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Early Insulin Delays Diabetes, Origin Revisited

Oct 12, 2012
For patients with impaired glucose tolerance or early diabetes, use of insulin glargine was the best predictor of maintaining a lower A1c level over 5 years, according to a subanalysis of the ORIGIN trial…. 

Matthew Riddle, MD, of Oregon Health & Science University, reported during a symposium at the European Association for the Study of Diabetes meeting that, patients on the long-acting insulin had a nearly threefold higher likelihood of maintaining a lower HbA1c over 5 years (OR 2.98, 95% CI 2.67 to 3.32, P<0.001).

But Thomas Pieber, MD, of the Medical University of Graz in Austria, warned that clinicians shouldn’t necessarily start patients on insulin so early in the disease process just to maintain glycemic control. "I don’t believe in this concept of using insulin to prevent type 2 diabetes," he said.

Pieber offered several criticisms of the study, noting that annual mortality rates were about twice as high in ORIGIN as they were in similar large diabetic trials — including ADDITION, ADVANCE, ACCORD, and PROactive — which weren’t explained by differences in age, diabetes duration, smoking, or hypertension.

The ORIGIN trial did have a large proportion of patients with cardiovascular disease at baseline, at about 60%, he said, but that wasn’t the highest rate. All patients in the PROactive trial had prior heart disease, but they still had a much lower mortality rate than seen in ORIGIN.

"It seems that something is different" with this population, Pieber said. "I’m not indicating the treatment had something to do with it, but we have to ask why these yearly mortality rates are twice as high."

Pieber also noted that patients on insulin in the ORIGIN trial had a threefold increase in severe hypoglycemia – a "substantial side effect without any clinical benefit" in mortality or cardiovascular events, he said. And while ORIGIN investigators have touted a 30% relative risk reduction in new diabetes cases, Pieber said the absolute risk reduction is only on the order of 6.5%, with a number needed to treat of 15.

He urged clinicians in the audience not to use insulin so early in the game.

"I don’t think this is really preventing diabetes," he said. "Please don’t fall into this trap that you can prevent diabetes with insulin."

Top-line results of the ORIGIN (Outcome Reduction with an Initial Glargine Intervention) trial were reported at the American Diabetes Association meeting in Philadelphia last June, showing no increased risk of cancer or cardiovascular disease with long-term insulin use in patients who had early signs of or had recently been diagnosed with diabetes.

Riddle and colleagues conducted sub-analyses of data from the trial, characterizing patients by their diabetes status, and looking at predictors of maintaining target HbA1c levels.

Of 12,537 patients enrolled in the study, 88% had diabetes, while the rest had impaired fasting glucose or impaired glucose tolerance. They were randomized to once-daily insulin glargine or to standard care.

Standard care for those without diabetes involved yearly screening for the disease, and diabetic patients were managed by clinician judgment with no insulin until they were uncontrolled on at least two oral antidiabetic agents.

As expected, Riddle said, diabetic patients randomized to insulin glargine had a higher HbA1c at baseline than those without diabetes who went on insulin, and the same pattern held for those given standard therapy.

Although hypertension was significantly more common among diabetics in both groups (P<0.001), more patients who didn’t have diabetes had a prior cardiovascular event, worse LDL cholesterol, and were taking more statins and beta-blockers than diabetics, Riddle said (P<0.001 for all).

He and colleagues found that all patients on insulin glargine had better drops in fasting plasma glucose and HbA1c, both of which were more pronounced in diabetic patients.

And more patients in both groups maintained an HbA1c below 6.5% at 5 years with insulin use (87% versus 79% for nondiabetics, 60% versus 45% for diabetics).

Having diabetes and a higher baseline HbA1c both independently predicted a lower chance of being able to achieve an HbA1c below 6.5% at 5 years, they found (OR 0.31, 95% CI 0.24 to 0.40, P<0.001 and OR 0.19, 95% CI 0.18 to 0.21, P<0.001, respectively).

On the other end of the spectrum, using insulin glargine was associated with a nearly threefold higher likelihood of maintaining the target HbA1c over that time (OR 2.98, 95% CI 2.67 to 3.32, P<0.001).

Oddly, Riddle said, moderate alcohol intake — at least two drinks a week — also made it more likely to hit that HbA1c target (OR 1.61, 95% CI 1.41 to 1.84, P<0.001).

He concluded that giving insulin early in dysglycemia – whether it’s impaired glucose tolerance or early diabetes — can help patients achieve target HbA1c levels in the long term.

Riddle MC, et al "Unpublished results from the ORIGIN trial" EASD 2012.