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

In routine care, many patients taking semaglutide or tirzepatide do not reach recommended maintenance doses. Using electronic health records from 29 million patients, researchers identified 814 individuals who sustained very low doses of semaglutide (0.25 mg) or tirzepatide (2.5 mg) for at least six months. Over 24 months, low-dose tirzepatide showed a worse adverse event profile than low-dose semaglutide, including higher rates of constipation (32.6% vs 22.4%), acute kidney injury (2.7% vs 0.4%), and muscle cramps (8.3% vs 4%). Low-dose tirzepatide also led to greater weight loss. Low-dose semaglutide was associated with broad cardiometabolic benefits despite minimal weight change, and better tolerability than low-dose tirzepatide.

Study at a glance

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.