Add-On Orforglipron: Good News for Type 2 Diabetes and Inadequate Glycemic Control

NEW ORLEANS — Once-daily orforglipron (Foundayo) improved outcomes in adults with type 2 diabetes and inadequate glycemic control, the international ACHIEVE-5 trial showed.

In patients already taking background insulin glargine, glycemic control was improved with add-on orforglipron, with HbA1c levels dropping by 1.58%, 1.88%, and 1.82% on average with the 3-, 12-, and 36-mg doses, respectively, versus 0.79% with placebo (P<0.001 for all), reported Francesco Giorgino, MD, of the University of Bari Aldo Moro in Bari, Italy, and colleagues.

Orforglipron therapy also yielded significant weight loss across doses, with reductions of 2.6% to 5.4% in mean body weight from baseline to 40 weeks compared with a weight gain of 0.2% with placebo.

Giorgino presented the ACHIEVE-5 trial at the American Diabetes Association (ADA) annual meeting here. The study was simultaneously published in JAMA.

Importantly, there was no increase in hypoglycemia risk observed with orforglipron. Moreover, the weight loss findings accompanied insulin doses rising by 30% to 33% among orforglipron users in the study.

Giorgino and colleagues noted that, in practice, basal insulin therapy is usually intensified for people with inadequate glycemic control, though this is a strategy limited by concerns about hypoglycemia and weight gain.

“The finding of weight loss [with add-on orforglipron] despite increases in insulin doses is clinically important because insulin therapy is associated with weight gain, which is believed to result from increased lipid storage and suppressed lipolysis,” wrote a trio led by Kishore Gadde, MD, of the University of California Irvine School of Medicine, in an accompanying editorial.

Of note, orforglipron was associated with gastrointestinal adverse events in ACHIEVE-5.

Treatment discontinuation rates due to gastrointestinal adverse events among those receiving orforglipron ranged from 1.5% to 6.7% compared with 0.7% in the placebo group. Treatment discontinuation due to any adverse events, mainly nausea and vomiting, reached as high as 9.6% with the 36-mg dose versus 3.6% with placebo.

Orforglipron is an oral, nonpeptide GLP-1 receptor agonist that was recently FDA approved for weight reduction in adults with overweight or obesity.

The expectation is that more indications will follow, as has been the trend for this wildly popular drug class that includes semaglutide injectables (Wegovy) and oral formulations (Rybelsus), among others.

Within the ACHIEVE research program, head-to-head comparisons against oral semaglutide and dapagliflozin (Farxiga) have already reported results favoring orforglipron for managing glucose. A dedicated cardiovascular outcomes trial, ACHIEVE-4, has also added topline evidence for the overall cardiovascular safety of orforglipron versus insulin glargine in high-risk participants.

Orforglipron is far from being the only GLP-1 drug in the pipeline for obesity and other cardiometabolic disorders, however. At this year’s ADA alone, investigational elecoglipron, retatrutide, cagrilintide-semaglutide, and mazdutide are also featured in the scientific program.

“More than 100 drugs targeting obesity and associated metabolic disorders are currently in preclinical or clinical development, which raises the question of how many could be regarded as too many and how they would fit into clinical practice,” Gadde and co-authors wrote. “While some of the GLP-1 receptor agonists appear to fall into the ‘me too’ category, others with dual- and triple-agonist actions and those combining incretin and non-incretin mechanisms may offer additional clinical benefits and improved administration and tolerance.”

ACHIEVE-5 was a phase III trial conducted in the U.S., Brazil, China, Japan, and Romania that included adults with type 2 diabetes taking insulin glargine with or without metformin and/or SGLT-2 inhibitors who had a baseline HbA1c of 7.0% to 10.5%.

After a 4-week screening period involving 781 patients, 546 patients (median age 61 years, 52.9% men) were randomized to varying doses of orforglipron or placebo while staying on titrated insulin glargine and measuring their fasting blood glucose once daily.

Median duration of type 2 diabetes was 14.6 years, mean HbA1c was 8.5%, and mean body mass index was 30.8. The majority of patients were on metformin (over 75%) and an SGLT-2 inhibitor (over 53%) at baseline.

Giorgino and colleagues reported several secondary outcomes supporting orforglipron’s efficacy:

• Proportion of participants achieving an HbA1c level under 5.7%: range of 8% to 18% across doses vs 2% with placebo
• Reductions in mean fasting serum glucose: from 40.0 mg/dL to 44.8 mg/dL vs 33.5 mg/dL with placebo
• Proportion of patients achieving fasting serum glucose under 100 mg/dL: range 48% to 60% vs 42% with placebo

The incidence of diabetic retinopathy adverse events was similar between groups.

Of note, there was an increase in pulse rate of 2.9 to 6.8 beats per minute observed with orforglipron treatment. This will be analyzed as part of the ACHIEVE-4 cardiovascular outcomes report, which is pending full publication.

The ACHIEVE-5 investigators acknowledged that their use of the standardized insulin algorithm and blood glucose targets may not be generalizable to real-world practice. This was also a relatively short-duration trial, with 92.9% of participants completing the study.

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