Prediabetes — defined by impaired fasting glucose, impaired glucose tolerance, or both — is one of the fastest-growing metabolic conditions on the planet, and it is far from benign. People carrying the diagnosis face a sharply elevated risk of progressing to type 2 diabetes and of developing cardiovascular disease, and some diabetic complications, including nerve damage, begin while blood sugar is still technically classified as normal. Standard care relies on intensive lifestyle modification, with metformin reserved for selected patients. The biological case for incretin-based therapy is compelling: glucagon-like peptide-1 is a gut hormone released after meals that amplifies glucose-dependent insulin secretion from pancreatic beta cells, slows gastric emptying and acts on hypothalamic appetite circuits. Landmark observational work, including the ADDITION-PRO study, has shown that this GLP-1 response to oral glucose is measurably blunted in prediabetes, obesity and screen-detected diabetes — providing a clear mechanistic rationale for pharmacologically replacing what the disease process takes away.

The experimental groundwork was laid long before these drugs became household names. Nearly thirty years ago, GLP-1 was shown to improve glucose sensitivity in the beta cells of prediabetic non-obese diabetic mice. In Goto-Kakizaki rats, a lean model of type 2 diabetes, treatment with native GLP-1 or the long-acting mimetic exendin-4 during the prediabetic phase increased pancreatic insulin content, stimulated beta-cell regeneration and lowered plasma glucose within days. More dramatically, twelve weeks of liraglutide in prediabetic Otsuka Long-Evans Tokushima rats essentially abolished progression: 87.5 percent of vehicle-treated animals developed diabetes by week 12, whereas none of the treated rats did, 42.9 percent returned to normoglycaemia, and histology revealed restored islet size alongside improved insulin sensitivity indices. In fructose-fed Wistar rats, exendin-4 reduced liver fructokinase, AMP-deaminase and glucose-6-phosphate dehydrogenase activity, hinting at hepatic benefits for fatty liver disease — a condition now affecting an estimated 42.4 percent of people with prediabetes. Tirzepatide, the newest agent reviewed, is distinct in kind: a single 39-amino-acid molecule that agonizes both the GIP and GLP-1 receptors.

The human data began with liraglutide at its 3 mg obesity dose. In a randomized, double-blind, three-year trial, only 2 percent of participants on the drug developed type 2 diabetes versus 6 percent on placebo — 3 percent versus 11 percent after statistical adjustment. Treatment stretched the average interval to diagnosis 2.7-fold (hazard ratio 0.21) and returned 66 percent of participants to normoglycaemia versus 36 percent of controls, a number needed to treat of just 3. HbA1c fell 0.21 percentage points, fasting glucose dropped 0.41 mmol/L, fasting insulin declined 10.1 percent, and body weight fell an estimated 4.3 percent more than placebo, with benefits independent of baseline BMI. Crucially, some protection outlasted the drug: twelve weeks after withdrawal, half of the treated participants were still normoglycaemic. Systolic blood pressure and C-reactive protein also fell, prespecified cardiovascular events occurred less often (12.1 versus 15.1 events per 100 person-years), and quality-of-life scores improved. Gastrointestinal side effects — nausea, diarrhoea, constipation — were mild to moderate and roughly four times more frequent than with placebo.

Subsequent studies probed how the drug works. In a post-hoc analysis of adults with prediabetes or early type 2 diabetes, liraglutide significantly shrank visceral adipose tissue without touching subcutaneous fat, improved the beta-cell function index and raised insulin-like growth factor II. A three-arm trial pitting liraglutide against the DPP-4 inhibitor sitagliptin and caloric restriction found that weight loss exceeding 5 percent occurred in 44 percent of dieters but only 22 percent on the drug — although liraglutide beat sitagliptin decisively and, uniquely, did so without provoking hunger, instead reducing feelings of fullness and the willingness to eat. Insulin resistance, measured by HOMA-IR, dropped 35.4 percent with dieting and 30.8 percent with liraglutide. The most revealing experiment came when researchers infused exendin 9-39, a GLP-1 receptor antagonist: the blocker reversed liraglutide’s effects on postprandial insulin, C-peptide and the Matsuda insulin-sensitivity index, and the team concluded that liraglutide enhances insulin sensitivity through a mechanism partly independent of weight loss — direct evidence that the drug reprograms glucose metabolism itself, not merely the bathroom scale.

