Efficacy and Safety Comparison of Add-on Therapy with Liraglutide, Saxagliptin and Vildagliptin, All in Combination with Current Conventional Oral Hypoglycemic Agents Therapy in Poorly Controlled Chinese Type 2 Diabetes

Abstract

Objective

To compare the efficacy and safety of adding liraglutide, saxagliptin and vildagliptin to current therapy in Chinese type 2 diabetes subjects with poor glycemic control.

Method:

A 24-week, randomized, open-label, parallel clinical trial was performed. A total 178 patients completed the trial who had been randomly assigned to add-on once daily liraglutide (1.2 mg/day injected subcutaneously), to saxagliptin (5 mg once daily) or to vildagliptin (50 mg twice daily). Glycosylated hemoglobin (HbA1c) values, fasting and postprandial blood glucose (FBG and P2BG), body weight, body mass index (BMI), episodes of hypoglycemia and adverse events were evaluated.

Results:

Over the 24-week treatment period, greater lowering of mean of HbA1c was achieved with 1.2 mg liraglutide (−1.50%, 95% CI [−1.67, −1.34]) than with saxagliptin (−1.23%, 95% CI [−1.36, −1.11]) and vildagliptin (−1.25%, 95% CI [−1.37, −1.13]). There was no significant between-group difference of percentages of subjects who reached a target HbA1c<7.0%, but significantly more subjects with liraglutide achieved HbA1c≤6.5% compared with saxagliptin and vildagliptin. The mean reduction of FBG value from baseline was 2.23 mmol/L with liraglutide, much greater than 1.83 mmol/L with saxagliptin (p=0.013), but similar to 2.03 mmol/L with ­vildaglitpin group. As to the P2BG value, greater reductions was found with liraglutide (−4.80 mmol/L) than −3.56 mmol/L with saxagliptin (p=0.000) and −3.57 mmol/L with vildagliptin (p=0.000). Moreover, greater mean reductions of body weight and BMI with liraglutide (−6.0 kg and −2.1 kg/m²) were achieved than with saxagliptin and vildagliptin (both p<0.001), whereas no significant difference was found between saxagliptin and vildagliptin group. The incidence of hypoglycemia was recorded low and similar in each treatment group. Nausea was more common with liraglutide (27%) than with saxagliptin (3.2%) and vildagliptin (5.2%), but no significant between-group difference was reported in other AEs.

Conclusions:

Adding liraglutide demonstrated superiority to saxagliptin and vildagliptin for reductions of HbA1c and weight loss in Chinese subjects with T2DM who had inadequate glycemic control with conventional oral hypoglycemic agents. These findings support the add-on of liraglutide could offer notable advantages over DPP-4 inhibitors in both efficacy and safety.

Key words

type 2 diabetes - GLP-1 - DPP-4 inhibitor

^* Chun-Jun Li and Qian Yu contributed equally to this study.

