Tirzepatide

Tirzepatide is a single peptide that activates both the glucose-dependent insulinotropic polypeptide (GIP) receptor and the glucagon-like peptide-1 (GLP-1) receptor. It is injected under the skin once a week [6]. It is approved for type 2 diabetes [1], and the US FDA approved it for chronic weight management in November 2023 under the name Zepbound [2].

Obesity. In SURMOUNT-1, 2,539 adults with obesity or overweight but no diabetes took 5, 10 or 15 mg or placebo for 72 weeks. Weight fell by 15.0%, 19.5% and 20.9% on the three doses, against 3.1% on placebo, and half or more of those on 10 or 15 mg lost at least 20% of their body weight [3]. Among participants who also had prediabetes, three years of treatment kept weight 12–20% lower. Only 1.3% developed type 2 diabetes, against 13.3% on placebo [7]. In SURMOUNT-5, an open-label head-to-head trial in 751 adults, tirzepatide lowered weight by 20.2% and semaglutide by 13.7% at 72 weeks [4].

Type 2 diabetes. Used alone, all three doses lowered HbA1c by about 1.9–2.1 points over 40 weeks without clinically significant hypoglycaemia [8]. Against semaglutide 1 mg it lowered HbA1c and weight more [9]. A meta-analysis of seven trials found larger, dose-dependent HbA1c and weight reductions than placebo, GLP-1 agonists or basal insulin [10]. In 13,299 people with diabetes and heart disease, tirzepatide was non-inferior to dulaglutide on heart attack, stroke and cardiovascular death, but did not prove superior (hazard ratio 0.92) [11].

Complications of obesity. In heart failure with preserved ejection fraction and obesity, fewer patients on tirzepatide died of cardiovascular causes or had worsening heart failure (9.9% vs 15.3%). Cardiovascular deaths alone were few and did not differ [12]. In sleep apnoea with obesity, it cut 20–24 more breathing events per hour than placebo [13].

Tirzepatide is a 39-amino-acid peptide with a fatty acid chain that binds albumin, which lets it last a week. It binds the GIP receptor about as strongly as native GIP does, and the GLP-1 receptor about five times more weakly than GLP-1 [6]. At clinically effective doses it occupies the GIP receptor more than the GLP-1 receptor. At the GIP receptor it behaves like native GIP. At the GLP-1 receptor it is biased: it drives the cAMP signal but recruits less β-arrestin and internalises the receptor less than GLP-1 does. In islet experiments, β-arrestin limited the insulin response to GLP-1 but not to tirzepatide [14].

In obese mice it lowered food intake and body weight more than a GLP-1 agonist alone [6]. In people with type 2 diabetes, it improved markers of insulin sensitivity and beta-cell function more than dulaglutide, and weight loss explained only part of the improvement [15]. Like GLP-1 agonists, it slows stomach emptying after the first dose, but this effect largely fades with repeated dosing [16].

The common side effects are gastrointestinal: nausea, diarrhoea, vomiting and constipation. They are mostly mild to moderate and happen mainly while the dose is being raised [3]. On 15 mg the odds of nausea were 5.6 times those on placebo, and more people on 15 mg stopped treatment because of side effects than on any comparator [10]. In SURMOUNT-1, 4.3–7.1% stopped because of side effects, against 2.6% on placebo [3].

A meta-analysis of nine trials found no significant increase in pancreatitis. Gallbladder or bile-duct disease was about twice as common as on placebo or basal insulin [17]. Hypoglycaemia was no more frequent than on placebo, and less frequent than on basal insulin [10].

Stopping leads to regain. In SURMOUNT-4, people who switched to placebo after 36 weeks regained 14% of their weight over the next year, while those who continued lost a further 5.5% [5].

Tirzepatide slows gastric emptying after the first doses [16]. No trial has combined it with another drug acting on the same receptors, such as Retatrutide.