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

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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://clinicaltrials.gov/ct2/show/NCT00535925

Supplementary Information

The online version contains supplementary material available at 10.1186/s12933-021-01343-1.

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Most cited references 35

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10-year follow-up of intensive glucose control in type 2 diabetes.

Rury R Holman, Sanjoy K Paul, M Angelyn Bethel … (2008)

During the United Kingdom Prospective Diabetes Study (UKPDS), patients with type 2 diabetes mellitus who received intensive glucose therapy had a lower risk of microvascular complications than did those receiving conventional dietary therapy. We conducted post-trial monitoring to determine whether this improved glucose control persisted and whether such therapy had a long-term effect on macrovascular outcomes. Of 5102 patients with newly diagnosed type 2 diabetes, 4209 were randomly assigned to receive either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin) for glucose control. In post-trial monitoring, 3277 patients were asked to attend annual UKPDS clinics for 5 years, but no attempts were made to maintain their previously assigned therapies. Annual questionnaires were used to follow patients who were unable to attend the clinics, and all patients in years 6 to 10 were assessed through questionnaires. We examined seven prespecified aggregate clinical outcomes from the UKPDS on an intention-to-treat basis, according to previous randomization categories. Between-group differences in glycated hemoglobin levels were lost after the first year. In the sulfonylurea-insulin group, relative reductions in risk persisted at 10 years for any diabetes-related end point (9%, P=0.04) and microvascular disease (24%, P=0.001), and risk reductions for myocardial infarction (15%, P=0.01) and death from any cause (13%, P=0.007) emerged over time, as more events occurred. In the metformin group, significant risk reductions persisted for any diabetes-related end point (21%, P=0.01), myocardial infarction (33%, P=0.005), and death from any cause (27%, P=0.002). Despite an early loss of glycemic differences, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up. A continued benefit after metformin therapy was evident among overweight patients. (UKPDS 80; Current Controlled Trials number, ISRCTN75451837.) 2008 Massachusetts Medical Society

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Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.

Peter Gæde, Pernille Vedel, Nicolai H. Larsen … (2003)

Cardiovascular morbidity is a major burden in patients with type 2 diabetes. In the Steno-2 Study, we compared the effect of a targeted, intensified, multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria. The primary end point of this open, parallel trial was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, revascularization, and amputation. Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment, with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with secondary prevention of cardiovascular disease with aspirin. The mean age of the patients was 55.1 years, and the mean follow-up was 7.8 years. The decline in glycosylated hemoglobin values, systolic and diastolic blood pressure, serum cholesterol and triglyceride levels measured after an overnight fast, and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group. Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease (hazard ratio, 0.47; 95 percent confidence interval, 0.24 to 0.73), nephropathy (hazard ratio, 0.39; 95 percent confidence interval, 0.17 to 0.87), retinopathy (hazard ratio, 0.42; 95 percent confidence interval, 0.21 to 0.86), and autonomic neuropathy (hazard ratio, 0.37; 95 percent confidence interval, 0.18 to 0.79). A target-driven, long-term, intensified intervention aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent. Copyright 2003 Massachusetts Medical Society

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Inflammation, atherosclerosis, and coronary artery disease.

Goran Hansson (2005)

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Author and article information

Contributors

Ferdinando Carlo Sasso:

ORCID: http://orcid.org/0000-0002-9142-7848

ferdinandocarlo.sasso@unicampania.it

Journal

Journal ID (nlm-ta): Cardiovasc Diabetol

Journal ID (iso-abbrev): Cardiovasc Diabetol

Title: Cardiovascular Diabetology

Publisher: BioMed Central (London )

ISSN (Electronic): 1475-2840

Publication date (Electronic): 16 July 2021

Publication date PMC-release: 16 July 2021

Publication date Collection: 2021

Volume: 20

Electronic Location Identifier: 145

Affiliations

[1 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Department of Advanced Medical and Surgical Sciences, , University of Campania “Luigi Vanvitelli”, ; Piazza Luigi Miraglia 2, 80138 Naples, Italy

[2 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Medical Statistics Unit, Department of Physical and Mental Health and Preventive Medicine, , University of Campania “Luigi Vanvitelli”, ; Piazza Luigi Miraglia 2, 80138 Naples, Italy

[3 ]GRID grid.9841.4, ISNI 0000 0001 2200 8888, Department of Precision Medicine, , University of Campania “Luigi Vanvitelli”, ; Via De Crecchio 7, 80138 Naples, Italy

Author information

Ferdinando Carlo Sasso http://orcid.org/0000-0002-9142-7848

Article

Publisher ID: 1343

DOI: 10.1186/s12933-021-01343-1

PMC ID: 8285851

PubMed ID: 34271948

SO-VID: ebbceb6d-187f-4ee0-b380-f9fd27b44d76

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 16 May 2021

Date accepted : 9 July 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003407, Ministero dell’Istruzione, dell’Università e della Ricerca;

Award ID: PRIN 2007

Award Recipient : Ferdinando Carlo Sasso

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ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetic nephropathy,multifactorial intervention,intensified treatment,cv risk factors,very high cv risk,mace

Data availability:

ScienceOpen disciplines: Endocrinology & Diabetes

Keywords: diabetic nephropathy, multifactorial intervention, intensified treatment, cv risk factors, very high cv risk, mace

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

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Journal of the ASEAN Federation of Endocrine Societies

Most cited references 35

10-year follow-up of intensive glucose control in type 2 diabetes.

Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.

Inflammation, atherosclerosis, and coronary artery disease.

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