By Louis Kuritzky, MD

When Basal Insulin is
Not Enough: Add Prandial
Insulin or a GLP-1 Agonist?

SOURCE: Digenio A, et al. Postgraduate Medicine 2014;126:49-59.

Because of its strong efficacy, long-term durability, and predictability when titrated with algorithms employed in clinical trials, basal insulin remains a mainstay of treatment for type 2 diabetes patients who are not able to attain or maintain glycemic control with oral agents alone. Because diabetes is a progressive disorder, even patients who are initially well-controlled on basal insulin will likely require "fine tuning" of their diabetes regimen, usually with agents that preferentially affect postprandial glucose levels.

GLP-1 agonists (e.g., albiglutide, dulaglutide, exenatide, liraglutide) can impact postprandial glucose levels by means of blunting glucagon release, as well as modulating gastric emptying. In patients who have achieved fasting glucose control on basal insulin — when postprandial glucose is the target — would prandial insulin or a GLP-1 agonist better serve their needs?

Digenio et al reported on a "real-world" data analysis that looked retrospectively at a large population of General Electric Centricity electronic health records (n = 33,848) from persons who had either prandial insulin or a GLP-1 agonist added to basal insulin when glucose control was not adequate.

At follow-up 6 months to 1 year later, GLP-1 agonists and prandial insulin provided similar A1c reductions, but there were substantial differences in weight (gain with rapid acting insulin vs loss with GLP-1 agonist) and hypoglycemia (more frequent with insulin).

Current American Diabetes Association/European Association for the Study of Diabetes guidelines include weight gain and risk of hypoglycemia as critical considerations for advancement of therapy. These data support the concept that in "real-world settings," GLP-1 agonists perform essentially as well as rapid-acting insulin, with less hypoglycemia and weight loss instead of gain.

Performance of Lorcaserin, a 5-HT2c Receptor Agonist, for Weight Loss

SOURCE: Aronne L, et al. Postgraduate Medicine 2014;126:7-18.

Clinicians may have some ambivalence about employing pharmacologic therapies for weight loss based on several reality-based observations: 1) some weight-loss drugs have been taken off the market after a brief sojourn due to serious toxicity (e.g., dexfenfluramine, of notorious Fen-Phen history); 2) some weight-loss drugs have been taken off the market after sustained use, even though early utilization seemed safe enough (e.g., sibutramine [Meridia]); and 3) many patients who embark on pharmacotherapeutic courses of weight-loss medication do not lose an amount of weight that is meaningful to them cosmetically (essentially all currently available medications).

One of the primary reasons that patients become dissatisfied with weight-loss pharmacotherapy is that the amount of weight lost does not typically result in achievement of ideal body weight or anything even close to that. Our role in the use of weight-loss agents should include re-orientation of the patient to include not just cosmetic effects of overweight/obesity, but long-term health consequences such as metabolic derangement, hypertension, diabetes, and cancer risks.

Currently available anorectic agents do perform well enough to achieve meaningful thresholds of weight reduction that lead to favorable metabolic changes. Two placebo-controlled clinical trials of lorcaserin (Belviq [BLOOM and BLOSSOM, combined n = 6380]) can inform us about what type of impact to anticipate with this 5-HT2c agonist.

At 1 year of lorcaserin treatment, 47% had lost at least 5% of their body weight and 22% had lost at least 10% of their body weight. As has been observed in numerous prior interventions that achieve this degree of weight loss, improvements in glycemic status, blood pressure, and lipids were also seen. Although an oral "magic bullet" to assist patients in attaining ideal body weight would be desirable, lorcaserin provides modest — but clinically relevant — weight loss.

Comparing GLP-1 Agonists: Dulaglutide vs Liraglutide

SOURCE: Dungan K, et al. Lancet 2014;384:1349-1357.

All currently available GLP-1 agonists (albiglutide, dulaglutide, exenatide, liraglutide) have four attributes in common: glucose-dependent stimulation of insulin secretion, glucose-dependent blunting of glucagon secretion, improved satiety, and delay in gastric emptying. These physiologic effects are associated with improved glucose control, less risk for hypoglycemia, and weight loss. Head-to-head trials can inform us about potential differences among these agents, but within this class, there is much more similarity than difference.

To date, head-to-head comparisons of GLP-1 agonists have suggested a modest A1c reduction advantage for liraglutide (Victoza). The most recently FDA-approved GLP-1 agonist, dulaglutide (Trulicity), is the subject of this head-to-head trial vs liraglutide. In the AWARD-6 trial, patients (n = 599) were randomized (open-label) to maximum as per-labeling dose of once-weekly dulaglutide 1.5 mg or once-daily liraglutide 1.8 mg.

The degree of A1c reduction at 26 weeks with dulaglutide (1.42%) was slightly greater than liraglutide (1.36%), which did meet the threshold for non-inferiority (the primary outcome of the study). The adverse effect profiles were very similar, except for a substantially lesser degree of hypoglycemia (0.34 vs 0.52 events/year) with dulaglutide.

Maximum dose once-weekly dulaglutide is non-inferior to maximum dose once-daily liraglutide.