Elsevier

The American Journal of Medicine

Volume 130, Issue 12, December 2017, Pages 1465.e27-1465.e39
The American Journal of Medicine

Clinical Research Study
Chronic Kidney Disease, Basal Insulin Glargine, and Health Outcomes in People with Dysglycemia: The ORIGIN Study

https://doi.org/10.1016/j.amjmed.2017.05.047Get rights and content

Abstract

Background

Early stages of chronic kidney disease are associated with an increased cardiovascular risk in patients with established type 2 diabetes and macrovascular disease. The role of early stages of chronic kidney disease on macrovascular outcomes in prediabetes and early type 2 diabetes mellitus is not known. In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial, the introduction of insulin had no effect on cardiovascular outcomes compared with standard therapy. In this post hoc analysis of ORIGIN, we compared cardiovascular outcomes in subjects without to those with mild (Stages 1-2) or moderate chronic kidney disease (Stage 3).

Methods

Τwo co-primary composite cardiovascular outcomes were assessed. The first was the composite end point of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes; and the second was a composite of any of these events plus a revascularization procedure, or hospitalization for heart failure. Several secondary outcomes were prespecified, including microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers.

Results

Complete renal function data were available in 12,174 of 12,537 ORIGIN participants. A total of 8114 (67%) had no chronic kidney disease, while 4060 (33%) had chronic kidney disease stage 1-3. When compared with nonchronic kidney disease participants, the risk of developing the composite primary outcome (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in those with mild to moderate chronic kidney disease was 87% higher; hazard ratio (HR) 1.87; 95% confidence interval (CI), 1.71-2.04 (P < .0001). The presence of chronic kidney disease 1-3 was also associated with a greater than twofold higher risk for both all-cause mortality (HR 2.17; 95% CI, 1.98-2.38; P < .0001) and cardiovascular mortality (HR 2.39; 95% CI, 2.13-2.69; P < .0001). Moreover, patients with mild to moderate chronic kidney disease had significantly higher risk for nonfatal myocardial infarction (50%), nonfatal stroke (68%), any stroke (84%), the above composite primary end point plus revascularization or heart failure requiring hospitalization (59%), or a major coronary artery disease event (56%). Furthermore, in patients with chronic kidney disease and early diabetes mellitus type 2, the primary end point occurred 83% more frequently as compared with nonchronic kidney disease participants (HR 1.83; 95% CI, 1.67-2.01; P < .001) and in patients with prediabetes and chronic kidney disease 67% more frequently (HR 1.67; 95% CI,1.25-2.24; P < .001).

Conclusions

In high-risk patients with dysglycemia (prediabetes and early diabetes), mild and moderate chronic kidney disease significantly increased cardiovascular events.

Introduction

Both chronic kidney disease and diabetes mellitus are major causes of morbidity and mortality worldwide.1, 2 Several cohort studies have shown that chronic kidney disease is an independent predictor of cardiovascular disease, and that chronic kidney disease progression is associated with an increase in morbidity and mortality.3, 4, 5 Diabetes mellitus affects approximately 40% of people with chronic kidney disease, and is itself a strong risk factor for both all-cause and cardiovascular mortality.3, 6 Moreover, the excess mortality in people with both type 1 and type 2 diabetes mellitus is predominantly attributable to people with diabetes who have chronic kidney disease.7

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, participants with early stages of chronic kidney disease experienced approximately twice as many cardiovascular disease outcomes as those without chronic kidney disease.8 Analyses of these findings also suggested the hypothesis that chronic kidney disease participants may experience greater mortality with tight glycemic control than those without chronic kidney disease, however, the absence of a significant interaction between glycemic control and chronic kidney disease on mortality left this question unresolved. Similar findings have been reported in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study.9 The higher mortality with early chronic kidney disease in the ADVANCE and ACCORD studies occurred in subjects with approximately 8 and 11 years of diabetes mellitus type 2 whose baseline median hemoglobin (Hb)A1c levels were 7.5% and 8.1%, respectively.8, 9

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN trial) of dysglycemic participants with either prediabetes or early type 2 diabetes (of average duration 5 years) reported that basal glargine insulin-mediated normoglycemia had a neutral effect on cardiovascular outcomes.10, 11 In this subgroup analysis we examined the impact of early chronic kidney disease and of insulin glargine, in people with and without early chronic kidney disease, on cardiovascular outcomes in the ORIGIN participants.

Section snippets

Materials and Methods

ORIGIN was a multicenter randomized controlled trial of 12,537 high-risk patients with prediabetes or early diabetes mellitus type 2. It was designed to assess the effect of basal insulin on health outcomes, and the design and the results have been previously reported.10, 11, 12 The median follow-up period was 6.2 years. In brief, subjects of both sexes were recruited, aged 50 years or older, with prediabetes (ie, impaired glucose tolerance or impaired fasting glucose), or type 2 diabetes on

Study Population

Within the ORIGIN cohort, 82% had established diabetes mellitus type 2, 6% had newly diagnosed diabetes mellitus type 2; and 12% had impaired fasting glucose or impaired glucose tolerance.11 Complete renal function data were available in 12,174/12,537 (97.1%) ORIGIN participants, with 4060 (33%) with chronic kidney disease stage 1-3 and 8114 (67%) without chronic kidney disease. Of those with chronic kidney disease, 4.2% had chronic kidney disease 1, 9.6% had chronic kidney disease 2 (13.8%

Discussion

This subgroup analysis of the ORIGIN data clearly identifies both mild (chronic kidney disease 1-2) and moderate chronic kidney disease (stage 3) as significant risk factors for macrovascular outcomes in people with early dysglycemia. Moreover, these results were not impacted by the use of basal insulin glargine compared with standard treatment. The adverse role of mild to moderate chronic kidney disease on macrovascular outcomes are very similar to a previous analysis of the ACCORD trial,

References (24)

  • H. Gerstein et al.

    Rationale, design, and baseline characteristics for a large international trial of cardiovascular disease prevention in people with dysglycemia: the ORIGIN Trial (Outcome Reduction with an Initial Glargine Intervention)

    Am Heart J

    (2008)
  • The ORIGIN Trial Investigators

    Basal insulin and cardiovascular and other outcomes in dysglycemia

    N Engl J Med

    (2012)
  • Cited by (0)

    Funding: The ORIGIN trial was funded by Sanofi; ORIGIN ClinicalTrials.gov number, NCT00069784.

    Conflicts of Interest: The authors have nothing to declare. HCG is supported by the McMaster-Sanofi Population Health Institute Chair in Diabetes Research and Care. He has received research grant support from Sanofi, Lilly, AstraZeneca and Merck, honoraria for speaking from Sanofi, Novo Nordisk, Boehringer Ingelheim, and AstraZeneca, and consulting fees from Sanofi, Lilly, AstraZeneca, Merck, Novo Nordisk, Abbot, Amgen, and Boehringer Ingelheim.

    Authorship: All authors had access to the data and a role in writing this manuscript.

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