Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study

Sabine Arnolds, Sibylle Dellweg, Janina Clair, Marie-Paule Dain, Michael A Nauck, Klaus Rave, Christoph Kapitza, Sabine Arnolds, Sibylle Dellweg, Janina Clair, Marie-Paule Dain, Michael A Nauck, Klaus Rave, Christoph Kapitza

Abstract

Objective: To assess the effect of a 4-week adjunctive therapy of exenatide (EXE) (5-10 microg b.i.d.) or sitagliptin (SITA) (100 mg once daily) in response to a standardized breakfast meal challenge in 48 men or women with type 2 diabetes receiving insulin glargine (GLAR) + metformin (MET).

Research design and methods: This was a single-center, randomized, open-label, active comparator-controlled study with a three-arm parallel group design, consisting of: screening, 4- to 8-week run-in period, 4-week treatment period, and follow-up. In all three groups, the GLAR dose was titrated according to an algorithm (fasting blood glucose <or=100 mg/dl).

Results: The unadjusted 6-h postprandial blood glucose excursion of both GLAR + MET + EXE and GLAR + MET + SITA was statistically significantly smaller than that of GLAR + MET (606 +/- 104 vs. 612 +/- 133 vs. 728 +/- 132 mg/dl/h; P = 0.0036 and 0.0008). A1C significantly decreased in all three groups (P < 0.0001), with the greatest reduction of -1.9 +/- 0.7 under GLAR + MET + EXE (GLAR + MET + SITA -1.5 +/- 0.7; GLAR + MET -1.2 +/- 0.5%-points; GLAR + MET + EXE vs. GLAR + MET P = 0.0154). The American Diabetes Association A1C target of <7.0% was reached by 80.0, 87.5, and 62.5% of subjects, respectively. GLAR + MET + EXE had the highest number (47) of adverse events, mostly gastrointestinal (56%) with one dropout. GLAR + MET or GLAR + MET + SITA only had 10 and 12 adverse events, respectively, and no dropouts. Hypoglycemia (blood glucose <50 mg/dl) rates were low and comparable among groups. Weight decreased with GLAR + MET + EXE (-0.9 +/- 1.7 kg; P = 0.0396) and increased slightly with GLAR + MET (0.4 +/- 1.5 kg; NS; GLAR + MET + EXE vs. GLAR + MET P = 0.0377).

Conclusions: EXE or SITA added to GLAR + MET further substantially reduced postprandial blood glucose excursions. Longer-term studies in a larger population are warranted to confirm these findings.

Trial registration: ClinicalTrials.gov NCT00971659.

Figures

Figure 1
Figure 1
Subject disposition. AE, adverse event; ALT, alanine aminotransferase; AST, aspartate transferase.
Figure 2
Figure 2
Mean (SEM) meal BG profiles.

References

    1. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 837–853
    1. Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B: Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2006; 29: 1963–1972
    1. van Avendonk MJ, Rutten GE: Insulin therapy in type 2 diabetes: what is the evidence? Diabetes Obes Metab 2009; 11: 415–432
    1. Mäkimattila S, Nikkilä K, Yki-Järvinen H: Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes mellitus. Diabetologia 1999; 42: 406–412
    1. Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, Kulkarni K, Clark NG: Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care 2004; 27: 2067–2073
    1. Owens DR, Bolli GB: Beyond the era of NPH insulin—long-acting insulin analogs: chemistry comparative pharmacology, and clinical application. Diabetes Technol Ther 2008; 10: 333–349
    1. sanofi-aventis Deutschland. Lantus. Summary of product characteristics [article online], 2008. Available from . Accessed 10 June 2009
    1. Riddle MC, Rosenstock J, Gerich J. Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients Diabetes Care 2003; 26: 3080–3086
    1. Bazzano LA, Lee LJ, Shi L, Reynolds K, Jackson JA, Fonseca V: Safety and efficacy of glargine compared with NPH insulin for the treatment of type 2 diabetes: a meta-analysis of randomized controlled trials. Diabet Med 2008; 25: 924–932
    1. Lilly Deutschland. Byetta. Summary of product characteristics, [article online], 2009. Available from . Accessed 10 June 2009
    1. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, Baron AD: Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083–1091
    1. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. GWAA Study Group. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes. Ann Intern Med 2005; 143: 559–569
    1. Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A, Brodows R, Trautmann M: A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia 2007; 50: 259–267
    1. Amori RE, Lau J, Pittas AG: Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007; 298: 194–206
    1. MSD Sharp & Dohme. Januvia. Summary of product characteristics, [article online], 2008. Available from . Accessed 10 June 2009
    1. Krentz AJ, Patel MB, Bailey CJ: New drugs for type 2 diabetes mellitus. What is their place in therapy? Drugs 2008; 68: 2131–2162
    1. Barnett AH: New treatments in type 2 diabetes: a focus on the incretin-based therapies. Clin Endocrinol 2009; 70: 343–353
    1. Nauck MA: Unraveling the science of incretin biology. Am J Med 2009; 122: S3–S10
    1. Gilbert MP, Pratley RE: Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus. Am J Med 2009; 122: S11–S24
    1. Mudaliar S, Henry RR: Incretin therapies: effects beyond glycemic control. Am J Med 2009; 122: S25–S36
    1. Kendall DM, Cuddihy RM, Bergenstal RM: Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use. Am J Med 2009; 122: S37–S50
    1. World Medical Association. Declaration of Helsinki. Ethical Principles for Medical Research Involving Human Subjects. 52nd WMA General Assembly, Edinburgh, Scotland, October 2000. Last amended with Note of Clarification on Paragraph 29 by the WMA general assembly, Washington 2002, and the Note of Clarification on Paragraph 30 by the WMA general assembly, Tokyo 2004
    1. Linnebjerg H, Kothare PA, Skrivanek Z, de la Peña A, Atkins M, Ernest CS, Trautmann ME: Exenatide: effect of injection time on postprandial glucose in patients with type 2 diabetes. Diabet Med 2006; 23: 240–245
    1. Amiel SA, Dixon T, Mann R, Jameson K: Hypoglycaemia in type 2 diabetes. Diabet Med 2008; 25: 245–254
    1. Monnier L, Colette C, Dunseath GJ, Owens DR: The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes. Diabetes Care 2007; 30: 263–269

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel