How do you lower a HbA1c that is too high?
Several medications demonstrably lower HbA1c: the weekly semaglutide injection has the strongest evidence base, but oral combinations involving empagliflozin or semaglutide also offer good evidence. Discuss with your doctor which option suits your situation, side-effect profile and reimbursement coverage.
Weekly semaglutide injection (1.0 mg) is currently one of the most powerful options for lowering HbA1c. In several large studies, HbA1c fell by 1.5 to 1.8 percentage points, significantly more than alternatives such as sitagliptin, dulaglutide or insulin glargine. When semaglutide is combined with basal insulin, HbA1c drops by as much as 1.4 to 1.8 percentage points after 30 weeks. The downside: gastrointestinal complaints cause 4.5 to 6% of users to discontinue the medication. Not every prescriber or reimbursement situation will make this the first choice; in addition, the SUSTAIN trials were funded by the manufacturer, which is worth factoring in.
If you prefer to avoid injections, tablets are also available. Oral semaglutide (14 mg per day) lowers HbA1c by 1.0 to 1.4 percentage points, considerably more than sitagliptin, although the pill form is less potent than the injection. The 7 mg dose also outperforms sitagliptin, but the lowest dose (3 mg) did not reach the efficacy threshold. Gastrointestinal complaints led to early discontinuation in 15 to 19% of participants here as well.
Another well-established injection-free alternative is the combination of an SGLT2 inhibitor and a DPP4 inhibitor as an add-on to metformin. The combination of empagliflozin plus linagliptin lowered HbA1c by 1.1 to 1.2 percentage points, clearly more than either drug alone, without serious hypoglycaemic events. A triple combination (dapagliflozin, sitagliptin and metformin together) also showed a greater reduction than dual combinations, but that study was short (16 weeks) and methodologically weaker, so this finding still requires confirmation.
Two directions that are scientifically intriguing but far from ready for clinical practice are: oral orforglipron, an experimental GLP-1 pill without a peptide structure (promising early results in 68 people, but phase 3 evidence is still lacking), and ingestion of the gut bacterium Akkermansia muciniphila. The latter only had an effect in people who naturally had low levels of this bacterium; in the overall group there was no significant difference compared with placebo. Neither option is currently available outside of clinical research.
Two large reviews were funded by Novo Nordisk (manufacturer of semaglutide). The remaining studies are RCTs, but vary in study duration (12-56 weeks). The triple combination study was open-label. The PMID for orforglipron is not a verifiable PMID and that study was phase 1b with n=68.