Study finds modest weight loss at starter doses of semaglutide and tirzepatide

People who stay on the lowest starter doses of the obesity drugs semaglutide and tirzepatide do lose weight, but much less than those who move up to higher doses, according to a study published Aug. 31 in the journal Biology Methods & Protocols ^[1][2]. The finding suggests the drugs have measurable effects below the doses most clinical trials were built around, the study's leader said ^[1][2].

What the study found

Researchers analyzed data on 534 patients who stayed on injectable semaglutide, sold as Ozempic and Wegovy, at the 0.25-milligram starter dose for at least six months, and the same number of patients who stayed on tirzepatide, sold as Mounjaro and Zepbound, at the 2.5-mg starter dose for at least that long ^[1][2].

At one year, the average percentage of body weight lost was 5.5% with tirzepatide and 2.2% with semaglutide at those lowest approved doses ^[1][2].

For comparison, average weight loss at one year at recommended higher doses was 20.2% with tirzepatide and 13.7% with semaglutide in an earlier head-to-head trial ^[1][2].

Both drugs are prescribed at a low dose first, followed by gradual increases, to help the body adjust and limit side effects ^[1][2]. Many patients never reach the recommended maintenance dose because of tolerability, access, cost, supply or their individual goals, according to the report ^[1][2].

Study leader Venky Soundararajan of the data analytics firm nference said the fact that patients who never escalated past the starting dose still lost some weight suggests the drugs have a measurable effect well below maintenance doses ^[1][2].

Side effects and kidney findings

Staying low did not mean avoiding side effects. Patients on the starter doses had substantially less nausea and constipation than has been reported at higher doses, but other problems still appeared, the study found ^[1][2].

Low-dose tirzepatide was associated with higher rates of several events over two years: kidney injury in 2.7% of patients versus 0.4% with semaglutide, constipation in 32.6% versus 22.4%, muscle cramps in 8.3% versus 4%, lumbar disc disease in 3.3% versus 0.3%, and shortness of breath on exertion in 9.6% versus 6.8% ^[1][2].

Patients on sustained low-dose semaglutide had higher rates of ear inflammation, at 5.6% versus 2.1% with tirzepatide, heavy sweating at 5.5% versus 3.2%, and ankle swelling at 6.9% versus 3.7% ^[1][2].

Semaglutide is currently considered better for kidneys because it has U.S. approval to reduce the risk of worsening chronic kidney disease. Tirzepatide is not yet approved specifically for kidney protection ^[1][2].

The study was observational, and Soundararajan noted that such studies cannot prove cause and effect ^[1][2].

Why it matters for patients

Millions of people take these medicines without ever reaching the top doses. The new data give a rough sense of what that choice produces: some weight loss, usually short of the double-digit percentages reported at higher doses, along with a side effect profile that differs by drug.

"These two medicines are not equivalent," Soundararajan said. "Patients who are not aiming for 20% or 30% weight loss need to know there's a chance they can lose a little weight on these low doses, and they deserve to know the picture around the adverse event profile" ^[1][2].

He added: "In the meantime, with real-world patients taking lower-than-recommended doses, there's a need for awareness" ^[1][2].

The reports did not disclose how much patients pay at each dose step, or whether insurers or manufacturer self-pay programs treat starter doses differently. No information on pricing by dose was included ^[1][2].

What happens next

Novo Nordisk recently launched a clinical trial to evaluate lower maintenance doses of its Wegovy pill, but results are years away ^[1][2]. No timeline for updated prescribing guidance or label changes based on this study has been reported. The study appears in Biology Methods & Protocols and was led by researchers at nference ^[1][2].