This year at the American Diabetes Association (ADA) Scientific Sessions, new Phase III data were presented evaluating the safety and efficacy of enlicitide, a late-stage investigational oral Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitor. The analysis demonstrated significant reductions in Low-Density Lipoprotein Cholesterol (LDL-C) among participants with and without diabetes mellitus, with no increased risk of worsening glycemia or new-onset diabetes. Together, these findings suggest that enlicitide may offer an effective oral treatment option for dyslipidemia without adversely affecting glycemic control.
Dyslipidemia is a metabolic disorder characterised by abnormal blood lipid levels, including cholesterol and triglycerides, and is a major risk factor for cardiovascular disease. PCSK9 inhibitors are an established class of lipid-lowering therapies used to treat dyslipidemia by reducing LDL-C levels. Currently approved PCSK9 inhibitors are administrated through subcutaneous injections, which could present a barrier to treatment initiation and long-term adherence.
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The findings were derived from an integrated analysis from the Phase III CORALreef Lipids and CORALreef HeFH studies. At Week 24, LDL-C was reduced by 65% in participants with diabetes and 61% in those without. Similar rates of new-onset or worsening diabetes were observed in both enlicitide and placebo arms, with no meaningful changes in HbA1c overtime. These results are clinically meaningful and highlight the potential of oral PCSK9 inhibition to achieve substantial LDL-C reductions regardless of diabetes status, while maintaining glycemic stability. The LDL-C reductions observed with enlicitide appear to approach those seen with established PCSK9 inhibitors. Future head-to-head studies may help clarify how oral and injectable PCSK9 inhibition compare in terms of efficacy, safety and patient acceptability.
From a commercial perspective, enlicitide, as an oral therapy with LDL-C reductions comparable to injectable PCSK9 inhibitors, may address an important unmet need among patients who are unwilling or unable to use injectable therapies. Rather than replacing existing PCSK9 inhibitors, enlicitide may expand the overall use of PCSK9 inhibition by reaching patients who otherwise would unlikely consider injectable therapies. Its oral formulation may also facilitate easier incorporation into existing lipid-lowering treatment pathways, including combination treatment strategies.
Overall, these results suggest that enlicitide has the potential to offer substantial LDL-C lowering through a convenient oral formulation, representing a promising addition to the dyslipidemia treatment landscape.
Phase III SYNCHRONIZE-1 results for survodutide
Dual agonist drugs are designed to activate two receptors in tandem to amplify a therapeutic effect. Pharmacologically that can mean stronger appetite control, greater metabolic shift, and potential advantages in side‑effect management over single-target medicines.
Current developments are focussed on the pairing of GLP‑1 receptor activation with a second receptor that adds complementary metabolic leverage. In the case of survodutide it pairs glucagon and GLP‑1 agonists. GLP‑1 helps curb hunger and smooth post‑meal glucose, while glucagon receptor activation can increase energy expenditure and influence metabolism.
In Phase II trials, survodutide produced significant weight loss in people with obesity without type 2 diabetes and has now continued that result in large Phase III testing. SYNCHRONIZE‑1 enrolled 725 adults across 14 countries with a mean BMI of around 38 and common obesity complications such as hypertension, dyslipidaemia, and prediabetes. Participants received once‑weekly injections, with careful up‑titration to reach target doses due to potential powerful gastrointestinal and other systemic effects.
Participants experienced sustained weight loss of up to an average of 16.6% after 76 weeks. Newly presented data at ADA 2026 on adverse events (AE) showed an issue with tolerability. Gastrointestinal AEs leading to discontinuation were observed in 17.8% of participants on the 3.6mg dose and 20.2% on the higher 6.0mg dose, in contrast to 2.9% for the control group.
Dual agonist drugs aim to reshape physiology more decisively by coordinating multiple metabolic pathways at once like the biological systems they target. The success of a dual agonist relies on identifying the right receptor pair, tuning in the balance between them, and finding stable therapies. Drugs that are able to accomplish this will present an attractive tool for patients and practitioners, helping to simplify treatment and potentially providing a more comfortable experience.
