Short-Term Effects of Liraglutide versus Vildagliptin on Insulin Secretion and Sensitivity in Type 2 Diabetes: A Single Blinded Randomized Controlled Trial (LIRAVIS Study)
Background: We aimed to evaluate the short-term metabolic effects of a GLP-1a, (liraglutide) versus a DPP-4i, (vildagliptin) in a group of sub-Saharan type 2 diabetes patients. Methods: We conducted a randomized controlled single blinded clinical trial in 14 uncontrolled type 2 diabetes patients (HbA1c ≥ 53 mmol/mol) with mean duration of diabetes of 8 [1 - 12] years and median age of 57 [49 - 61] years. Baseline treatment consisted of metformin in monotherapy or metformin plus sulfonylureas. Participants were randomly allocated to 2 groups of add-on 1.2 mg/day subcutaneous liraglutide in group 1 or 100 mg/day of oral vildagliptin in group 2 for 2 weeks. In all participants, insulin secretion in response to mixed meal tolerance test, insulin sensitivity by 80 mU/m2/min hyperinsulinemic-euglycemic clamp, body composition, and lipid profile were measured before and after intervention. Results: At the end of intervention, insulin sensitivity remained unchanged both with liraglutide from 6.6 [4.2 - 7.9] to 6.9 [4.3 - 10.8] mg/kg/min; p = 0.61 and vildagliptin from 7.1 [5.3 - 9.0] to 6.5 [5.6 - 9.4] mg/kg/min (p = 0.86). The area under the C-peptide curve varied from 5.5 [1.0 - 10.9] to 14.9 [10.8 - 17.2] nmol/L/120min, p = 0.09 in group 1 and from 1.1 [0.5 - 14.1] to 13.0 [9.6 - 16.9] nmol/L/120min (p = 0.17) in group 2. LDL Cholesterol levels decreased significantly with liraglutide from 0.85 g/L [0.51 - 1.02] to 0.54 g/L [0.50 - 0.73] (p = 0.04) but not with Vildagliptin. Body weight tended to decrease in group 1 (−0.6 kg) versus modest increase in group 2 (+1.1 kg). Conclusion: Short-term metabolic effects of Liraglutide and Vildagliptin add-on therapy are comparable in sub-Saharan type 2 diabetes patients with a more favorable trend for Liraglutide on body weight, lipid profile, and insulin secretion.
References
[1]
Verspohl, E.J. (2012) Novel Pharmacological Approaches to the Treatment of Type 2 Diabetes. Pharmacological Reviews, 64, 188-237. https://doi.org/10.1124/pr.110.003319
[2]
Nauck, M.A. and Meier, J.J. (2016) The Incretin Effect in Healthy Individuals and Those with Type 2 Diabetes: Physiology, Pathophysiology, and Response to Therapeutic Interventions. The Lancet Diabetes & Endocrinology, 4, 525-536. https://doi.org/10.1016/S2213-8587(15)00482-9
[3]
Pratley, R.E. and Gilbert, M. (2008) Targeting Incretins in Type 2 Diabetes: Role of GLP-1 Receptor Agonists and DPP-4 Inhibitors. The Review of Diabetic Studies, 5, 73-94. https://doi.org/10.1900/RDS.2008.5.73
[4]
Jinnouchi, H., Sugiyama, S., Yoshida, A., et al. (2015) Liraglutide, a Glucagon-Like Peptide-1 Analog, Increased Insulin Sensitivity Assessed by Hyperinsulinemic-Euglycemic Clamp Examination in Patients with Uncontrolled Type 2 Diabetes Mellitus. Journal of Diabetes Research, 2015, Article ID: 706416. https://doi.org/10.1155/2015/706416
[5]
Horie, A., Tokuyama, Y., Ishizuka, T., et al. (2014) The Dipeptidyl Peptidase-4 Inhibitor Vildagliptin Has the Capacity to Repair β-Cell Dysfunction and Insulin Resistance. Hormone and Metabolic Research. Hormon-und Stoffwechselforschung. Hormones et metabolisme, 46, 814-818. https://doi.org/10.1055/s-0034-1382015
[6]
Derosa, G., Ragonesi, P.D., Carbone, A., et al. (2012) Vildagliptin Added to Metformin on β-Cell Function after a Euglycemic Hyperinsulinemic and Hyperglycemic Clamp in Type 2 Diabetes Patients. Diabetes Technology & Therapeutics, 14, 475-484. https://doi.org/10.1089/dia.2011.0278
[7]
Eng, J. (2003) Sample Size Estimation: How Many Individuals Should Be Studied? Radiology, 227, 309-313. https://doi.org/10.1148/radiol.2272012051
[8]
Tai, M.M. (1994) A Mathematical Model for Determination of Total Area under Glucose Tolerance and Other Metabolic Curves. Diabetes Care, 17, 152-154. https://doi.org/10.2337/diacare.17.2.152
[9]
Azuma, K., Rádiková, Z., Mancino, J., et al. (2008) Measurements of Islet Function and Glucose Metabolism with the Dipeptidyl Peptidase 4 Inhibitor Vildagliptin in Patients with Type 2 Diabetes. The Journal of Clinical Endocrinology & Metabolism, 93, 459-464. https://doi.org/10.1210/jc.2007-1369
[10]
Krasner, N.M., Ido, Y., Ruderman, N.B. and Cacicedo, J.M. (2014) Glucagon-Like Peptide-1 (GLP-1) Analog Liraglutide Inhibits Endothelial Cell Inflammation through a Calcium and AMPK Dependent Mechanism. PLOS ONE, 9, e97554. https://doi.org/10.1371/journal.pone.0097554
[11]
Langlois, A., Dal, S., Vivot, K., et al. (2016) Improvement of Islet Graft Function Using Liraglutide Is Correlated with Its Anti-Inflammatory Properties. British Journal of Pharmacology, 173, 3443-3453. https://doi.org/10.1111/bph.13575
[12]
Henry, R.R., Buse, J.B., Sesti, G., et al. (2011) Efficacy of Anti Hyperglycemic Therapies and the Influence of Baseline Hemoglobin A1C: A Meta-Analysis of the Liraglutide Development Program. Endocrine Practice, 17, 906-913. https://doi.org/10.4158/EP.17.6.906
[13]
Nauck, M., Frid, A., Hermansen, K., et al. (2009) 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, 32, 84-90. https://doi.org/10.2337/dc08-1355
[14]
Zinman, B., Gerich, J., Buse, J.B., et al. (2009) Efficacy and Safety of the Human Glucagon-Like Peptide-1 Analog Liraglutide in Combination with Metformin and Thiazolidinedione in Patients with Type 2 Diabetes (LEAD-4 Met+TZD). Diabetes Care, 32, 1224-1230. https://doi.org/10.2337/dc08-2124
[15]
Buse, J.B., Rosenstock, J., Sesti, G., et al. (2009) 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). The Lancet, 374, 39-47. https://doi.org/10.1016/S0140-6736(09)60659-0
[16]
Foley, J.E. and Jordan, J. (2010) Weight Neutrality with the DPP-4 Inhibitor, Vildagliptin: Mechanistic Basis and Clinical Experience. Vascular Health and Risk Management, 6, 541-548. https://doi.org/10.2147/VHRM.S10952
[17]
Welty, F.K., Lewis, S.J., Friday, K.E., Cain, V.A. and Anzalone, D.A. (2016) A Comparison of Statin Therapies in Hypercholesterolemia in Women: A Subgroup Analysis of the STELLAR Study. Journal of Women’s Health, 25, 50-56. https://doi.org/10.1089/jwh.2015.5271
[18]
Decara, J., Arrabal, S., Beiroa, D., et al. (2016) Antiobesity Efficacy of GLP-1 Receptor Agonist Liraglutide Is Associated with Peripheral Tissue-Specific Modulation of Lipid Metabolic Regulators. BioFactors (Oxford, England), 42, 600-611. https://doi.org/10.1002/biof.1295
[19]
Marso, S.P., Daniels, G., Brown-Frandsen, K., et al. (2016) Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. The New England Journal of Medicine, 375, 311-322. https://doi.org/10.1056/NEJMoa1603827
[20]
Blonde, L. and Montanya, E. (2012) Comparison of Liraglutide versus Other Incretin-Related Anti-Hyperglycaemic Agents. Diabetes, Obesity and Metabolism, 14, 20-32. https://doi.org/10.1111/j.1463-1326.2012.01575.x
[21]
Takeshita, Y., Takamura, T., Kita, Y., et al. (2015) Vildagliptin vs Liraglutide as a Second-Line Therapy Switched from Sitagliptin-Based Regimens in Patients with Type 2 Diabetes: A Randomized, Parallel-Group Study. Journal of Diabetes Investigation, 6, 192-200. https://doi.org/10.1111/jdi.12269
[22]
Li, C.-J., Yu, Q., Yu, P., et al. (2014) 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. Experimental and Clinical Endocrinology & Diabetes, 122, 469-476. https://doi.org/10.1055/s-0034-1374586
[23]
Horowitz, M., Flint, A., Jones, K.L., et al. (2012) Effect of the Once-Daily Human GLP-1 Analogue Liraglutide on Appetite, Energy Intake, Energy Expenditure and Gastric Emptying in Type 2 Diabetes. Diabetes Research and Clinical Practice, 97, 258-266. https://doi.org/10.1016/j.diabres.2012.02.016
[24]
Heruc, G.A., Horowitz, M., Deacon, C.F., et al. (2014) Effects of Dipeptidyl Peptidase IV Inhibition on Glycemic, Gut Hormone, Triglyceride, Energy Expenditure, and Energy Intake Responses to Fat in Healthy Males. American Journal of Physiology-Endocrinology and Metabolism, 307, E830-E837. https://doi.org/10.1152/ajpendo.00370.2014
[25]
Russell-Jones, D., Vaag, A., Schmitz, O., et al. (2009) Liraglutide vs Insulin Glargine and Placebo in Combination with Metformin and Sulfonylurea Therapy in Type 2 Diabetes Mellitus (LEAD-5 met+SU): A Randomised Controlled Trial. Diabetologia, 52, 2046-2055. https://doi.org/10.1007/s00125-009-1472-y
[26]
Garber, A., Henry, R., Ratner, R., et al. (2009) Liraglutide versus Glimepiride Monotherapy for Type 2 Diabetes (LEAD-3 Mono): A Randomised, 52-Week, Phase III, Double-Blind, Parallel-Treatment Trial. The Lancet, 373, 473-481. https://doi.org/10.1016/S0140-6736(08)61246-5