Empagliflozin and metformin combination therapy in Type 2 diabetes mellitus

R. Jeyalalitha


Diabetes mellitus (DM) is a spectrum of metabolic disorder characterized by chronic hyperglycemia either due to an absolute or a relative insulin deficiency. The prevalence of diabetes varies between various countries and ethnic groups and of late, it has reached epidemic proportions in both the developed as well as in the developing countries. There is an intense need for new and effective therapies for Type 2 DM (T2DM) with improved safety and tolerability profiles to reduce the outcome of the acute and chronic complications of this condition. Empagliflozin is a new class of selective sodium glucose cotransporter-2 inhibitor approved for the treatment of T2DM in 2014. It has a novel and a unique mechanism of action in that it inhibits the reabsorption of glucose in the kidneys, promotes excessive glucose excretion through a non-insulin dependent mechanism and induces glycosuria. Metformin is the only biguanide which is currently the widely accepted first-line drug for T2DM. It is effective as monotherapy and as combination therapy and has proven beneficial effects on microvascular and macrovascular complications of DM. Recently, the US Food and Drug Administration has approved the fixed dose combination of empagliflozin with metformin hydrochloride during August 2015. The combination of empagliflozin/metformin hydrochloride can be used as an adjunctive therapy to diet and exercise in patients those who are not adequately controlled with monotherapy of either empagliflozin or metformin. This drug update focuses on the insulin-independent unique mechanism of action of empagliflozin and its beneficial effects alone and in combination with metformin in patients with T2DM.


Type 2 diabetes mellitus, Empagliflozin, Sodium glucose co-transporter 2, Metformin, Activated protein kinase, Fixed dose combination, Food and Drug Administration approved

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Lajara R. The potential role of sodium glucose co-transporter 2 inhibitors in combination therapy for type 2 diabetes mellitus. Expert Opin Pharmacother. 2014;15(17):2565-85.

Riser Taylor S, Harris KB. The clinical efficacy and safety of sodium glucose cotransporter-2 inhibitors in adults with type 2 diabetes mellitus. Pharmacotherapy. 2013;33(9):984-99.

Abdul-Ghani MA, DeFronzo RA. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr Pract. 2008;14(6):782-90.

Bays H. From victim to ally: the kidney as an emerging target for the treatment of diabetes mellitus. Curr Med Res Opin. 2009;25(3):671-81.

Nair S, Wilding JP. Sodium glucose cotransporter 2 inhibitors as a new treatment for diabetes mellitus. J Clin Endocrinol Metab. 2010;95(1):34-42.

Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83-90.

Ferrannini E, Seman L, Seewaldt-Becker E, Hantel S, Pinnetti S, Woerle HJ. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(8):721-8.

Bolinder J, Ljunggren Ö, Johansson L, Wilding J, Langkilde AM, Sjöström CD, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16(2):159-69.

Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the hypertension optimal treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351(9118):1755-62.

Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):703-13.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N Engl J Med. 2015;10: N Engl J Med. 2015;373(22):2117-28.

Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2):90-100.

Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124(2):509-14.

Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia. 2014;57(5):891-901.

Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75(1):33-59.

Seman L, Macha S, Nehmiz G, Simons G, Ren B, Pinnetti S, et al. Empagliflozin (BI 10773) a potent and selective SGLT 2inhibitor, induces dose dependent glucosuria in healthy subjects. Clin Pharmacol Drug Dev. 2013;2:152-61.

Macha S, Mattheus M, Halabi A, Pinnetti S, Woerle HJ, Broedl UC. Pharmacokinetics, pharmacodynamics and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in subjects with renal impairment. Diabetes Obes Metab. 2014;16(3):215-22.

Martha S, Kennedy N, Masharani U. Pancreatic hormones and antidiabetic drugs. In: Katzung BG, Trevor’s AJ, editors. Basic and Clinical Pharmacology. 13th Edition. India: McGraw-Hill; 2015. p. 723-46.

Macha S, Rose P, Mattheus M, Cinca R, Pinnetti S, Broedl UC, et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab. 2014;16(2):118-23.

Powers AC, Alessio DD. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 12th Edition. New York, NY: McGraw-Hill; 2001: 1237-73.

Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, et al. American association of clinical endocrinologists’ comprehensive diabetes management algorithm 2009 consensus statement. Endocr Pract. 2009;15(6):540-59.

Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, Hach T, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013;15(12):1154-60.

McGill JB. The SGLT2 inhibitor empagliflozin for the treatment of type 2 diabetes mellitus: a bench to bedside review. Diabetes Ther. 2014;5(1):43-63.