ORIGIN and Insulin: Old Fears Put to Rest

The long-awaited and much anticipated Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial results were released on June 11 and published online in the New England Journal of Medicine.¹ This very large, long-term study looked at patients with impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or type 2 diabetes (T2D) and at high risk for cardiovascular disease who were treated early in the course of the disease with insulin glargine. (Participants assigned to standard care were treated according to investigators’ best judgment). The results help clarify many issues that now surround long-term insulin use and safety. The finding will greatly reassure the many clinicians who have been reluctant to start insulin early in T2D treatment because of concerns about drug-associated macrovascular risk, side effects, or risk for cancer.

Evidence to the Contrary
Keeping in mind that the ORIGIN study patient was both recently diagnosed (or even “pre-diabetic”) and at high risk for cardiovascular (CV) events, it is significant that early use of insulin glargine was not associated with any accelerated risk of CV adverse events. (The Kaplan-Meier curves reflectig CV events for both arms were nearly indistinguishable.). This finding defuses the old teaching (from my years in medical school, at least) that “insulin is atherosclerotic.” In the absence of robust studies on which to base revised lessons, many clinicians still believe what they learned. ORIGIN provides evidence to bust this myth.

Fears of hypoglycemia and weight gain are major barriers to early initiation of insulin therapy and affect patients and clinicians, alike.² ORIGIN found the risk of both side effects to be exceedingly low. The incidence of hypoglycemia averaged approximately 1 episode per 100 patient years-a very minor risk. Weight gain was modest, amounting to about 12 ounces a year.¹ These 2 potent and long-standing barriers to insulin use appear much less formidable than commonly perceived.

Findings from ORIGIN also seem to confirm results of other recent studies^3,4 that suggest a degree of glycemic remission induced by early insulin use (presumably the result of reduced glucotoxicity and allowing beta-cell “rest”).^3,4 Results showed that insulin glargine delayed by 28% (vs standard care) the progression from pre-diabetes (IFG or IGT) to T2D during the course of the trial.¹ After glargine therapy was stopped, normal glucose control seemed to persist for at least the 3-month observation period.  Ongoing evaluation is needed to fully understand this effect, but the preliminary results are promising.

No Risk of Cancer 
In 2009, Diabetologia published several articles^5-8 that associated insulin glargine with a potential risk for cancer. The findings, some of which were based on pharmacy data base review, seemed weak when set against the vast post-marketing experience with insulin glargine and the bulk of expert opinion on the drug. Not surprisingly to many, ORIGIN found no signaling for cancer¹ and these results should be the foundation for ongoing appreciation of insulin glargine safety.

An interesting aspect of the ORIGIN trial was the study arm that examined the impact of omega-3 fish oil on the risk of CV events in this group of very high-risk patients. The study showed no effect-positive or negative-on CV events.¹ This finding will certainly generate discussion about the future of this widely used therapy.

Delayed Cardioprotection
It would be less than transparent if I failed to mention that many clinicians (including me) were very hopeful that ORIGIN would show that early use of basal insulin reduces the rate of CV events in patients with T2D. Not surprisingly, that benefit was not confirmed and, in fact, many experts had informally predicted this outcome. (Had such findings emerged, the trial would likely have been halted early.) So, does this lack of event reduction constitute a failure of early insulin use to provide macrovascular benefit?  From the expert researchers I have spoken with the answer is a qualified “no.”

In the Diabetes Control and Complications Trial (DCCT) of intensively controlled patients with type 1 diabetes, significant reduction in macrovascular events was seen at 10 year follow-up.⁹ In the UK Prospective Diabetes Study (UKPDS) of patients with  T2D, reduction of macrovascular events was not seen at a statistically significant level at the end of the trial.¹⁰ At the 10-year follow-up, however, very significant reduction in macrovascular events was seen.¹¹ It seems that a reduction in the rate of adverse cardiac events may take years to achieve after good glycemic control is established. I have already heard some investigators suggesting that it may be in a longer extension trial of ORIGIN, similar to the UKPDS extension, that we will see specific macrovascular benefits.

The apparent lack of macrovascular protection actually may be a reminder to all of us that macrovascular risk reduction is the result of a global therapeutic approach and that we cannot rely on a single therapy to exert protective effect.¹² I choose to interpret ORIGIN’s cardiovascular results this way: glargine as a basal insulin is safe to use for glycemic control and I will complement that treatment with an agent for blood pressure control, with statins for lipid control, with ongoing encouragement of lifestyle change (including smoking cessation), and with aspirin use in appropriate patients.

I am sure that discussion and evaluation of the ORIGIN results will be ongoing, much as we continue to rehash the data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study. It is almost certain that new ideas will emerge regarding the meaning and implications of the ORIGIN outcomes.  For now, the take-home is the fact that early basal insulin use may have some benefits with very few safety issues. Some of our reasons to reserve insulin use as a last resort seem to have been swept away.

References:
1. The ORIGIN Trial Investigators; Gerstein HC, Bosch J, Dagenais GR, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012 Jun 11; [Epub ahead of print].  doi:10.1056/NEJMoa1203858. 
2. Peyrot M, Rubin RR, Lauritzen T, et al, and on behalf of the International DAWN Advisory Panel. Resistance to insulin therapy among patients and providers: results of the cross-national diabetes attitudes, wishes, and needs (DAWN) study. Diabetes Care. 2005;28:2673-2679.
3. Weng J, Li Y, Xu W, et al. Effect of intensive insulin therapy on β-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371:1753-1760.
4. Hu Y, Li L, Xu Y, et al. Short-term intensive therapy in newly diagnosed type 2 diabetes partially restores both insulin sensitivity and β-cell function in subjects with long-term remission. Diabetes Care. 2011;34:1848-1853.
5. Hemkens LG, Grouven U, Bender R, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732-1744.
6. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766-1777.
7. Jonasson JM, Ljung R, Talbck M, et al. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia. 2009;52:1745-1754.
8. Colhoun HM; SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52:1755-1765.
9. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381-389.
10. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
11. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589.
12. Inzucchi SE, Bergenstahl RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient centered approach. Diabetes Care. 2012 Apr 19; [Epub ahead of print].