Giuseppe Derosa,1–4 Giovanni Gaudio,5 Gianfranco Pasini,6 Angela D’Angelo,1,4 Pamela Maffioli1 1Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S Matteo, Pavia, Italy; 2Center for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University of Pavia, Pavia, Italy; 3Center for Prevention, Surveillance, Diagnosis and Treatment of Rare Diseases, Fondazione IRCCS Policlinico S Matteo, Pavia, Italy; 4Laboratory of Molecular Medicine, University of Pavia, Pavia, Italy; 5Internal Medicine Division, Ospedale Angelo Bellini, Somma Lombardo, Varese, Italy; 6Cardiologic Unit, Ospedale di Gavardo, Brescia, Italy Aim: The aim of this study was to evaluate the effects of canrenone compared to hydrochlorothiazide (HCTZ) added to angiotensin II receptor blockers (ARBs) on glycemia, lipid profile, potassium, aldosterone and renal function in patients with hypertension and type 2 diabetes mellitus.Patients and methods: The study enrolled 182 Caucasian patients with hypertension and type 2 diabetes mellitus. Patients were already taking ARBs and were randomized to canrenone, 50mg once a day, or HCTZ, 12.5mg once a day for 1month. After the first month, patients not reaching an adequate blood pressure (BP) were up-titrated to canrenone 100mg or HCTZ 25mg once a day for 12months. The following parameters were considered at 6 and 12months: BP, body weight, body mass index (BMI), fasting plasma glucose (FPG), post-prandial glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin (HOMA-IR), lipid profile, potassium, plasma aldosterone, urine albumin excretion rate and estimated glomerular filtration rate (eGFR).Results: We observed a similar decrease in BP with both treatments. Canrenone led to a significant decrease in FPG, PPG and HOMA index compared to baseline, while there was a significant increase in the same parameters with HCTZ. HCTZ also worsened glycated hemoglobin (HbA1c), while canrenone did not change it. No variations in lipid profile were recorded with canrenone, while there was a worsening of total cholesterol (TC) and triglycerides (Tg) with HCTZ. Potassium levels were decreased and uric acid levels were increased by HCTZ, but not by canrenone that had a neutral effect on these parameters. We recorded a slight decrease in eGFR with HCTZ and an improvement with canrenone; creatinine and eGFR were improved by canrenone compared to HCTZ. Plasma aldosterone levels were decreased by canrenone and increased by HCTZ.Conclusion: Canrenone and HCTZ have a similar effect on BP; however, canrenone seems to improve metabolic parameters, while HCTZ worsens them. Keywords: canrenone, hydrochlorothiazide, type 2 diabetes mellitus, metabolismA Letter to the Editor has been received and published for this article.