Tirzepatide Leads to Long-Term Glucose Control

MADRID — The majority of patients achieving high rates of glucose control and weight loss in the first year of tirzepatide treatment have sustained success in the second year; however, factors predicting a sustained response are less clear for weight loss, new research showed.

“The analysis shows that in the SURPASS-4 trial, approximately 80% of individuals who were treated with tirzepatide and who reached an A1c of 6.5% or weight loss of > 10% at 52 weeks retained those [achievements] at 104 weeks,” said first author Steven Kahn, MD, of the VA Puget Sound Health Care System and University of Washington, Seattle, Washington, in presenting the research at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

The findings are from a post hoc analysis of the SURPASS-4 trial in which patients with poorly controlled type 2 diabetes, obesity, and a risk for cardiovascular events were randomized to one of three doses of tirzepatide, a dual agonist of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), at 5 mg (n = 328), 10 mg (n = 328), or 15 mg (n = 338).

Patients had a mean baseline A1c of 8.5% and a mean baseline body weight of 90.3 kg.

For the trial’s primary endpoint of the proportion of participants who achieved glycemic control, defined as A1c levels at week 52 (≤ 6.5% with < 0.2% increase), the rates were 67% with 5 mg, 73% with 10 mg, and 81% with 15 mg of tirzepatide, representing a total of 619 patients.

Among those achieving glycemic control at 52 weeks, the proportions of patients who went on to sustain glycemic control at 104 weeks were 75% in the 5 mg group, 80% in the 10 mg group, and 83% in the 15 mg group.

In addition to a higher tirzepatide dose, key factors associated with initially achieving A1c ≤ 6.5% at week 52 included the baseline characteristics of having a shorter duration of diabetes, lower A1c, higher HOMA-B (representing beta-cell function), use of metformin only, and normal urine albumin-creatinine ratio.

Factors associated with sustained glycemic control at 104 weeks included lack of sulfonylurea use (odds ratio [OR], 0.56), smaller decrease in fasting glucose (OR, 0.97), greater weight loss (OR, 1.25), along with a higher HOMA-B at week 52 (OR, 1.34).

Weight Loss Achievement, Sustainability Predictors

In terms of weight loss, the proportions of the 437 participants achieving the endpoint of ≥ 10% weight loss at week 52 were 35% with 5 mg tirzepatide, 52% with 10 mg tirzepatide, and 65% with 15 mg tirzepatide.

The proportions able to sustain that weight loss at week 104 were 79% in the 5 mg group, 81% in the 10 mg group, and 82% in the 15 mg group, for approximately a 20% reduction in each group.

The main factors predicting weight loss of ≥ 10% at week 52 were higher tirzepatide dose and being female, in addition to baseline characteristics such as lower A1c, estimated glomerular filtration rate, triglycerides, and no history of cardiovascular disease.

In terms of predictors of sustained weight loss at 104 weeks, only a greater decrease in LDL-cholesterol during the first 52 weeks was associated with the maintained weight loss (OR, 1.05).

“In looking at predictors of the sustained weight loss response, somewhat to our surprise, there was rather little that we could find — only LDL-cholesterol, and we have no good explanation for this,” Kahn said.

Glycemic Control Achieved Well Before Weight Loss Leveled Off

Of note, the analysis further showed that overall, patients treated with tirzepatide achieved glycemic control by about week 24 that was sustained through week 104, whereas body weight did not level off in all three dose groups until about week 52.

“Something we’ve seen repeatedly now with GLP-1 receptor agonists is this trajectory of A1c that reaches a nadir at somewhere around 20-24 weeks; in other words, in less than half a year you’ve achieved the lowest A1c you’re likely to get to,” Kahn explained.

“Whereas the weight takes a year or more to get to the lowest weight,” he said.

Further elaborating to Medscape Medical News, Kahn noted that “this effect is related to the heterogeneous effects of GLP-1 receptor agonists and has been observed with others as well, particularly semaglutide, which provides more similar in glucose and weight change.”

“The dissociation is because they stimulate the beta cell to release insulin, which will lower glucose independent of the effect on weight, which is largely mediated by the central effects of these medications,” Kahn said.

Regarding the approximate 20% decrease in response observed after the first year, Kahn noted that the findings are consistent with those of other long-term trials.

“In the SELECT trials using semaglutide, for instance, which involved longer-term studies, we can see that, over time, A1c is increasing,” he said.

Speculating on the causes of the decline in response to tirzepatide, Kahn added that adherence could also play a role.

“For both (glycemic control and weight loss) measures, it could be not tolerating the medicine, so stopping it (less likely) or noncompliance (possibly) are factors,” he said.

“For glycemia, it could be progressive loss of beta-cell function, which we know characterizes the disease, and for weight changes in other factors, such as lifestyle, that can change over time.”

“In this study, we have not determined any of these, so they are all hypothetical,” he noted.

Kahn noted that the ongoing SURPASS-CVOT trial of tirzepatide looking at cardiovascular outcomes, in which he is a co-author, may offer important further insights due to its long-term study duration.

Gender a Predictor for Weight Loss?

While gender was not associated with a greater response to tirzepatide in the analysis, a separate exploratory analysis looking at all four SURMOUNT trials, presented in the same EASD session, did show differences based on gender in terms of weight loss, with women showing significantly greater weight loss than men.

“Body weight reduction was associated with sex, and tirzepatide was associated with greater weight reduction in women than in men,” said first author Luis-Emilio García-Pérez, MD, of Eli Lily and Company, in presenting the findings at the meeting.

In the exploratory analysis, 51%-71% of participants in the four trials were women.

Across all the trials, the reductions in weight were ≤ 24.5% in women vs ≤ 18.0% in men (P < .05). Whereas both men and women showed similar odds of achieving weight reduction thresholds with tirzepatide, which were higher than those with placebo, in the SURMOUNT-3 trial, tirzepatide-treated women showed significantly greater odds of achieving ≥ 5% and ≥ 10% weight reduction thresholds than tirzepatide-treated men (P < .05).

Furthermore, across the trials, women had greater reductions in the percentage of weight than men (≤ 24.6% vs ≤ 18.1%; P < .05).

“All tirzepatide doses significantly reduced body weight compared to placebo regardless of sex; however, greater body weight reduction was achieved with tirzepatide in women than in men,” Garcia-Perez said.

Kahn disclosed serving on the advisory boards for Abarceo Pharma, Amgen, Anji Pharmaceuticals, Biomea Fusion, Corcept Therapeutics, Eli Lilly and Company, Merck, Neurochem Laboratories, Novo Nordisk, and Oramed. Garcia-Perez is an employee of Eli Lilly and Company.