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Observational Study
. 2019 Nov 16;18(1):159.
doi: 10.1186/s12933-019-0961-7.

Microvascular complications burden (nephropathy, retinopathy and peripheral polyneuropathy) affects risk of major vascular events and all-cause mortality in type 1 diabetes: a 10-year follow-up study

Monia Garofolo  1 , Elisa Gualdani  2 , Rosa Giannarelli  1 , Michele Aragona  1 , Fabrizio Campi  1 , Daniela Lucchesi  1 , Giuseppe Daniele  1 , Roberto Miccoli  1 , Paolo Francesconi  2 , Stefano Del Prato  3 , Giuseppe Penno  1
Affiliations
Observational Study

Microvascular complications burden (nephropathy, retinopathy and peripheral polyneuropathy) affects risk of major vascular events and all-cause mortality in type 1 diabetes: a 10-year follow-up study

Monia Garofolo et al. Cardiovasc Diabetol. .

Abstract

Background: Microvascular complications (MC) have been claimed to increase the risk for cardiovascular disease in diabetic subjects. However, the effect of MC burden on the risk of major vascular outcomes and all-cause mortality in type 1 diabetes is still poorly explored. We evaluated the relationship between microvascular complications burden and incidence of major cardiovascular events and all-cause mortality in subjects with type 1 diabetes.

Methods: We recruited 774 participants with type 1 diabetes in a single-center observational study over a follow-up of 10.8 ± 2.5 years. Hazard ratios (HR) for cardiovascular outcomes and all-cause death associated with microvascular complications were determined by unadjusted and adjusted Cox regression analysis.

Results: Out of 774 individuals, 54.9% had no-MC, 32.3% 1 MC, 9.7% 2 MC and 3.1% 3 MC. A total of 54 deaths (7.0%) occurred. Death rate increased from no-MC 2.1% (Ref) to 1 MC 7.2% (HR 3.54 [95% CI 1.59-7.87]), 2 MC 14.7% (HR 6.41 [95% CI 2.65-15.49]) and 3 MC 66.7% (HR 41.73 [95% CI 18.42-94.57], p < 0.0001). After adjustments, HRs were: 1 MC 2.05 (95% CI 0.88-4.76), 2 MC 1.98 (95% CI 0.75-5.21), 3 MC 7.02 (95% CI 2.44-20.20, p = 0.002). Forty-nine subjects (6.7%) had at least one cardiovascular event, and cumulative incidence went from no-MC 2.2% (Ref) to 1 MC 5.0%; (HR 2.27 [95% CI 0.96-5.38]), 2 MC 26.8% (HR 12.88 [95% CI 5.82-28.50]) and 3 MC 40.9% (HR 29.34 [95% CI 11.59-74.25], p < 0.0001). Upon adjustments, HRs were: 1 MC 1.59 (95% CI 0.65-3.88), 2 MC 4.33 (95% CI 1.75-10.74), 3 MC 9.31 (95% CI 3.18-27.25, p < 0.0001). Thirty-five individuals (4.8%) had at least one coronary event, which cumulative incidence increased with MC burden (p < 0.0001).

Conclusions: In type 1 diabetes, microvascular complications burden increases in an independent dose-dependent manner the risk of major cardiovascular outcomes and all-cause mortality. The presence and number of microvascular complications should be considered in stratifying overall cardiovascular risk in type 1 diabetes.

Keywords: All-cause mortality; Cardiovascular disease; Diabetic kidney disease; Diabetic retinopathy; Microvascular burden; Microvascular complications; Peripheral diabetic polyneuropathy; Type 1 diabetes mellitus.

