Novel Dual-mechanism Agent Acts on Diabetes, Metabolic Complications

GLUCAGON-LIKE PEPTIDE-1 MOLECULE

Tirzepatide, an investigational agent with dual mechanisms of action, demonstrated potential to improve glycemic control and promote weight loss in patients with type 2 diabets (T2DM) as well as reducing biommarkers of both diabetes and non-alcoholic steatohepatitis (NASH), in 4 studies presented at the American Diabetes Association (ADA) Scientific Sessions meeting in San Francisco, CA June 7-11.

Tirzepatide acts as an agonist at the receptors of both the gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), two primary incretin hormones which are secreted from the intestine to stimulate insulin secretion in response to ingested nutrients.

The primary findings reported:

• Significant reductions in A1c and body weight among Japanese T2DM patients at week 8

• Improved tolerability of tirzepatide at lower starting doses and with smaller subsequent dose increases

• Improvements in markers of beta cell function and insulin sensitivity, suggesting efficacy beyond the drug’s impact on weight loss; and,

• Improvements in serum markers of NASH

Next: Impact on A1c and body weight at week 8

The first tirzepatide study investigated the effects of the agent on glycemic control and body weight in 48 Japanese patients with type 2 diabetes (T2DM) in a double-blind, placebo-controlled randomized phase 1 trial. The study, explained Kenji Ohwaki, PhD, Senor Clinical Research Scientist, Lilly Research Laboratories, Kobe, Japan, compared a weekly 5 mg fixed dose (N=11) with two dose-titration regimens, increasing weekly from 2.5 mg to 10 mg (N=12) and from 5 mg to 15 mg (N=16), and to placebo (N=9).¹ Ohwaki reported that the active drug was associated with marked reductions from baseline to week 8 in fasting plasma glucose (FPG), A1c, and body weight.

In contrast to a mean reduction in FPG with placebo of 3.81 mg/dL, the mean FPG reduction in those receiving the 5 mg fixed dose was 56.52 mg/dL, and those on both escalation regimens had reductions of approximately 73 mg/dL.

A1c reduction was 1.62%, 1.78% and 2.05% with 5 mg, titration to 10 mg and titration to 15 mg, respectively. Body weight was reduced by 1.46kg with placebo; and 1.92, 3.58 and 5.13 kg with 5 mg, titration to 10 mg and titration to 15 mg, respectively.

The most frequently reported treatment-emergent adverse events were decreased appetite and gastrointestinal adverse events, including constipation, diarrhea, abdominal discomfort and distension, vomiting and nausea.

Next: Dose adjustment to mitigate tirzepatide GI effects

A second study of tirzepatide examined whether a lower starting dose (2.5 mg and 4 mg) with more gradual escalation could reduce the incidence and severity of gastrointestinal adverse events.

Julian Frias, MD, Medical Director and Principal Investigator, National Research Institute, Los Angeles, Calif, reported results from the 12-week, randomized, placebo-controlled phase 2b study of three dose-escalation regimens in 111 participants with T2DM.2  One escalation regimen increased by 4 mg increments to 12 mg in 8 weeks; and two others achieved 15 mg after initiating with 2.5 mg.

As with the 8-week trial, active drug was associated with statistically significantly greater reductions than placebo in markers of glycemic control, and weight loss. The incidence of gastrointestinal adverse events was lower than in previous trials, but still prominent:

Total incidence of nausea, vomiting, and/or diarrhea was 11.5% with placebo, and 48.3%, 57.1% and 46.4% with the 12 mg, 15 mg-1 and 15 mg-2 groups, respectively.

Taken together, these studies support going forward to Phase 3 investigations, asserted Frias. “These new tirzepatide data build upon the positive results seen in patients with type 2 diabetes to date,” he indicated in a statement released during the meeting. “The results offer additional evidence of tirzepatide’s potential to meaningfully reduce A1C and body weight in people with type 2 diabetes and treat other metabolic conditions.”

