15 mg of tirzepatide or placebo as add-on to their existing therapies. Primary efficacy outcome was mean change in HbA1c from baseline to week 40. The SURPASS-5 data were initially reported in a late-breaking poster presentation.
Researchers found all three tirzepatide doses were superior to placebo for change from baseline in HbA1c, with mean estimated treatment differences at 40 weeks of –1.3 (95% CI, –1.52 to –1.07), –1.66 (95% CI, –1.88 to –1.43) and –1.65 (95% CI, –1.88 to –1.43), respectively, Welch said.
“In the tirzepatide arms, we saw a 2.2% to 2.9% decrease in HbA1c over the duration of the 40 weeks,” Welch said.
Between 93% and 97% of participants receiving tirzepatide achieved an HbA1c of less than 7% and between 26% and 62% of participants achieved an HbA1c of less than 5.7% during the study, Welch said.
Researchers observed an expected rise in body weight with titrated insulin glargine in the placebo arm and a decrease in body weight with tirzepatide arms, corresponding with a mean 6.2 kg to 10.9 kg body weight decrease at 40 weeks, with the highest drop observed in the 15 mg dose arm, Welch said.
Mechanism debated
During a live Q&A session after the SURPASS presentations, researchers acknowledged that it remains unknown why the effects of tirzepatide are so robust in adults with type 2 diabetes.
“This is going to be endlessly debated, and if you want to make the next best co-agonist, one really wants to understand this,” Drucker said, responding to a question about the drug’s mechanism of action. “Previous attempts with various ratios of GIP to GLP-1 were not successful in producing superb molecules. When you give GIP alone to animals in preclinical studies, it is not that impressive in terms of its metabolic effects. The ratio is always an open question, but until someone proves to me otherwise, I think it is the ability of tirzepatide to interact at the GLP-1 receptor in a special manner that is predominant in its superlative activity. We need more human data.”
Perspective
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The SURPASS clinical trial program demonstrates that tirzepatide is a potentially promising addition to the toolkit for managing type 2 diabetes. In SURPASS-2, the reduction in HbA1c is impressive at up to –2.3%. Despite the decrease in HbA1c, rates of hypoglycemia were low (0.2-1.7% in the tirzepatide group vs. 0.4% in the semaglutide group). The weight loss is similarly impressive at –13.1% on the highest dose at 40 weeks and did not appear to plateau. The fundamental limitations of the study are that the comparison dose of 1 mg semaglutide does not reflect the FDA-approved 2.4 mg weight-loss dose for semaglutide, making it difficult to easily compare the weight loss outcomes.
To summarize, combination incretin therapy is likely to be an impactful tool to add the armamentarium for the treatment of type 2 diabetes, given this outcome data.
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Drucker DJ, et al. 3-CT-SY19. Presented at: American Diabetes Association Scientific Sessions; June 25-29, 2021 (virtual meeting).
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