ABSTRACT & COMMENTARY

By Jeff Unger, MD

Director, Unger Primary Care Concierge Medical Group, Rancho Cucamonga, CA

Dr. Unger serves as an advisor, speaker and clinical investigator for Novo Nordisk.

SYNOPSIS: Fifty-one patients with type 2 diabetes of 2.6 +/- 1.9 years duration and an A1C of 6.8 % completed 4 weeks of intensive insulin therapy in order to eliminate glucose toxicity which is injurious to pancreatic beta cells. Thereafter, patients were randomized to receive daily subcutaneous liraglutide or an equivalent volume of placebo. Serial assessments of beta-cell function following oral glucose tolerance testing was performed at 12 week intervals for 48 weeks. Patients using liraglutide noted a rebust enhancement of beta cell function which was sustained over the course of the trial, yet lost within two weeks after stopping treatment.

SOURCE: Retnakaran R, et al. Liraglutide and the preservation of pancreatic beta-cell function in early type 2 diabetes. The LIBRA Trial. Diabetes Care 2014;37:3270-3278.

Type 2 diabetes is characterized by progressive loss of beta cell function over time. Beta cell loss occurs via two mechanism; a) glucotoxicity (i.e., chronic elevation of plasma glucose levels > 240 mg/dL) and b) programmed cell death (apoptosis — which is genetically determined and triggered by multiple environmental factors). Short-term intensive insulin therapy provided to patients with type 2 diabetes eliminates glucotoxicity creating a level playing field upon which to objectively evaluate the potential beta-cell protective potential of anti-diabetic medications.

Liraglutide is a GLP-1 receptor agonist with multiple beneficial metabolic effects, including glucose-dependent stimulation of insulin secretion from pancreatic beta-cells, suppression of postprandial glucagon secretion, slowing of gastric emptying, enhanced glucose disposal within myocytes, weight-loss promotion, and preclinical data favoring beta-cell mass augmentation in animal models. The objective of the Liraglutide and Beta-Cell Repair (LIBRA) trial was to evaluate the effect of liraglutide on the preservation of beta-cell function over 1 year in patients with early type 2 diabetes following the amelioration of glucose toxicity with intensive insulin therapy.1-3

The primary outcome of baseline-adjusted insulin secretion-sensitivity index-2 (a measure of beta-cell function) at 48 weeks was 339.8 + 27.8 vs 229.3 + 28.4 for the liraglutide vs. placebo cohort (P = 0.008). The baseline-adjusted A1C was 6.2% vs. 6.6% for the liraglutide vs. placebo group (P = 0.055). No difference was noted in the incidence of hypoglycemia among the two groups. Two weeks after stopping treatment, the beneficial effect of ISSI-2 of liraglutide vs placebo was entirely lost (191.9 +/- 24.7 vs. 238.1 +/- 25.2; P = .20).

COMMENTARY

Early initiation and maintenance of liraglutide certainly suggests that beta-cell preservation is possible. Liraglutide offers many advantages as an antidiabetic agent. Liraglutide can effectively reverse seven of the eight pathogenetic defects that result in hyperglycemia. The addition of an SGLT-2 inhibitor to liraglutide will effectively reverse all eight of DeFronzo’s ominous octet. The drug is simple to use, lowers fasting and postprandial hyperglycemia, and minimizes one’s risk of hypoglycemia. The drug can be used in patients with chronic kidney disease as well as those taking basal insulin. Patients should be admonished to remain adherent to their liraglutide prescriptions, as premature termination of the drug can result in loss of beta-cell function and glucose toxicity.

REFERENCES

  1. DeFronzo RA, et al. Preservation of beta-cell function: The key to diabetes prevention. J Clin Endocrinol Metab 2011; 96:2354-2366.
  2. Leahy JL, et al. Targeting beta-cell function early in the course of therapy for type 2 diabetes mellitus. J Clin Endocrinol Metab 2010; 95:4206-4216.
  3. Drucker DJ. Incretin-based therapy and quest for sustained
    improvements in beta-cell health. Diabetes Care 2011:34: 2133-2135.