Promising outcomes from latest landmark diabetes trials: tirzepatide and finerenone in the spotlight

Abstract

SURPASS trials The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon line peptide 1 (GLP-1), are responsible for the increased insulin secretion from oral, as compared to intravenous, glucose administration which increases the amount of glucose ingested – known as the ‘incretin effect’. Incretins also slow down the digestion of food so that glucose from your meals takes longer to be absorbed, and thereby appetite is reduced with resulting weight loss. This has been exploited therapeutically by GLP-1 receptor agonists and dipeptidyl peptidase (DPP4) inhibitors. SURPASS is an array of double-blind, randomised phase 3 trials studying tirzepatide, a novel dual GIP and GLP-1 receptor agonist, a weekly subcutaneous injection in people with type 2 diabetes. The preceding 2018 phase 2 trials showed supportive results leading to much anticipation for this ‘twincretin’. Each trial included four arms of 5mg, 10mg and 15mg tirzepatide and placebo. The primary endpoint was mean change in HbA1c along with secondary outcomes of change in body weight and achieving target HbA1c. SURPASS-11 investigated tirzepatide monotherapy in 478 participants with a short duration of diabetes across 40 weeks (mean baseline HbA1c 63mmol/mol [7.9%], age 54, diabetes duration 4.7years, BMI 31.9kg/m2). HbA1c reductions were 21mmol/mol (1.9%), 21mmol/mol (1.9%) and 23mmol/mol (2%) with 5mg, 10mg and 15mg tirzepatide respectively. A dose dependent weight loss of 7–9.2kg was seen. SURPASS-22 was a 40-week head-to-head study of tirzepatide vs injectable semaglutide in 1879 people with a mean diabetes duration of 8.6 years. Tirzepatide showed improved outcomes with a 23–27mmol/mol (2.1–2.5%) vs 21mmol/mol (1.9%) HbA1c reduction and weight reductions of 7.6–11.2kg vs 5.7kg. Comparatively, the best weight loss seen in the phase 3 semaglutide SUSTAIN-7 trials was 6.5kg (mean baseline 95.2kg, duration of diabetes 7.4 years) and 20mmol/mol (1.8%) HbA1c drop. SURPASS-33 compared tirzepatide against the basal insulin degludec in 1444 participants taking metformin with or without an SGLT2 inhibitor. After 52 weeks, all three tirzepatide arms had decreased bodyweight (-7.5kg to -12.9kg), whereas insulin patients’ bodyweight increased by 2.3kg. Mean tirzepatide HbA1c reduction was 21–25mmol/mol(1.9–2.3%) vs 14mmol/mol (1.3%). The SURPASS-MRI sub-study4 involved participants with non-alcoholic fatty liver disease. Liver fat content was measured by MRI-proton density fat fraction with an absolute reduction of 8.1% in the pooled 10mg and 15mg tirzepatide groups vs 3.4% with insulin degludec. SURPASS-45 recruited a high cardiovascular risk cohort (87% had a previous event), who had lived with diabetes for a median of 10.5 years and mean HbA1c 69.7mmol/L (8.5%) despite multiple oral antihyperglycaemics. In a head-to-head 52-week trial vs insulin glargine U100, 5mg, 10mg and 15mg doses of tirzepatide led to HbA1c reductions of 24mmol/mol (2.2%), 26mmol/mol (2.4%) and 29mmol/mol (2.6%) respectively vs 15mmol/mol (1.4%) with insulin. At 78 weeks (1166 participants) and 104 weeks (199) the tirzepatide glycaemic and weight benefits were sustained. SURPASS-56 investigated those established on basal insulin with or without metformin over 40 weeks. A total of 475 participants (mean baseline HbA1c 67mmol/mol [8.3%], age 60, diabetes duration 13.4 years, BMI 3.4kg/m2) received either tirzepatide or placebo. Mean HbA1c reductions were 23mmol/mol (2.1%), 26mmol/mol (2.4%), 24mmol/mol (2.3%) vs 10mmol/mol (0.9%) in the placebo arm. Mean body weight reductions of 5.4kg, 7.5kg and 8.8kg compared with an increase of 1.6kg on placebo. Premature treatment discontinuation was high at 10–18% in the intervention arms vs 3% with placebo. Tirzepatide also showed statistically significant improvements in cholesterol in addition to improvements in blood pressure readings. Adverse effects observed across all tirzepatide studies were mainly mild to moderate gastrointestinal based and decreased over time. Clinically significant or severe hypoglycaemia events rates were below 1 per patient-year in all treatment groups but higher in SURPASS-5, understandably due to the combination with basal insulin. The SURPASS series collectively shine a light towards the future of type 2 diabetes treatments, particularly with the present sidelining of incretin-based therapies in the most recent NICE guidelines.7 However, crucial data are expected in 2024 from SURPASS-CVOT, the cardiovascular outcome trial with dulaglutide as a comparator, which will ultimately inform future practices. SURPASS-4 included cardiovascular outcomes with no excess risk Promising outcomes from latest landmark diabetes trials: tirzepatide and finerenone in the spotlight