HbA1c alone cannot prove semaglutide parity

When a new compound matches semaglutide on HbA1c reduction in a short-term trial, that finding is genuinely useful. It is also incomplete. A letter published on 8 July 2026 in Diabetes, Obesity and Metabolism by Awadhesh Kumar Singh, Akriti Singh, and Ritu Singh makes the case that short-term glycaemic equivalence and full therapeutic interchangeability are different claims, and that conflating the two sets patients and prescribers up for a misleading read of the evidence^[1].

What triggered the letter

The authors appear to be responding to a Phase 2b trial comparing bofanglutide, a synthetic GLP-1 receptor agonist, with semaglutide 1 mg weekly in 272 Chinese adults with type 2 diabetes. The trial ran for 24 weeks, was open-label, and enrolled participants exclusively from Chinese clinical centres. At 24 weeks, bofanglutide 18 mg biweekly cut HbA1c by 2.28 percentage points, compared with 1.60 for semaglutide. Gastrointestinal adverse events ran substantially higher in the bofanglutide arms (81.8 to 87.3 percent versus 51.9 percent for semaglutide), though most were mild to moderate^[2]. The trial authors themselves flagged the open-label design, the short duration, and the single-country enrolment as key limitations.

Why HbA1c at 24 weeks is not the whole story

HbA1c is the standard short-term glycaemic marker, and it is a legitimate primary endpoint in phase 2 and phase 3 diabetes trials. The problem arises when non-inferiority on that one marker at 24 weeks is taken to imply that two compounds are interchangeable in all the ways that matter to a patient on long-term therapy.

Semaglutide carries a multi-year evidence base that goes far beyond blood-sugar control. The SELECT cardiovascular outcomes trial enrolled 17,604 adults with obesity and established cardiovascular disease but without diabetes. Participants receiving semaglutide had a 20 percent lower rate of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke compared with placebo, a hazard ratio of 0.80 (95 percent CI 0.72 to 0.90)^[3]. That benefit accrued over a median follow-up well beyond 24 weeks. A review of the SUSTAIN and PIONEER programme data also documents renoprotective and anti-inflammatory effects beyond glucose control^[4]. A short-term HbA1c match between a synthetic compound and branded semaglutide does not establish that those downstream outcomes would replicate.

What full interchangeability would require

Researchers writing on pharmacosimilars in obesity medicine have proposed a framework that goes well beyond comparative efficacy. The factors that should govern substitution decisions include regulatory approval status, the accumulated evidence base across multiple populations and durations, the regulatory rules governing interchange in each market, cold-chain and supply-chain requirements, and real-world clinical experience^[5]. A synthetic compound that matches branded semaglutide on HbA1c in a 24-week open-label trial in a single country has addressed only one corner of that framework.

The regulatory pathway is a specific sticking point. Branded semaglutide products (Ozempic, Wegovy, Rybelsus) are approved following full clinical programmes reviewed by the FDA, the EMA, and the MHRA. A synthetic or compounded version produced outside that programme has not gone through the same pre-market scrutiny, regardless of how its short-term efficacy compares. The FDA, for instance, has been explicit that compounded versions of semaglutide produced during the drug-shortage period are not approved medicines and that their safety and effectiveness have not been demonstrated in the same way.

What this means when reading trial coverage

The Singh et al. letter is not an argument against research into synthetic semaglutide analogues. Short-term efficacy data in a phase 2 setting is exactly what that stage of development is designed to generate, and the bofanglutide results are an appropriate contribution at that phase. The argument is narrower: those results should not be read as licensing claims of full therapeutic equivalence with an established, long-studied medicine.

For patients and clinicians the practical implication is that the question to ask when encountering a "non-inferior on HbA1c" claim about any synthetic or compounded semaglutide product is: non-inferior over what timeframe, in what population, on what endpoints, and with what regulatory backing? HbA1c at 24 weeks is one answer. Long-term cardiovascular outcomes in a broad population under a licensed indication is a different question, and one for which the answer is not yet available for most alternatives.

The regulatory picture for semaglutide alternatives

Originator semaglutide is approved as a prescription-only medicine across all seven jurisdictions covered on this site. Biosimilar or pharmacosimilar semaglutide products are at various stages of development and regulatory review in different markets. In markets where no approved pharmacosimilar exists, a compounded or grey-market alternative carries a different evidentiary status than the originator, even if a 24-week HbA1c readout looks similar. Country-by-country regulatory status is on the semaglutide regulation pages.

This article covers published scientific and regulatory commentary. It does not constitute medical advice. Any decision about which medicine to prescribe or take belongs with a clinician who knows the individual case.