Improved Beta Cell Glucose Sensitivity Plays Predominant Role in the Decrease in HbA1c with Cana and Lira in T2DM.

AIM To examine the effect of combination therapy with canagliflozin plus liraglutide versus each agent alone on beta cell function in type 2 diabetes mellitus (T2DM) patients. RESEARCH DESIGN AND METHODS 45 poorly controlled (HbA1c=7-11%) T2DM patients received oral glucose tolerance test (OGTT) before and after 16 weeks of treatment with: (1) liraglutide (LIRA); (2) canagliflozin (CANA); (3) liraglutide plus canagliflozin (CANA/LIRA). RESULTS Both liraglutide and canagliflozin significantly lowered HbA1c with no significant additive effect of the combination on HbA1c (0.89%, 1.43%, and 1.67% respectively). Insulin secretion during the OGTT, measured with (∆C-Pep/∆G)0-120, increased in the three groups (from 0.30±0.06 to 0.48±0.10; 0.29±0.05 to 0.98±0.23; and 0.24±0.06 to 1.09±0.12 in subjects receiving CANA, LIRA and CANA/LIRA respectively, p=0.02 for CANA Vs LIRA, p<0.0001, CANA/LIRA Vs CANA), and the increase in insulin secretion was associated with an increase in beta cell glucose sensitivity (29±5 to 55±11; 33±6 to 101±16; and 28±6 to 112±12, respectively, p=0.01 for CANA Vs LIRA, p<0.0001, CANA/LIRA Vs CANA). No significant difference in the increase in insulin secretion or beta cell glucose sensitivity was observed between subjects in LIRA or CANA/LIRA groups. The decrease in HbA1c strongly and inversely correlated with the increase in beta cell glucose sensitivity (r=0.71, p<0.001). In multivariate regression model, improved beta cell glucose sensitivity was the strongest predictor of HbA1c decrease with each therapy. CONCLUSION Improved beta cell glucose sensitivity with canagliflozin monotherapy and liraglutide monotherapy or in combination is major factor responsible for the HbA1c decrease. Canagliflozin failed to produce an additive effect to improve beta cell glucose sensitivity above that observed with liraglutide.

[1]  É. Hardy,et al.  Efficacy and tolerability of exenatide once weekly over 7 years in patients with type 2 diabetes: An open-label extension of the DURATION-1 study. , 2019, Journal of diabetes and its complications.

[2]  R. DeFronzo,et al.  Combination Therapy With Exenatide Plus PioglitazoneVersus Basal / Bolus Insulin in Poorly Controlled Patients With Type 2 Diabetes on Sulfonylurea Plus Metformin : The Qatar Study , 2017 .

[3]  R. DeFronzo,et al.  Renal, metabolic and cardiovascular considerations of SGLT2 inhibition , 2017, Nature Reviews Nephrology.

[4]  J. Holst The physiology of glucagon-like peptide 1. , 2007, Physiological reviews.

[5]  E. Ferrannini,et al.  Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes , 2014, Diabetologia.

[6]  M. Nauck,et al.  Incretin hormones: Their role in health and disease , 2018, Diabetes, obesity & metabolism.

[7]  R. DeFronzo,et al.  Combination Therapy With Canagliflozin Plus Liraglutide Exerts Additive Effect on Weight Loss, but Not on HbA1c, in Patients With Type 2 Diabetes , 2020, Diabetes Care.

[8]  R. DeFronzo,et al.  Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add‐on therapy in subjects with new‐onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial , 2015, Diabetes, obesity & metabolism.

[9]  R. Heine,et al.  Exenatide improves β-cell function up to 3 years of treatment in patients with type 2 diabetes: a randomised controlled trial. , 2016, European journal of endocrinology.

[10]  R. DeFronzo,et al.  Empagliflozin Treatment Is Associated With Improved β-Cell Function in Type 2 Diabetes Mellitus , 2018, The Journal of clinical endocrinology and metabolism.

[11]  M. Taskinen,et al.  Effects of Exenatide on Measures of β-Cell Function After 3 Years in Metformin-Treated Patients With Type 2 Diabetes , 2011, Diabetes Care.

[12]  R. DeFronzo,et al.  Dapagliflozin lowers plasma glucose concentration and improves β-cell function. , 2015, The Journal of clinical endocrinology and metabolism.

[13]  R. DeFronzo,et al.  Distinct β-Cell Defects in Impaired Fasting Glucose and Impaired Glucose Tolerance , 2012, Diabetes.

[14]  S. Del Prato,et al.  Long‐term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add‐on therapy to metformin in patients with type 2 diabetes: 4‐year data , 2015, Diabetes, obesity & metabolism.

[15]  M. Matsuda,et al.  The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance. , 2008, American journal of physiology. Endocrinology and metabolism.

[16]  R. DeFronzo,et al.  Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus. , 2015, American journal of physiology. Renal physiology.

[17]  D. Drucker The biology of incretin hormones. , 2006, Cell metabolism.

[18]  R. DeFronzo,et al.  Endogenous Glucose Production and Hormonal Changes in Response to Canagliflozin and Liraglutide Combination Therapy , 2018, Diabetes.

[19]  R. DeFronzo,et al.  Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. , 2014, The Journal of clinical investigation.

[20]  R. DeFronzo,et al.  Dapagliflozin Enhances Fat Oxidation and Ketone Production in Patients With Type 2 Diabetes , 2016, Diabetes Care.

[21]  T. Heise,et al.  Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. , 2014, The Journal of clinical investigation.

[22]  Ralph A. DeFronzo,et al.  From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus , 2009, Diabetes.