Semaglutide then raised the stakes. In STEP 10, a phase 3 trial of once-weekly 2.4 mg subcutaneous semaglutide in people with obesity and prediabetes (baseline HbA1c 6.0–6.4 percent), 81 percent of treated participants achieved normal glucose regulation at 52 weeks versus 14 percent on placebo — an odds ratio of 19.8. Body weight fell 7.9 percent versus 1.3 percent, HbA1c dropped 0.5 percentage points, fasting glucose 0.6 mmol/L, waist circumference 8.3 centimetres and systolic blood pressure 7.8 mmHg, alongside improvements in cholesterol and triglycerides. Only 3 percent of the semaglutide group progressed to diabetes versus 8 percent of controls. Yet the mandated 28-week off-treatment period told the other half of the story: normal glucose was maintained in just 44 percent versus 18 percent, some weight returned — though no participant regained it all — and lipid benefits largely faded. The longer STEP 1 extension, tracking participants for 52 weeks after withdrawal, echoed the pattern: 93.6 percent normoglycaemia on treatment fell to 43.3 percent, still ahead of placebo’s 34.0 percent, while a 17.3 percent weight loss eroded to a net 5.6 percent.

Tirzepatide has now produced the most dramatic prevention results ever recorded for this class. In a phase 3 trial published in the New England Journal of Medicine, 1,092 adults with overweight or obesity and prediabetes were randomized to 5, 10 or 15 mg of weekly tirzepatide or placebo. Weight losses ranged from 12.3 percent to 19.7 percent of body weight — up to 21.4 kilograms — versus 1.3 percent on placebo. Across three years, between 0.4 and 2.0 percent of treated participants developed type 2 diabetes, versus 13.3 percent of controls, and nearly every participant on the drug achieved normoglycaemia compared with 58.9 percent of controls. The benefit survived a 17-week off-treatment period: only 2.4 percent of former tirzepatide users developed diabetes versus 13.7 percent of controls, a hazard ratio of 0.12, and 73.7 to 82.1 percent maintained normal glucose. Mediation analysis attributed 38.9 percent of the diabetes-risk reduction to weight loss itself — meaning nearly two-thirds of the protective effect operated through other channels, including insulin secretion and insulin sensitivity.

Post-hoc analyses of the three-year SURMOUNT-1 programme quantify those channels. Using the Cardiometabolic Disease Staging risk engine, investigators calculated that tirzepatide cut participants’ median predicted 10-year diabetes risk by roughly 60 percent versus about 11 percent on placebo, with absolute reductions of 8.9 to 14.0 percentage points depending on dose. Cardiovascular modelling with the ACC/AHA and PREVENT equations showed that treated participants were 2.4 to 3.5 times more likely to move into a better risk category; their composite 10-year risk for atherosclerotic disease and heart failure fell to 2.5–3.2 percent while placebo users climbed to 4.3 percent — total predicted cardiovascular risk rose 43.8 percent in controls over the trial while edging down under tirzepatide. Detailed metabolic testing showed HOMA2-IR normalizing to the levels of people without dysglycaemia by week 72, significantly improved beta-cell glucose sensitivity, and enhancements in insulin secretion that remained attributable to the drug itself after adjustment for weight loss. Among Chinese participants in SURMOUNT-CN, predicted diabetes risk fell 76 to 80 percent. And in a real-world cohort of 5,100 patients per group, 4.7 percent of those on tirzepatide progressed to diabetes versus 12.5 percent on metformin — a risk ratio of 0.37.

The authors are careful about limits. Most tirzepatide evidence comes from post-hoc analyses of trials designed for obesity, nearly all participants had overweight or obesity, off-treatment follow-up is short and heterogeneous, and the gains in HbA1c and weight demonstrably decay after withdrawal. Safety, at least, appears manageable: mild-to-moderate gastrointestinal complaints dominate, with rare pancreatitis and gallbladder disease reported in trials. The field is already moving beyond today’s drugs — the triple agonist retatrutide, targeting GLP-1, GIP and glucagon receptors, produced prediabetes remission in 72 percent of phase 2 participants versus 22 percent on placebo. Economics loom equally large: Americans spent roughly 71 billion dollars on GLP-1 receptor agonists in 2023, and cost-effectiveness analyses suggest prices must fall about 70 percent for widespread preventive use — a target the 2024 expiry of liraglutide’s patent and emerging generics may approach, notably for the best-studied agent in this indication. The review’s conclusion is unequivocal: liraglutide, semaglutide and tirzepatide improve weight, insulin sensitivity, glycaemia and cardiovascular risk in prediabetes, with tirzepatide the most powerful agent to date, but large randomized prevention trials must now define who benefits most — and for how long.