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

Piero Ruggenenti, Giuseppe Lauria, Ilian Petrov Iliev, Anna Fassi, Aneliya Parvanova Ilieva, Stefano Rota, Carlos Chiurchiu, Drazenka Pongrac Barlovic, Angelo Sghirlanzoni, Raffaella Lombardi, Paola Penza, Guido Cavaletti, Maria Luisa Piatti, Barbara Frigeni, Marco Filipponi, Nadia Rubis, Greta Noris, Nicola Motterlini, Bogdan Ene-Iordache, Flavio GaspariAnnalisa Perna, Jelka Zaletel, Antonio Bossi, Alessandro Roberto Dodesini, Roberto Trevisan, Giuseppe Remuzzi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)776-783
Number of pages8
JournalHypertension
Volume58
Issue number5
DOIs
Publication statusPublished - Nov 2011

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manidipine
Type 2 Diabetes Mellitus
Randomized Controlled Trials
Placebos
Therapeutics
Albuminuria
delapril
Iohexol

Keywords

  • ACE inhibitors
  • Calcium channel blockers
  • Cardiovascular complications
  • Diabetic nephropathy
  • Diabetic neuropathy
  • Diabetic retinopathy
  • Manidipine

ASJC Scopus subject areas

  • Internal Medicine

Cite this

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. / Ruggenenti, Piero; Lauria, Giuseppe; Iliev, Ilian Petrov; Fassi, Anna; Ilieva, Aneliya Parvanova; Rota, Stefano; Chiurchiu, Carlos; Barlovic, Drazenka Pongrac; Sghirlanzoni, Angelo; Lombardi, Raffaella; Penza, Paola; Cavaletti, Guido; Piatti, Maria Luisa; Frigeni, Barbara; Filipponi, Marco; Rubis, Nadia; Noris, Greta; Motterlini, Nicola; Ene-Iordache, Bogdan; Gaspari, Flavio; Perna, Annalisa; Zaletel, Jelka; Bossi, Antonio; Dodesini, Alessandro Roberto; Trevisan, Roberto; Remuzzi, Giuseppe.

In: Hypertension, Vol. 58, No. 5, 11.2011, p. 776-783.

Research output: Contribution to journalArticle

Ruggenenti, P, Lauria, G, Iliev, IP, Fassi, A, Ilieva, AP, Rota, S, Chiurchiu, C, Barlovic, DP, Sghirlanzoni, A, Lombardi, R, Penza, P, Cavaletti, G, Piatti, ML, Frigeni, B, Filipponi, M, Rubis, N, Noris, G, Motterlini, N, Ene-Iordache, B, Gaspari, F, Perna, A, Zaletel, J, Bossi, A, Dodesini, AR, Trevisan, R & Remuzzi, G 2011, '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', Hypertension, vol. 58, no. 5, pp. 776-783. https://doi.org/10.1161/HYPERTENSIONAHA.111.174474
Ruggenenti, Piero ; Lauria, Giuseppe ; Iliev, Ilian Petrov ; Fassi, Anna ; Ilieva, Aneliya Parvanova ; Rota, Stefano ; Chiurchiu, Carlos ; Barlovic, Drazenka Pongrac ; Sghirlanzoni, Angelo ; Lombardi, Raffaella ; Penza, Paola ; Cavaletti, Guido ; Piatti, Maria Luisa ; Frigeni, Barbara ; Filipponi, Marco ; Rubis, Nadia ; Noris, Greta ; Motterlini, Nicola ; Ene-Iordache, Bogdan ; Gaspari, Flavio ; Perna, Annalisa ; Zaletel, Jelka ; Bossi, Antonio ; Dodesini, Alessandro Roberto ; Trevisan, Roberto ; Remuzzi, Giuseppe. / 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. In: Hypertension. 2011 ; Vol. 58, No. 5. pp. 776-783.
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T1 - Effects of manidipine and delapril in hypertensive patients with type 2 diabetes mellitus

T2 - The delapril and manidipine for nephroprotection in diabetes (DEMAND) randomized clinical trial

AU - Ruggenenti, Piero

AU - Lauria, Giuseppe

AU - Iliev, Ilian Petrov

AU - Fassi, Anna

AU - Ilieva, Aneliya Parvanova

AU - Rota, Stefano

AU - Chiurchiu, Carlos

AU - Barlovic, Drazenka Pongrac

AU - Sghirlanzoni, Angelo

AU - Lombardi, Raffaella

AU - Penza, Paola

AU - Cavaletti, Guido

AU - Piatti, Maria Luisa

AU - Frigeni, Barbara

AU - Filipponi, Marco

AU - Rubis, Nadia

AU - Noris, Greta

AU - Motterlini, Nicola

AU - Ene-Iordache, Bogdan

AU - Gaspari, Flavio

AU - Perna, Annalisa

AU - Zaletel, Jelka

AU - Bossi, Antonio

AU - Dodesini, Alessandro Roberto

AU - Trevisan, Roberto

AU - Remuzzi, Giuseppe

PY - 2011/11

Y1 - 2011/11

N2 - 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.

AB - 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.

KW - ACE inhibitors

KW - Calcium channel blockers

KW - Cardiovascular complications

KW - Diabetic nephropathy

KW - Diabetic neuropathy

KW - Diabetic retinopathy

KW - Manidipine

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