Battle of the Once-Weekly Incretin Treatments for Type 2 Diabetes

Three recent studies test the efficacy of incretin therapies in treating type 2 diabetes with promising results.

Illustration of three knights in different styles of armor ready for battleImage by Kimberly Bjugstad PhD

Incretin therapies for the treatment of type 2 diabetes are at the forefront of current reasearch. Two studies, tirzepatide (TZP) and efpeglenatide, are monotherapies for the treatment of early type 2 diabetes. Participants in a third study, semaglutide, were slightly heavier and had a longer disease duration. It was studied as a combination therapy with metformin. 

Tirzepatide (TZP)- SURPASS-1 Trial

Tirzepatide (TZP) is a dual GIP/GLP-1 receptor agonist, modified from a native GIP peptide sequence. In vitro studies suggest TZP favors GIP activity more so than GLP-1. Because it has a mean half-life of ~5 days, TZP has been studied as a once-weekly injection monotherapy in the treatment of type 2 diabetes. 

In the ADA presented study by Julio Rosenstock MD, Dallas Diabetes Research Center at Medical City, Dallas, TX, participants were randomly assigned (1:1:1:1) to one of three groups of TZP (0-Placebo, 5, 10, and 15 mg subcutaneously once weekly) with >= 115 participants per group. The study groups were controlled for age, sex, diabetes duration, weight, BMI, A1c, FSG, and prior use of oral antihyperglycemic medications (OAM). Study duration was 40 weeks.

Changes in HbA1C at 40 weeks

Only 20% of placebo participants achieved an A1c level below 7%, where more than 85% of those treated with TZP reached the 7% goal. Most (>80%) had A1c levels below 6.5% and in the highest TZP treatment group (15mg), 52% were below 5.7%. 

Data from all patients with at least 1 dose of TZP had mean HbA1C decreases of 1.75, 1.71, and 1.69 percent points for those given 5, 10, or 15 mg TZP.  Placebo treated patients had an average loss less than 0.1. 

Changes in Weight at 40 weeks

Weight remained stable in the placebo group, but those in the treatment group experienced a steady weight loss observable by 4 weeks compared to their baseline weights. By 40 weeks, those on the highest TZP dose had the greatest weight loss. Only 14% of placebo patients reached the target weight loss of 5% and only 1% reached a 10% weight loss. 

Adverse events (AEs)

Because of the mechanism of action by which incretin agonists work, most AE were gastrointestinal in nature.  Nausea and diarrhea affected the greatest proportion of participants ranging from 6% and 8% in the placebo group and 18% and 12% in the 15 mg TZP group, respectively. 

The placebo group suffered from higher percentages of hyperglycemia (27%) compared to 3%, 4%, and 2.5% in the TZP treated groups (5, 10, and 15 mg respectively). The only death also occurred in the placebo group.

Study details comparison table

Efpeglenatide- Late Phase 3 AMPLITUDE-M Trial 

Efpeglenatide is a GLP-1 receptor agonist with a half-life of up to 7 days due to a low renal and vascular endothelial clearance. Previous studies revealed efpeglenatide’s superior ability to improve glycemic and weight control compared to placebo. The current study is a phase 3 trial investigating weekly treatment with one of three doses as a monotherapy compared to placebo.

This was a randomized, double blind placebo control study with participants given Efpeglenatide (0-placebo, 2, 4, 6 mg) once weekly as subcutaneous monotherapy. Patients in the 4 and 6 mg dosing groups were titrated up to their dose in 2-week increments. The study duration was 30 weeks for changes in HbA1C and 56 weeks for weight, change in fasting plasma glucose, and HbA1C again. 

Patients were controlled for baseline characteristics: age, sex, diabetes duration, HbA1c, body weight/BMI, fasting plasma glucose, and eGFR (~101.3 +/- 31.3 mL/min/1.73m2).

Changes in HbA1C at 30 weeks

By 30 weeks, the HbA1C levels decreased on average by 1.1, 1.5, and 1.6 percent points for the low, medium, and higher efpeglenatide treated groups. Those in the placebo group dropped 0.5 HbA1c percentage points. At 56 weeks, average group HbA1C levels were 6.9, 6.6, and 6.6 for the low to high treatment groups respectively. Placebo treated patients had an average HbA1c level of 7.5 at 30 weeks and 7.4 at 56 weeks. 

Changes in Weight at 30 weeks

Those in the placebo group lost on average 1 kg over the course of 30 weeks. Patients treated with 4 and 6 mg efpeglenatide had an average loss of over 3 kg. The low dose efpeglenatide showed significant promise of weight loss in the first 12 weeks but then rose to placebo levels at 30 weeks. Study author Juan Pablo Frias MD, from the National Research Institution in Los Angeles, CA, stated that the increase in weight in the 2 mg group was due to a single subject who gained 22 kg and then maintained the weight through the end of the study. Weight loss continued at a more gradual pass through 56 weeks, with final group weights of 98, 93, and 90 kg for the 2, 4, 6 mg groups respectively. 

Adverse events (AEs)

GI issues were again the most prominent adverse events with 2% and 9% of participants in the placebo group experiencing nausea or diarrhea. More participants in the 6 mg treatment group experienced nausea and diarrhea, with 22% and 25% respectively.  

Serious AEs emerged in 9% of those in the placebo group. AEs that lead to discontinuation affected nearly 5% in the low dose and 3% in the high dose, and only 1% of those in the 4 mg and placebo groups. No deaths were reported in any group.   

Study results comparison table

Semaglutide- SUSTAINED FORTE Trial 

Semaglutide is a GLP-1 receptor agonist with a high similarity to native GLP-1 and a half-life of ~7 days. Once-weekly semaglutide (0.5 and 1.0 mg) are currently approved for type 2 diabetes, however only 20-30% of patients on 1.0 mg dose achieved HbA1c goals of <7.0%.  The current study then was used to determine if a higher dose (2.0 mg) of semaglutide would be a more clinically efficacious option. This study was also authored by Juan Pablo Frias MD.   

Semaglutide was given as a once-weekly injection at either 1 mg or 2 mg. T2D patients were randomized in a 1:1 fashion to one of the semaglutide doses. All patients were on a stable dose of metformin and could be treated with sulfonylureas or not. 

Changes in HbA1C at 40 weeks

Changes in HbA1c levels were significantly lower by 12 weeks and began to stabilize at 20 weeks, maintaining a relatively even level through 40 weeks. By 40 weeks, the 2 mg treated patients had a 2.2 percentage point drop in HbA1c levels compared to 1.9% in the 1 mg treatment group.

Changes in Weight at 40 weeks

Measurable weight loss by 4 weeks was found in both groups. They continued to lose weight at a similar rate throughout the 40-week trial period.  At the final measure, those on the 2 mg dose lost nearly 7 kg while those on the 1 mg dose lost 6 kg. While this is a statistically significant difference, it may not be overly significant clinically.  

Adverse events (AEs)

Again, AEs mostly centered around GI issues with approximately 14% of participants in both treatment groups experiencing nausea, with diarrhea present in about 9%. Decreased appetite was greater in the 2 mg treated group than the 1 mg group. AEs that led to discontinuation affected 3.8% of original participants receiving the 1 mg dose compared to only 2.5% in the higher 2 mg dose.   

Continue Reading:
FDA Approves Once-Weekly GLP-1 Agonist for Type 2 Diabetes
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