The evolution of obesity medications

A narrative review published in JGH Open on 4 September 2026 traces how obesity medicines travelled from thyroid extract to weekly injections. Its headline statement is that the current generation of injectable incretin analogs, semaglutide and tirzepatide, is associated with mean weight loss in the range of 15% to 20% over approximately 12 to 18 months.^[1] The authors, Gill and Sumithran, are based in Melbourne, Australia. The review is a synthesis of published data, not a new trial.

A long record of drugs pulled from the market

The review opens with a blunt summary of the field's own history: many obesity medications have been withdrawn from the market due to safety concerns.^[1] Its timeline starts with thyroid hormone in 1892 and the adverse consequences of hyperthyroidism that followed. It then covers 2,4-dinitrophenol, abandoned after a high rate of adverse effects including hyperthermia, heavy sweating, fast heart rate and rapid breathing, and the mid-century combination products known as rainbow pills, which the review associates with many reported complications, including death.^[2]

Amphetamines and related sympathomimetic drugs sit in the same section. The review groups phentermine, benzphetamine, diethylpropion and phendimetrazine together and describes concerns about their adverse effect profiles, potential for abuse and cardiovascular risk.^[2] That history is why safety data, and not the number on the scale, decides whether an obesity drug survives.

What the licensed injectables actually reported

The evidence behind the 15% to 20% figure comes from two large trials. In STEP 1, the trial administered once-weekly subcutaneous semaglutide at 2.4 mg or placebo for 68 weeks alongside a lifestyle intervention, in 1961 adults with obesity or with overweight plus a related condition. The mean change in body weight from baseline to week 68 was minus 14.9% in the semaglutide group compared with minus 2.4% on placebo.^[3]

SURMOUNT-1 tested tirzepatide, which acts on the GIP and GLP-1 receptors, two gut hormone systems involved in insulin release and appetite. The trial assigned 2539 adults to once-weekly tirzepatide at 5 mg, 10 mg or 15 mg, or to placebo, for 72 weeks. Mean weight change at week 72 was minus 15.0% on the 5 mg dose, minus 19.5% on 10 mg and minus 20.9% on 15 mg, against minus 3.1% on placebo.^[4] Those are group averages under trial conditions, with monitoring and dose escalation that ordinary prescribing does not always match.

The case rests on more than the scale

The review's argument for calling this a genuine shift is that the weight number is no longer the only readout. It states that these agents confer additional substantial cardiometabolic benefits, including reductions in adverse cardiovascular and kidney outcomes, and improvements in glycaemia, blood pressure, lipid profile and steatohepatitis.^[1] Steatohepatitis is fatty liver disease with inflammation. Read that as a class-level summary drawn from several trial programmes rather than as a forecast for any one person.

What is still in development

The pipeline runs well past the two licensed injectables. A phase 2 trial of retatrutide, which targets the GIP, GLP-1 and glucagon receptors, reported a least-squares mean body weight change of minus 24.2% at 48 weeks on the 12 mg dose, against minus 2.1% on placebo.^[5] Retatrutide remains investigational and is not licensed for obesity in any market we cover.

The review also summarises the oral GLP-1 agent orforglipron, the amylin analog combination CagriSema and the dual agonist survodutide. It reports CagriSema at 20.4% weight loss against 3% on placebo in an obesity cohort, and survodutide at minus 12.2% and minus 13.0% on its two doses against minus 5.4% on placebo at week 76.^[2] None of that changes what a prescriber can offer today.

What we do not yet know

Two limitations run through the whole class. The review states that all current approaches to obesity management lead to loss of lean mass, typically representing around 25% of total weight lost, and possibly more at larger weight losses. It also states that cessation of treatment results in loss of therapeutic effect, with regain in weight and deterioration in blood pressure, lipid profile and health-related quality of life.^[2] Trials with up to three or four years of follow-up show sustained weight reduction with continued treatment, which is a different claim from a durable result after stopping.

Side effects are common rather than rare. For semaglutide 2.4 mg in STEP 1, the review records nausea in 44.2% of participants against 17.4% on placebo, vomiting in 24.8% against 6.6%, and diarrhea in 31.5% against 15.9%.^[2] Meta-analyses cited in the review have not demonstrated an association between GLP-1 agonist use and acute pancreatitis, while gallbladder disease shows a reported 37% increase in relative risk against controls.^[2]

Why this matters

The useful takeaway from this review is a sense of proportion. Obesity pharmacotherapy has a long record of withdrawals behind it, and the current drugs look different mainly because their outcome data extends beyond weight into cardiovascular and kidney endpoints.^[1] That is a reason to take the evidence seriously and also a reason to keep asking what happens after year four.

Both licensed agents are prescription medicines. Our tirzepatide regulation overview sets out how national regulators classify them, and the semaglutide reference page covers the evidence base in more detail. If you are considering treatment, or thinking about stopping, that conversation belongs with the clinician who would prescribe it rather than with a review article.