Feasibility of high-dose tadalafil and effects on insulin resistance in well-controlled patients with type 2 diabetes (MAKROTAD): a single-centre, double-blind, randomised, placebo-controlled, cross-over phase 2 trial

**Background:** Endothelial dysfunction is an early pathophysiological feature in type 2 diabetes (T2D) that impairs insulin-mediated vasodilation via nitric oxide (NO) signalling. Phosphodiesterase-5 (PDE-5) inhibitors, which enhance NO signalling and vasodilation, have shown positive vascular and metabolic effects in preclinical and clinical studies, but no pre-registered trial had examined their effect on insulin resistance in well-controlled T2D patients of both sexes. The MAKROTAD trial tested whether high-dose tadalafil (20 mg daily) could reduce whole-body insulin resistance and improve metabolic control.

**Methods:** This single-centre, double-blind, randomised, placebo-controlled, two-period crossover phase 2 trial was conducted at Sahlgrenska University Hospital, Gothenburg, Sweden. Eligible participants were men (40–70 years) and post-menopausal women (55–70 years) with T2D duration 3 months to 10 years, HbA1c < 60 mmol/mol, and BMI 27–40 kg/m². Participants received tadalafil 20 mg once daily or placebo for 6 weeks, separated by an 8-week washout. The primary endpoint was difference in glucose disposal rate (M-value, mg/kgLBM/min) during a 3-hour euglycaemic hyperinsulinemic clamp. Secondary endpoints included HbA1c, fasting glucose, endothelial function (reactive hyperaemia index, RHI), liver markers (ALT, AST, ALP), inflammatory markers, beta-cell function, and tolerability. Statistical analysis used Fisher's non-parametric permutation test with period adjustment.

**Key Results:** Between January 2016 and January 2019, 23 participants were enrolled; 18 were included in the full analysis set (FAS; 12 men, 6 women; mean age 63.3 years, BMI 31.4 kg/m², diabetes duration 4 years, HbA1c 46 mmol/mol). Tadalafil did not significantly improve the primary endpoint: M-value mean difference 0.467 mg/kgLBM/min (95% CI −0.450 to 1.43, p = 0.39). However, tadalafil significantly reduced HbA1c by −2.50 mmol/mol (95% CI −4.20 to −0.78, p = 0.0051). Endothelial function improved significantly: RHI mean difference 0.306 (95% CI 0.083 to 0.525, p = 0.0064), and RHI correlated with HbA1c reduction (r = −0.39, p = 0.020). ALT, a marker of liver steatosis, was significantly reduced: −0.080 μkat/l (95% CI −0.127 to −0.034, p = 0.0013). Plasma lactate response during clamp increased (mean 198.7 μmol/l, 95% CI 53.1 to 358.3, p = 0.0078) and fasting plasma lactate decreased (mean −128.8 μmol/l, 95% CI −262.6 to 0.7, p = 0.025). No significant effects were seen on M/I value, HOMA-IR, fasting glucose, insulin, body composition, blood pressure, lipids, beta-cell function, or inflammatory markers. Adverse events were more frequent with tadalafil: gastrointestinal disorders (71.4% vs 27.3%, p = 0.0059), musculoskeletal disorders (71.4% vs 36.4%, p = 0.033), and nervous system disorders (57.1% vs 22.7%, p = 0.031). Common symptoms included headache (48%), dyspepsia (33%), and back pain (24%). Two participants withdrew due to adverse events.

**Clinical Implications:** High-dose tadalafil (20 mg daily) did not improve whole-body insulin resistance measured by glucose clamp in well-controlled T2D patients, but it significantly reduced HbA1c, improved endothelial function, and reduced liver steatosis markers. These effects may be mediated through improved microcirculation and hepatic metabolism rather than enhanced skeletal muscle insulin sensitivity. The HbA1c reduction of −2.50 mmol/mol (approximately 0.23%) is modest but clinically relevant, particularly given the short 6-week treatment duration. The correlation between improved endothelial function and HbA1c suggests a potential mechanistic link. However, tolerability was moderate, with approximately 50% of participants requiring temporary medication for headache, dyspepsia, or back pain. Larger, longer-term trials are warranted to determine whether lower doses or less frequent dosing (e.g., three times weekly) can maintain metabolic benefits with improved tolerability. The study was limited by small sample size, short duration, and multiple secondary outcomes increasing risk of false positives.