Efficacy and durability of multifactorial intervention on mortality and MACEs: a randomized clinical trial in type-2 diabetic kidney disease

Abstract

Background: Multiple modifiable risk factors for late complications in patients with diabetic kidney disease (DKD), including hyperglycemia, hypertension and dyslipidemia, increase the risk of a poor outcome. DKD is associated with a very high cardiovascular risk, which requires simultaneous treatment of these risk factors by implementing an intensified multifactorial treatment approach. However, the efficacy of a multifactorial intervention on major fatal/non-fatal cardiovascular events (MACEs) in DKD patients has been poorly investigated.

Methods: Nephropathy in Diabetes type 2 (NID-2) study is a multicentre, cluster-randomized, open-label clinical trial enrolling 395 DKD patients with albuminuria, diabetic retinopathy (DR) and negative history of CV events in 14 Italian diabetology clinics. Centres were randomly assigned to either Standard-of-Care (SoC) (n = 188) or multifactorial intensive therapy (MT, n = 207) of main cardiovascular risk factors (blood pressure < 130/80 mmHg, glycated haemoglobin < 7%, LDL, HDL and total cholesterol < 100 mg/dL, > 40/50 mg/dL for men/women and < 175 mg/dL, respectively). Primary endpoint was MACEs occurrence by end of follow-up phase. Secondary endpoints included single components of primary endpoint and all-cause death.

Results: At the end of intervention period (median 3.84 and 3.40 years in MT and SoC group, respectively), targets achievement was significantly higher in MT. During 13.0 years (IQR 12.4-13.3) of follow-up, 262 MACEs were recorded (116 in MT vs. 146 in SoC). The adjusted Cox shared-frailty model demonstrated 53% lower risk of MACEs in MT arm (adjusted HR 0.47, 95%CI 0.30-0.74, P = 0.001). Similarly, all-cause death risk was 47% lower (adjusted HR 0.53, 95%CI 0.29-0.93, P = 0.027).

Conclusion: MT induces a remarkable benefit on the risk of MACEs and mortality in high-risk DKD patients. Clinical Trial Registration ClinicalTrials.gov number, NCT00535925. https://ichgcp.net/clinical-trials-registry/NCT00535925.

Keywords: CV risk factors; Diabetic nephropathy; Intensified treatment; MACE; Multifactorial intervention; Very high CV risk.

Conflict of interest statement

Luca De Nicola has received fees for scientific consultation and/or lectures by Astellas, AstraZeneca, Mundibiopharma and Vifor Pharma. Roberto Minutolo has been member of Advisory Boards for Astellas, and invited speaker at meetings supported by Amgen, Vifor Pharma. Ferdinando Carlo Sasso has been member of Advisory Boards for Boehringer and for Ely-Lilly and has received fees for scientific consultation and/or lectures by Jansen, Roche Diagnostics, Novo Nordisk, Sanofi, MSD, Astrazeneca. Pia Clara Pafundi, Vittorio Simeon, Paolo Chiodini, Raffaele Galiero, Luca Rinaldi, Riccardo Nevola, Teresa Salvatore, Raffaele Marfella, Celestino Sardu, and Luigi Elio Adinolfi have no conflict of interest to disclose.

© 2021. The Author(s).

Figures

Fig. 1

Flow chart of patients participating to the study

Fig. 2

Changes in Blood Pressure, Glycemic and Lipids Control during the Interventional Study Period in the two arms of the study. A–E Mean (± SD) values for selected risk factors during the interventional part of the study for patients under Standard of Care (SoC) treatment (grey lines) and multifactorial therapy (MT) (black lines). Mean values were obtained at baseline, after 1-year, after 2-years and at end of interventional period (3.84 years in MT and 3.40 years in SoC). At these intervals, the total numbers of patients in both study groups were 395, 380, 372, and 368, respectively

Fig. 3

Kaplan–Meier Estimates of the Composite Endpoint of MACEs during the whole study period (intervention and follow-up) (A) and of mortality during the whole study period (intervention and follow-up) (B) in the Conventional-Therapy and Intensive-Therapy Groups, respectively