Basal insulin and cardiovascular and other outcomes in dysglycemia
Basal Insulin and Cardiovascular and Other Outcomes in Dysglycemia
The ORIGIN Trial Investigators
NEJM 2012 (published online before print) DOI: 10.1056/NEJMoa1203858
An elevated fasting plasma glucose level is an independent risk factor for adverse cardiovascular outcomes [1-7]. Elevated fasting plasma glucose levels (above 5.6 mmol/l) indicate an insufficient endogenous insulin secretion to overcome underlying insulin resistance [8,9]. Correcting this deficiency by early provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular outcomes and may also reduce incident diabetes in people at risk for diabetes.
The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial tested these hypotheses.
In a 2 x 2 factorial design, more than 12,500 patients with impaired fasting glucose, impaired glucose tolerance, or diabetes were randomized to either insulin glargine or standard care.
Insulin glargine versus standard care:
- Nonfatal MI, nonfatal stroke, or CV death: 16.6% versus 16.1% (hazard ratio, 1.02, CI 0.94 – 1.11, p = 0.63)
- Nonfatal MI, nonfatal stroke, CV death, revascularization or HF hospitalization: 28.6% versus 27.5%, HR 1.04, CI 0.97 – 1.11, p = 0.27)
Daily insulin glargine injections, started during the early stages of type 2 diabetes, neither increased nor reduced the risks for myocardial infarction, stroke, cancer, or CV-related mortality. The glycemic benefit of insulin glargine might have an impact on microvascular or other outcomes, but the trial does not support changing standard therapies for early dysglycemia.
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The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events, but such a possibility has not been formally tested.
We randomly assigned 12,537 people (mean age, 63.5 years) with cardiovascular risk factors plus impaired fasting glucose, impaired glucose tolerance, or type 2 diabetes to receive insulin glargine (with a target fasting blood glucose level of ≤95 mg per deciliter [5.3 mmol per liter]) or standard care and to receive n–3 fatty acids or placebo with the use of a 2-by-2 factorial design. The results of the comparison between insulin glargine and standard care are reported here. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure. Microvascular outcomes, incident diabetes, hypoglycemia, weight, and cancers were also compared between groups.
The median follow-up was 6.2 years (interquartile range, 5.8 to 6.7). Rates of incident cardiovascular outcomes were similar in the insulin-glargine and standard-care groups: 2.94 and 2.85 per 100 person-years, respectively, for the first coprimary outcome (hazard ratio, 1.02; 95% confidence interval [CI], 0.94 to 1.11; P=0.63) and 5.52 and 5.28 per 100 person-years, respectively, for the second coprimary outcome (hazard ratio, 1.04; 95% CI, 0.97 to 1.11; P=0.27). New diabetes was diagnosed approximately 3 months after therapy was stopped among 30% versus 35% of 1456 participants without baseline diabetes (odds ratio, 0.80; 95% CI, 0.64 to 1.00; P=0.05). Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years. Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the standard-care group. There was no significant difference in cancers (hazard ratio, 1.00; 95% CI, 0.88 to 1.13; P=0.97).
When used to target normal fasting plasma glucose levels for more than 6 years, insulin glargine had a neutral effect on cardiovascular outcomes and cancers. Although it reduced new-onset diabetes, insulin glargine also increased hypoglycemia and modestly increased weight.