Ever since the discovery of insulin in 1922 there has been a debate whether administration of exogenous insulin might increase mortality in the long run. A major concern has been the possibly increased risk of cardiovascular events. More recently, after the publication of some observational studies, a second worry arose: does insulin treatment, and especially treatment with insulin glargine, increase cancer risk? In the ORIGIN study both these issues have been addressed in a randomized controlled trial in patients with impaired fasting glucose, impaired glucose tolerance and type 2 diabetes. And the short answer is a double negative one: insulin glargine did neither increase the risk of cardiovascular events nor that of incident cancer.
Fasting hyperglycaemia in prediabetes and type 2 diabetes is a hallmark of endogenous insulin secretion failing to correct insulin resistance. What’s more, fasting hyperglycaemia appears to be an independent risk factor for an adverse cardiovascular outcome. Thus, it seems logical to correct fasting hyperglycaemia in these individuals with exogenous insulin. However, there are arguments to suggest that administration of insulin per se might increase cardiovascular risk. This could be due to a detrimental effect of insulin on the vasculature by stimulating the sympathetic nervous system. Short term hyperinsulinemia results in vasoconstriction. Whether long-term hyperinsulinemia also contributes to such sympathetic activation is less sure. Large outcome trials with different targets of glucose control using insulin did not demonstrate a cardiovascular benefit of intensive glycemic control. Drawbacks of using insulin in such trials are the increased risk of hypoglycemia and the increase in body weight. Whether or not administration of basal insulin as such alters cardiovascular risk has not been documented so far in a large clinical study. In the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial the effect of adding basal insulin glargine on the cardiovascular events in patients with early type 2 diabetes and prediabetes has been tested.
In this manufacturer-funded trial 12,537 patients (mean age 63.5 years) with impaired fasting glucose, impaired glucose tolerance or early type 2 diabetes and an elevated cardiovascular risk were randomly assigned to receive standard care plus evening insulin glargine titrated to a target fasting glucose level of 5.3 mmol/l or lower or standard care alone. The coprimary outcomes were nonfatal myocardial infarction, nonfatal stroke and death from cardiovascular causes and these events plus hospitalization for heart failure and revascularization. Other relevant outcomes were incident diabetes, hypoglycaemia, weight and cancer.
After a median follow-up of 6.2 years the event rates per 100 person-years for the composite outcome nonfatal myocardial infarction, nonfatal stroke and death from cardiovascular causes were 2.94 and 2.85 in the insulin glargine group and in the standard care group respectively (hazard ratio[HR], 1.02 [95% CI, 0.94 to 1.11];p=0.63). (Figure 1)
Figure 1. The primary composite outcome (myocardial infarction, stroke, or death from cardiovascular causes) in the ORIGIN trial showed no difference between early treatment with insulin glargine and guideline-based conventional therapy.The event rates per 100 person-years for the composite outcome plus hospitalization for heart failure and revascularization were 5.52 and 5.28 in the insulin glargine group and in the standard care group respectively (hazard ratio[HR], 1.04[CI, 0.97 to 1.11];p=0.27).
Newly diagnosed diabetes at 3 months after discontinuation of therapy was less likely in the insulin glargine users (odds ratio, 0.72[CI, 0.58 to 0.91]; p=0.006). Severe hypoglycaemia occurred more frequently in the insulin glargine group compared to the standard care group (1.00 vs. 0.31 events per 100 person-years; p<0.001) as did nonsevere symptomatic hypoglycaemia confirmed by a self-measured glucose level of 3.0 mmol/l or less (9.83 and 2.68 per 100 person-years; p< 0.001). Patients in the glargine group gained weight, whereas the patients in the standard group lost weight (median gain, 1.6 kg vs. median loss, 0.5kg). No difference was found in incident cancer (HR, 1.00[CI, 0.88 to 1.13]; p=0.97), nor in death from cancer (HR, 0.94; 95% CI, 0.77 to 1.15; p=0.52), nor in site of cancer. There were no differences in development of angina, in amputations or in cardiovascular or noncardiovascular hospitalizations.
Several substudies of the ORIGIN trial have been published subsequently. The most relevant one is probably the study on microvascular outcomes. These outcomes were compared in participants whose baseline HbA1c was above or below the median of 6.4%. It appeared that allocation to the insulin glargine group reduced the incidence of the primary microvascular composite outcome of kidney and eye disease in participants whose baseline HbA1c level was ≥6.4% (46.4 mmol/mol; HR 0.90 [95% CI 0.81,0.99]) but not in participants with a lower baseline HbA1c (HR 1.07 [95% CI 0.95, 1.20]; p value for interaction 0.031). It is striking that even a tiny reduction in median HbA1c of 0.33% in patients with only modestly increased baseline HbA1c levels resulted in less microvascular complications.
Use of basal insulin to decrease fasting glucose levels to the normal range in patients with prediabetes and early type 2 diabetes with an increased cardiovascular risk did neither increase nor decrease their cardiovascular outcome compared with guideline suggested glycemic control. Has the ORIGIN study fully answered the question of a possibly increased risk of cardiovascular events due to insulin? No. We now know that a limited dose (average 28 units per day in a 70-kg person) of long acting insulin continued for more than 6 years in patients with prediabetes and early type 2 diabetes does not increase the risk and that there was not even a trend to an increase. However, the majority of insulin treated type 2 patients use a much higher average dose of insulin, use it for longer than 6 years and have a longer duration of diabetes. Therefore the findings of the ORIGIN study as for cardiovascular risk of insulin, although reassuring, have a limited external validity for the total diabetes population. A question posed by the authors themselves is whether the different percentage of patients using metformin in the glargine group (47%) and in the standard group (60%) might have influenced the results, as metformin is considered cardioprotective. And the possibly increased cancer risk? If there would be an increased risk, what could be the mechanism? It has been suggested that exogenous insulin and especially insulin analogues could bind not only to the insulin receptor but also to the insulin-like growth factor-1(IFG-1) receptor. Binding to this receptor could activate not only metabolic effects but also mitogenic effects such as cell proliferation. No indication for an increased risk of cancer has been found in the ORIGIN trial. A more detailed discussion of this topic can be found on the page The insulin glargine story elsewhere in Diapedia. Apart from the reservations presented above, the ORIGIN study has reassuring results for both patients and doctors: a six years during treatment with basal insulin did neither increase cardiovascular nor cancer risk and reduced microvascular risk in those with baseline HbA1c above 6.4%.
^ Sarwar N, Gao P, Seshasai SR, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet 2010; 375: 2215-22
^ The ORIGIN trial investigators. Basal insulin glargine and microvascular outcomes