COMMENTARY

Paradigm Change in Diabetes Care: Prompt, Intensive Therapy

Gregory A. Nichols, PhD

Disclosures

October 04, 2016

Follow-up of Steno-2

The Steno-2 trial[1] was an open parallel trial in Denmark that compared intensive vs conventional diabetes therapy using a goal-driven treatment approach (Table).

Table. Goals of Diabetes Management in Steno-2

Target Intensive
Therapy
Conventional
Therapy
A1c 6.5% 7.5%
Blood pressure (mm Hg) 140/85 160/95
Total cholesterol (mg/dL) <190 <250
Triglycerides (mg/dL) <150 <195

A1c = glycated hemoglobin. Data from Gaede P, et al.[1]

At the conclusion of 8 years, the primary endpoint (composite of death from cardiovascular disease [CVD], myocardial infarction, stroke, revascularization, and amputation) was 53% lower in the intensive group, and risk for secondary endpoints including nephropathy and retinopathy was reduced by more than 50%. Given these benefits, the trial was stopped and all patients were offered the same intensive target-driven intervention. After an additional 5.5 years of observational follow-up, the relative risk reductions for CVD death and events were still greater than 50% in the intensive group.[2]

Big Benefits That Last a Lifetime

Gaede and colleagues[3] have now reported their findings of a median of 21 years (13 years beyond the end of the 7.8-year trial) of follow-up. Patients who received intensive therapy were 45% less likely to have died compared with those who received conventional therapy. Intensive therapy patients survived for a median of 7.9 years longer than conventional therapy patients.

The median time to first CVD event was 8.1 years longer for intensive therapy patients. Furthermore, risk for progression to macroalbuminuria was 48% lower, and risk for retinopathy development or progression was 33% lower for intensive therapy patients. The intensive therapy group fared better despite the fact that the conventional therapy group received the same intensive therapy for the final 13 years of observational follow-up after the trial's conclusion.

Kramer and colleagues[4] conducted a post-hoc analysis of the placebo arm of the LIraglutide and Beta-cell RepAir (LIBRA) trial in which 25 patients with diabetes for less than7 years were exposed to 4 weeks of intensive insulin therapy (IIT) and achieved a fasting glucose of <125 mg/dL, followed by 48 weeks of placebo therapy. An oral glucose tolerance test (OGTT) was performed every 12 weeks, as were other assessments, including glycated hemoglobin (A1c). The current study compared 14 patients who were in diabetes remission (defined as A1c <6.5% and taking no antihyperglycemia drugs after the 48-week follow-up) with 11 patients who were not in remission on several demographic and clinical characteristics. These included beta-cell function and insulin resistance calculated from the OGTT; insulin doses needed to obtain the fasting glucose criterion; and, of importance, duration of diabetes at trial entry.

It's All About Diabetes Duration

With some notable exceptions, there were relatively few differences between patients who did and did not remain in diabetes remission after 48 weeks. Compared with nonremitters, those in remission had better beta-cell function and lower A1c levels at baseline, they required lower doses of insulin to achieve fasting glucose <125 mg/dL at 4 weeks, and their duration of diabetes at baseline was substantially shorter. In multivariable analysis, diabetes duration was the key predictor of remission, whereas beta-cell function and A1c level were not statistically significant predictors. Remission rates were 78%, 71%, and 58% among those with diabetes duration of less than 1, 2, and 3 years, respectively. Survival analysis showed that time to loss of remission was significantly greater in those with duration less than 2 years compared with longer durations of diabetes.

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