Sustained Low-Dose Semaglutide Is Linked to Broad-Spectrum Cardiometabolic Benefits, and Better Tolerability Profile over Low-Dose Tirzepatide, Motivating Semaglutide Microdosing Studies

Abstract

Semaglutide and tirzepatide are typically evaluated through dose escalation, yet many patients in routine care do not reach a recommended maintenance dose due to tolerability, access, cost, supply or individualized goals. Here we used sustained 0.25 mg-only semaglutide and sustained 2.5 mg-only tirzepatide exposures as real-world proxies for “microdosing” and analyzed de-identified electronic health records from a federated system of 29 million patients. Among 490,072 semaglutide-treated patients, 814 met stringent sustained low-dose criteria including at least 3 distinct 0.25 mg prescriptions with at least 6 months between the first and last qualifying prescriptions. In a matched head-to-head comparison aided by AI-enabled curation of clinical notes, sustained low-dose tirzepatide showed a worse 24-month adverse event profile (p<0.05) than sustained low-dose semaglutide, including constipation (32.6% vs 22.4%), acute kidney injury (2.7% vs 0.4%), muscle cramps (8.3% vs 4%), lumbar disc disease (3.3% vs 0.3%), dyspnea on exertion (9.6% vs 6.8%), lentigo (4.7% vs 0.8%) and actinic keratosis (3.3% vs 0.6%). Only a minority of profiled adverse events had higher incidence rates with sustained low-dose semaglutide, including otitis (2.1% vs 5.6%), diaphoresis (3.2% vs 5.5%) and ankle swelling (3.7% vs 6.9%). Sustained low-dose tirzepatide was also associated with greater weight loss, while both low-dose agents produced comparable effectiveness across incident disease outcomes. Analyses of medications associated with incident diseases provided further evidence supporting the findings from clinical notes. Renal-supportive and hyperkalemia therapies increased after low-dose tirzepatide (5.6% to 9.5% at 12 months, p=0.016) but not after low-dose semaglutide (8.2% to 6.6%, p=0.382), and wakefulness/stimulant therapies use increased after low-dose tirzepatide through 24 months. Examining 1:1 propensity-matched comparisons of sustained low-dose semaglutide against anti-diabetic drugs (metformin, DPP-4 and SGLT-2 inhibitors) for each pre-existing cardiovascular, neuropsychiatric, hepatic, pulmonary, renal, or viral disease burden cohort shows markedly better broad-spectrum clinical effectiveness for sustained low-dose semaglutide despite minimal weight change. The strongest lowering of 24-month event probabilities for sustained low-dose semaglutide over anti-diabetic drugs (p<0.05) occurred for patients with baseline cardiovascular conditions, for instance, relative to DPP-4 inhibitors for all-cause mortality (0.3% vs 7.1%), composite cardiovascular events (6.6% vs 14.5%), heart failure (1.8% vs 9.9%), arrhythmia (3.5% vs 10.9%), ischemic heart disease (4.3% vs 8.5%), and venous thromboembolism (0.9% vs 4.4%). Matched comparison of patients with low-dose (0.25 mg) vs high-dose (>1.7 mg) semaglutide shows mean percent weight loss at 12 months after initiation was 1.8% vs 12% (p<0.001), respectively, emphasizing that cardiometabolic benefits of low-dose semaglutide are likely independent of weight loss. Taken together, sustained maintenance of initiation-dose semaglutide appears linked to broad cardiometabolic benefits with minimal weight change, and better tolerability profile relative to sustained low-dose tirzepatide, motivating prospective studies of sustained semaglutide microdosing.