1. Journal Club 9/15/11 Sanaz Sakiani, MD 1 st Year Endocrine Fellow Combining Basal Insulin Analogs with Glucagon-Like Peptide-1 Mimetics

2. INTRODUCTION Addition of basal insulin or sulfonylurea to first line metformin has been recognized as an effective method of reaching glycemic control. Indications (ADA) HgbA1c > 7% for more than 2-3 months HgbA1c > 8.5% with symptoms of hyperglycemia Other options to add… TZD GLP-1 mimetics

3. When a more intense regimen becomes necessary? Addition of short acting prandial insulin to target post-prandial glucose excursions Results in Increased risk of hypoglycemia Weight gain

4. ACCORD TRIAL Investigated if intensive insulin therapy to target HgbA1C would reduce cardiovascular events in patients with DM2 and CV disease and/or RF randomized study, n=10,251 After 1yr, A1C of 6.4% and 7.5 in the intensive-therapy group and the standard-therapy group, respectively. Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive- therapy group (P<0.001). The finding of higher mortality in the intensive-therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; P=0.04) led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up.

5. A POTENTIAL SOLUTION? What about GLP-1 mimetics to supplement basal insulin, and target post prandial blood glucose numbers...

6. Glucagon-Like Peptide-1 An incretin that is secreted endogenously by ileal L cells In response to presence of protein, lipids, and carbohydrates Stimulates insulin secretion from β-cell and suppresses glucagon secretion Glucose-depended actions – so will not cause hypoglycemia Other actions: Appears to restore glucose sensitivity of β-cells, inhibit β- cell death and actually stimulate their proliferation and differentiation. Also inhibits gastric secretion and motility, contributing to a satiating effect. Once in circulation, half life is 1.5-3 minutes Degraded rapidly by dipeptidyl peptidase-4

7. GLP-1 Mimetics Shown to have significant effect on glycemic control by lowering post-prandial glucose levels In addition Lower risk of hypoglycemia Moderate, but significant, weight loss Would complement actions of basal insulin Have not yet been approved for this use

8. Exanatide (Byetta) Amylin Pharmaceuticals 39-amino acid; based on exendin-4 protein found in saliva of Gila monster lizard Activates GLP-1 Receptor Approved in US in 2005 Terminal mean half life 2.4h, suitable with BID admin, 30-60min before meal Extended release version for once weekly administration currently in clinical development.

9. Liraglutide (Victoza) Novo Nordisk Acetylated analog of GLP-1 (approx 97% aa sequence homology with endogenous GLP-1 Approved in 2010 Half life 11-15hrs in healthy individuals Suitable for once daily administration, independent of meals

10. Others in development… Lixisenatide Taspoglutide Albiglutide CJC-1134-PC

11. CLINICAL EVIDENCE 2003, Kolterman et. al 5-day, placebo controlled crossover study Addition of exenatide to 6 patients with DM2 who were already on once daily long acting insulin improved post prandial glucose control.

19. Unanswered Questions and Future Studies GLP-1 mimetics with insulin, without oral meds How to adjust doses when in combination Insulin with once daily or once weekly GLP-1 mimetics Future studies should include 3 outcomes Glucose control Weight gain Hypoglycemia Identification of populations that would benefit most Cost

20. Conclusions Current recommendations by ADA are that both insulin and GLP-1 mimetics are suitable additions to patients failing lifestyle mod. and metformin Insulin or sulfonylurea are, however, preferred based on efficacy and experience Preliminary evidence may show that intensification of regimen by adding GLP-1 mimetics to basal insulin may be a reasonable alternative But we have yet to identify target population, and optimal way to introduce into regimen

21. Potential patients that may benefit are those who Weight gain is a concern Hypoglycemia may be hazardous However may increase GI side effects For now, this combination remains off label Multiple studies currently underway, will hopefully answer some questions

23. We’ll just have to wait and see…