Next: Tirzepatide improves metabolic biomarkers

A third study found evidence that tirzepatide also improves markers of beta-cell function and insulin sensitivity, addressing the possibility that glocuse-lowering efficacy of the dual agent may not be due primarily to weight loss.

Melissa Thomas, MD, PhD, Medical Fellow, Diabetes and Complications, Eli Lilly and Company, Indianapolis, Ind, reported on a 26-week, randomized, double-blind phase 2b study that compared tirzepatide in weekly doses of 1 mg, 5 mg, 10 mg ,or 15 mg, to placebo, and to the selective GLP-1 RA dulaglutide (Trulicity) 1.5 mg weekly.³

In addition to statistically significantly greater glucose control and weight loss, biomarkers of beta cell function also were significantly  improved with tirzepatide at the 10 mg and 15 mg doses versus placebo or dulaglutide, Thomas indicated.

Proinsulin to insulin ratios (insulin processing markers of beta cell stress) were also found to be reduced more by tirzepatide 10 and 15 mg than with placebo or dulaglutide. In addition, the homeostasis model assessment 2 (HOMA2)-B was significantly increased with tirzepatide at all doses and with dulaglutide; and the 10 mg and 15 mg tirzepatide doses significantly improved insulin sensitivity as reflected by lower HOMA2-IR compared with placebo and dulaglutide.

“Weight loss significantly explained 22% and 28% of variation in HOMA2-IR with tirzepatide 15 mg and 10 mg, respectively,” Thomas indicated, “suggesting the insulin sensitizing effects of tirzepatide are only partly attributable to weight loss.

“These data suggest that, compared with the selective GLP-1 RA dulaglutide, tirzepatide has greater impact on insulin sensitivity and beta cell function, resulting in improved glycemic control,” Thomas concluded.

Next: Tirzepatide impact on biomarkers of NASH

The fourth study considered the effect of tirzepatide on biomarkers of NASH, a common comordibity or risk of T2DM. Data from a population with NASH was examined for potential effects of tirzepatide, compared to the GLP-1 RA dulaglutide, and placebo on ALT, AST, Keratin-18 M30 fragment (K-18, a marker of apoptosis), Pro-C3 (a marker for fibrosis), and adiponectin (an adipokine that protects liver from inflammation and fibrosis).

Brad Woodward, MD, Global Development Leader, Incretins, Eli Lilly and Company, Indianapolis, Ind, indicated in a statement released during the meeting that treatment with tirzepatide led to improvements in NASH-related markers, and that a phase 2b study to further explore its effects in NASH is planned to start later this year.

“We are excited about tirzepatide’s potential to make an important impact on people with type 2 diabetes and other conditions, including obesity and NASH,” Woodward stated.

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References

1. Ohwaki K, Furihata K, Mimura H, et al. Efffect of tirzepatide, a dual GIP and GLP-1 receptor agonist, on glycemic control and body weight in Japanese patients with T2DM. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco, CA. Abstract 1024-P.

2. Frias JP, Nauck MA, Van J, et al. A 12-week, randomized, placebo-controlled study assessing the efficacy and safety of three dose-escation algorithms of tirzepatide, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco, CA. Abstract 993-P.

3. Thomas MK, Nikooienejad A, Bray R, et al. Tirzepatide, a dual GIP and GLP-1 receptor agonist, improves markers of beta-cell function and insulin sensitivity in type 2 diabetes patients. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco, CA. Abstract 980-P.

4. Hartman ML, Sanyal A, Loomba R, et al. Effects of Tirzepatide (TZP), a novel dual GIP and GLP-1 receptor agonist, on biomarkers of nonalcoholic steatohepatitis (NASH) in patients with T2D. Paper presented at the American Diabetes Association 79th Scientific Sessions; June 7-11, San Francisco, CA. Abstract 134-OR.