title: Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus: the delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial.
abstract: To assess whether angiotensin-converting enzyme inhibitors and third-generation dihydropyridine calcium channel blockers ameliorate diabetic complications, we compared glomerular filtration rate (GFR; primary outcome), cardiovascular events, retinopathy, and neuropathy in 380 hypertensive type 2 diabetics with albuminuria <200 mg/min included in a multicenter, double-blind, placebo-controlled trial (DEMAND [Delapril and Manidipine for Nephroprotection in Diabetes]) and randomized to 3-year treatment with manidipine/delapril combination (10/30 mg/d; n=126), delapril (30 mg/d; n=127), or placebo (n=127). GFR was centrally measured by iohexol plasma clearance. Median monthly GFR decline (interquartile range [IQR]) was 0.32 mL/min per 1.73 m(2) (IQR: 0.16-0.50 mL/min per 1.73 m(2)) on combined therapy, 0.36 mL/min per 1.73 m(2) (IQR: 0.18-0.53 mL/min per 1.73 m(2)) on delapril, and 0.30 mL/min per 1.73 m(2) (IQR: 0.12-0.50 mL/min per 1.73 m(2)) on placebo (P=0.87 and P=0.53 versus combined therapy or delapril, respectively). Similar findings were observed when baseline GFR values were not considered for slope analyses. Albuminuria was stable in the 3 treatment groups. The hazard ratio (95% CI) for major cardiovascular events between combined therapy and placebo was 0.17 (0.04-0.78; P=0.023). Among 192 subjects without retinopathy at inclusion, the hazard ratio for developing retinopathy between combined therapy and placebo was 0.27 (0.07-0.99; P=0.048). Among 200 subjects with centralized neurological evaluation, the odds ratios for peripheral neuropathy at 3 years between combined therapy or delapril and placebo were 0.45 (0.24-0.87; P=0.017) and 0.52 (0.27-0.99; P=0.048), respectively. Glucose disposal rate decreased from 5.8±2.4 to 5.3±1.9 mg/kg per min on placebo (P=0.03) but did not change on combined or delapril therapy. Treatment was well tolerated. In hypertensive type 2 diabetic patients, combined manidipine and delapril therapy failed to slow GFR decline but safely ameliorated cardiovascular disease, retinopathy, and neuropathy and stabilized insulin sensitivity.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Bergamo, Italy. pruggenenti@ospedaliriuniti.bergamo.it
authors.forename: Piero
authors.initials: P
authors.lastname: Ruggenenti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lauria
authors.forename: Ilian Petrov
authors.initials: IP
authors.lastname: Iliev
authors.forename: Anna
authors.initials: A
authors.lastname: Fassi
authors.forename: Aneliya Parvanova
authors.initials: AP
authors.lastname: Ilieva
authors.forename: Stefano
authors.initials: S
authors.lastname: Rota
authors.forename: Carlos
authors.initials: C
authors.lastname: Chiurchiu
authors.forename: Drazenka Pongrac
authors.initials: DP
authors.lastname: Barlovic
authors.forename: Angelo
authors.initials: A
authors.lastname: Sghirlanzoni
authors.forename: Raffaella
authors.initials: R
authors.lastname: Lombardi
authors.forename: Paola
authors.initials: P
authors.lastname: Penza
authors.forename: Guido
authors.initials: G
authors.lastname: Cavaletti
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Piatti
authors.forename: Barbara
authors.initials: B
authors.lastname: Frigeni
authors.forename: Marco
authors.initials: M
authors.lastname: Filipponi
authors.forename: Nadia
authors.initials: N
authors.lastname: Rubis
authors.forename: Greta
authors.initials: G
authors.lastname: Noris
authors.forename: Nicola
authors.initials: N
authors.lastname: Motterlini
authors.forename: Bogdan
authors.initials: B
authors.lastname: Ene-Iordache
authors.forename: Flavio
authors.initials: F
authors.lastname: Gaspari
authors.forename: Annalisa
authors.initials: A
authors.lastname: Perna
authors.forename: Jelka
authors.initials: J
authors.lastname: Zaletel
authors.forename: Antonio
authors.initials: A
authors.lastname: Bossi
authors.forename: Alessandro Roberto
authors.initials: AR
authors.lastname: Dodesini
authors.forename: Roberto
authors.initials: R
authors.lastname: Trevisan
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D001786:Blood Glucose / Q000032:analysis / Q000187:drug effects*; D015992:Body Mass Index; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000009:adverse effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy; D003928:Diabetic Nephropathies / Q000517:prevention & control; D004095:Dihydropyridines / Q000008:administration & dosage* / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension / Q000150:complications* / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D007189:Indans / Q000008:administration & dosage* / Q000009:adverse effects; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D009578:Nitrobenzenes; D010879:Piperazines; D011379:Prognosis; D018570:Risk Assessment; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D001786:Blood Glucose; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007189:Indans; D009578:Nitrobenzenes; D010879:Piperazines; C054218:manidipine; C047759:delapril