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Conflict of interest statement

MG has received travel grants from AstraZeneca and Novo Nordisk. MA has received speaker/advisory honoraria from Abbott Laboratories. FC has received travel grants from Novo Nordisk. GD reports past participation in advisory boards from AstraZeneca, Eli Lilly and Co and Novartis Pharmaceuticals. SDP reports past participation in advisory boards and/or receiving research grants from Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, Sanofi, Servier, and Takeda Pharmaceuticals. GP has received travel grants and speaker/advisory honoraria from AstraZeneca, Boehringer Ingelheim, Eli Lilly and Co, Merck Sharp & Dohme, Mundipharma Pharmaceuticals, Novo Nordisk, and Takeda Pharmaceuticals. All other authors (EG, RG, DL, MR, and PF) declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Kaplan–Meier curves for all-cause death and cumulative incidences of major vascular and coronary events by MC. no-MC: dotted green line, 1 MC: dashed blue line, 2 MC: dashdotted violet line, 3 MC: solid red line. Percentages of events and Cox proportional unadjusted HRs (95% CI) are shown for each MC group. a Survival from all-cause death: K–M Logrank 187.35, p < 0.0001. Pairwise over strata logrank statistic provides the following results: 1 MC vs. no-MC, logrank 10.96 (p = 0.0009); 2 MC vs. no-MC, logrank 22.77 (p < 0.0001); furthermore, 3 MC vs. no-MC, logrank 223.18, vs. 1 MC, logrank 78.94 and vs. 2 MC, logrank 30.62 (p < 0.0001, for all). b Cumulative incidence of major vascular events: K–M Logrank 127.61, p < 0.0001. Pairwise over strata logrank statistic provides the following results: 1 MC vs. no-MC, logrank 3.71 (p = 0.054); 2 MC vs. no-MC, logrank 67.22 and vs. 1 MC, logrank 28.49 (p < 0.0001, for both); furthermore, 3 MC vs. no-MC, logrank 110.38, vs. 1 MC, logrank 57.81 (p < 0.0001, for both) and vs. 2 MC, logrank 4.15 (p = 0.042). c Cumulative incidence of coronary events: K–M Logrank 81.47, p < 0.0001. Pairwise over strata logrank statistic provides the following results: 2 MC vs. no-MC, logrank 40.60 and vs. 1 MC, logrank 26.17 (p < 0.0001, for both); 3 MC vs. no-MC, logrank 55.23, vs. 1 MC, logrank 44.18 (p < 0.0001, for both)
Fig. 2
Fig. 2
Adjusted HR for all-cause mortality by MC in the whole cohort. Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, smoking habits, age at diagnosis of diabetes ≤ 18 years (n = 342; 44.2%), diabetes duration, BMI, HbA1c, LDL-cholesterol, HDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension and prior CV events. Model 3: adjusted for sex, smoking habits, age at diagnosis of diabetes ≤ 18 years, diabetes duration, LDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension, previous CV events and EURODIAB PCS risk score categories
Fig. 3
Fig. 3
Adjusted HR for all-cause mortality by MC in CVD−. Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, smoking habits, age at diagnosis of diabetes ≤ 18 years (n = 324; 44.2%), diabetes duration, BMI, HbA1c, LDL-cholesterol, HDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension and prior CV events. Model 3: adjusted for sex, smoking habits, age at diagnosis of diabetes ≤ 18 years, diabetes duration, LDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension, previous CV events and EURODIAB PCS risk score categories
Fig. 4
Fig. 4
Adjusted HR for major vascular (a) and coronary events (b) by MC in the whole cohort. Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, smoking habits, age at diagnosis of diabetes ≤ 18 years (n = 322, 43.8%), diabetes duration, BMI, HbA1c, LDL-cholesterol, HDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension and prior CV events. Model 3: adjusted for sex, smoking habits, age at diagnosis of diabetes ≤ 18 years, diabetes duration, LDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension, previous CV events and EURODIAB PCS risk score categories
Fig. 5
Fig. 5
Adjusted HR for major vascular (a) and coronary events (b) by MC in CVD−. Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, smoking habits, age at diagnosis of diabetes ≤ 18 years (n = 305, 43.8%), diabetes duration, BMI, HbA1c, LDL-cholesterol, HDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension and prior CV events. Model 3: adjusted for sex, smoking habits, age at diagnosis of diabetes ≤ 18 years, diabetes duration, LDL-cholesterol, triglycerides, uric acid, fibrinogen, hypertension, previous CV events and EURODIAB PCS risk score categories
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