Chronobiology and Insulin Glargine

SOURCE: Porcellati F, et al. Diabetes Care 2015;38:503-512.

The “Indications” labeling for insulin glargine (Lantus) simply says, “Administer subcutaneously once daily at any time of day, but at the same time every day.” Some patients and clinicians prefer morning administration, some prefer evenings, and some even prefer twice-daily injections, although the latter is clearly off-label. The important question is, then, does it make any difference when you give insulin glargine, or is it just personal preference?

The pharmacokinetics and pharmacodynamics of insulin glargine were studied in 10 subjects with type 2 diabetes who had already been receiving insulin glargine as part of their therapeutic regimen. Subjects were randomized in a crossover design to dose insulin glargine at either 10:00 a.m. or 10:00 p.m., with dose optimization attained during a 2-week run-in period to achieve fasting blood glucose (FBG) ? 100 mg/dL without experiencing nocturnal hypoglycemia (glucose < 72 mg/dL).

Several interesting results were noted. First, the actual dose needed for optimization of FBG was slightly greater when glargine was administered at 10:00 a.m. than 10:00 p.m. Second, morning administration of glargine had less glucagon-suppression effect in the second half of the 24-hr cycle than evening administration had in the second half of its 24-hr cycle. Evening administration also limited lipolysis more than morning, resulting in lower levels of plasma fatty acids.

The differences between morning and evening glargine administration demonstrated here are quite modest, but do suggest that overall, evening administration may be superior in reference to some dysregulations seen in type 2 diabetes such as glucagon and fatty acids.

Dual Add-on Therapy for Type 2 Diabetes When Metformin is Not Enough

SOURCE: Rosenstock J, et al. Diabetes Care 2015;38:376-383.

The current (2015) American Diabetes Association (ADA) guidance for progression of treatment when A1c goals are not attained with metformin imply stepwise initiation of additional monotherapies. But would it make sense to consider dual add-on?

Rosenstock et al studied patients with type 2 diabetes (T2DM) whose A1c was 8.9% at baseline on monotherapy with metformin. Subjects were randomized to add either a DPP4 inhibitor (saxagliptin), an SGLT2 inhibitor (Dapagliflozin), or both and were followed for 24 weeks.

All three regimens were successful to reduce A1c from baseline, and it probably comes as no surprise that the addition of two drugs (DPP4 inhibitor AND SGLT2 inhibitor) to metformin outperformed the addition of either monotherapy. The addition of an SGLT2 to metformin demonstrated substantially better A1c reductions than the addition of a DPP4 inhibitor (-0.9% vs -0.59%), but the three-drug combination was far more effective, providing a -1.5% A1c reduction.

The simultaneous addition of two drugs to metformin monotherapy is probably an uncommon step for clinicians, who are more accustomed to progressive monotherapeutic step advancements. The fact that there were no episodes of major hypoglycemia during the 6 months of the trial is reassuring that similar therapeutic steps may be safely taken in practice settings where patients continue to have an elevated A1c on metformin. Because of the very potent A1c reduction, however, it is equally important to select patients with a sufficiently elevated A1c on metformin (at least 8.9%) so that the addition of dual add-on treatment does not lead to problematic hypoglycemia.

Might Long-term Dual Antiplatelet Therapy Be Better? Not

SOURCE: Elmariah S, et al. Lancet2014;385:792-798.

Risk reduction provided by dual antiplatelet therapy (DAT) in the short-term interval (3-12 months) after coronary stenting is well established, and published guidelines provide consistent advice about appropriate duration of such therapy. In essentially every large randomized trial that has compared DAT to monotherapy, bleeding risks go up to a sufficient level that it counterbalances any risk reduction in reference to cardiovascular events. Indeed, two major mega-trials comparing DAT to monotherapy in stable patients with established vascular disease failed to demonstrate beneficial reduction in stroke (the MATCH trial) or stable coronary disease (the CHARISMA trial), but did find more bleeding risk.

Elmariah et al performed a meta-analtsis of randomized controlled trials employing DAT post coronary stenting to compare “short duration therapy” (i.e., 6 months or less) or aspirin alone with longer treatment.

Based on data from 14 clinical trials (n = 69,644), they found no evidence of improved outcome associated with longer duration treatment. While this may appear disappointing, one rationale for the investigation was the finding in the large DAPT Study (Dual Antiplatelet Therapy Study, n = 11,648) that non-cardiovascular deaths were actually increased if DAT was extended beyond 12 months, which was not confirmed in the meta-analysis.