• References

• 1 Yang W, Lu J, Weng J et al. Prevalence of diabetes among men and women in China. N Engl J Med 2010; 362: 1090-1101
• 2 Chan JC, Malik V, Jia W et al. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 2009; 301: 2129-2140
• 3 Prospective Diabetes Study Group . U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 1995; 44: 1249-1258
• 4 UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2. diabetes (UPKDS 34). Lancet 1998; 352: 854-865
• 5 Turner RC, Cull CA, Frighi V et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999; 281: 2005-2012
• 6 U.K. Prospective Diabetes Study Group . Sulfonylurea inadequacy: efficacy of addition of insulin over 6 years in patients with type 2 diabetes in the U.K. Prospective Diabetes Study (UKPDS 57). Diabetes Care 2002; 25: 330-336
• 7 DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care 2013; 36: 127-138
• 8 DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 2009; 58: 773-795
• 9 Rodbard HW, Jellinger PS, Davidson JA et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Prac 2009; 15: 540-559
• 10 Qian L, Xu L, Wang X et al. Early insulin secretion failure leads to diabetes in Chinese subjects with impaired glucose regulation. Diabetes Metab Res Rev 2009; 25: 144-149
• 11 Toft-Nielsen MB, Damholt MB, Madsbad S et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001; 86: 3717-3723
• 12 Kjems LL, Holst JJ, Vølund A et al. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003; 52: 380-386
• 13 Holst JJ, Gromada J. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004; 287: 199-206
• 14 van Genugten RE, Möller-Goede DL, van Raalte DH et al. Extra-pancreatic effects of incretin-based therapies: potential benefit for cardiovascular-risk management in type 2 diabetes. Diabetes Obes Metab 2013; 15: 593-606
• 15 Yang Z, Xing X, Xiao J et al. Prevalence of cardiovascular disease and risk factors in the Chinese population with impaired glucose regulation: the 2007–2008 China national diabetes and metabolic disorders study. Exp Clin Endocrinol Diabetes 2013; 121: 372-374
• 16 Bao 1 W, Holt LJ, Prince RD et al. Novel fusion of GLP-1 with a domain antibody to serum albumin prolongs protection against myocardial ischemia/reperfusion injury in the rat. Cardiovasc Diabetol 2013; 12: 148-156
• 17 Zhao TC. Glucagon-like peptide-1 (GLP-1) and protective effects in cardiovascular disease: a new therapeutic approach for myocardial protection. Cardiovasc Diabetol 2013; 12: 90-102
• 18 Nielsen R, Wiggers H, Halbirk M et al. Metabolic effects of short-term GLP-1 treatment in insulin resistant heart failure patients. Exp Clin Endocrinol Diabetes 2012; 120: 266-272
• 19 Nathan DM, Buse JB, Davidson MB et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: 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. Diabetologia 2009; 52: 17-30
• 20 Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2012; 55: 1577-1596
• 21 Watson E, Jonker DM, Jacobsen LV et al. Population pharmacokinetics of liraglutide, a once-daily human glucagon-like peptide-1 analog, in healthy volunteers and subjects with type 2 diabetes, and comparison to twice-daily exenatide. J Clin Pharmacol 2010; 50: 886-894
• 22 Gwaltney 2nd SL. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase IV. Curr Top Med Chem 2008; 8: 1545-1552
• 23 DeFronzo RA, Okerson T, Viswanathan P et al. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin 2008; 24: 2943-2952
• 24 Pratley RE, Nauck M, Bailey T et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet 2010; 375: 1447-1456
• 25 Cervera A, Wajcberg E, Sriwijitkamol A et al. Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab 2008; 294: 846-852
• 26 Cersosimo E, Gastaldelli A, Cervera A et al. Effect of exenatide on splanchnic and peripheral glucose metabolism in type 2 diabetic subjects. J Clin Endocrinol Metab 2011; 96: 1763-1770
• 27 Nauck M, Frid A, Hermansen K et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 2009; 32: 84-90
• 28 Garber A, Henry R, Ratner R et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009; 373: 473-481
• 29 Göke B, Gallwitz B, Eriksson JG et al. Saxagliptin vs. glipizide as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: long-term (52-week) extension of a 52-week randomised controlled trial. Int J Clin Pract 2013; 67: 307-316
• 30 Schweizer A, Couturier A, Foley JE et al. Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1 year in drug-naïve patients with Type 2 diabetes. Diabet Med 2007; 24: 955-961
• 31 Mathieu C, Barnett AH, Brath H et al. Effectiveness and tolerability of second-line therapy with vildagliptin vs. other oral agents in type 2 diabetes: a real-life worldwide observational study (EDGE). Int J Clin Pract 2013; 67: 947-956
• 32 Deacon 1 CF, Mannucci E, Ahrén B. Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes – a review and meta analysis. Diabetes, Obesity and Metabolism 2012; 14: 762-767
• 33 Aroda VR, Henry RR, Han J et al. Efficacy of GLP-1 Receptor Agonists and DPP-4 Inhibitors: Meta-Analysis and Systematic Review. Clin Ther 2012; 34: 1247-1258
• 34 Scott KA, Moran TH. The GLP-1 agonist exendin-4 reduces food intake in nonhuman primates through changes in meal size. Am J Physiol Regul Integr Comp Physiol 2007; 293: 983-987
• 35 Williams DL, Baskin DG, Schwartz MW. Evidence that intestinal glucagon-like peptide-1 plays a physiological role in satiety. Endocrinology 2009; 150: 1680-1687
• 36 Linnebjerg H, Park S, Kothare PA et al. Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept 2008; 151: 123-129
• 37 Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705
• 38 LEAD-6 Study Group . Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39-47
• 39 Vendrell J, El Bekay R, Peral B et al. Study of the potential association of adipose tissue GLP-1 receptor with obesity and insulin resistance. Endocrinology 2011; 152: 4072-4079
• 40 Vella A, Bock G, Giesler PD et al. The effect of dipeptidyl peptidase-4 inhibition on gastric volume, satiation and enteroendocrine secretion in type 2 diabetes: a double-blind, placebo-controlled crossover study. Clin Endocrinol (Oxf) 2008; 69: 737-744
• 41 Look AHEAD Research Group . Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial. Diabetes Care 2007; 30: 1374-1383
• 42 Dibonaventura MD, Wagner JS, Girman CJ et al. Multinational internet-based survey of patient preference for newer oral or injectable type 2 diabetes medication. Patient Prefer Adherence. Patient Prefer Adherence 2010; 4: 397-406
• 43 Houlden R, Ross S, Harris S et al. Treatment satisfaction and quality of life using an early insulinization strategy with insulin glargine compared to an adjusted oral therapy in the management of Type 2 diabetes: the Canadian INSIGHT Study. Diabetes Res Clin Pract 2007; 478: 254-258