Pharmacokinetic drug evaluation of empagliflozin plus linagliptin for the treatment of type 2 diabetes

References

• Lipscombe LL, Hux JE. Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a population-based study. Lancet. 2007;369:750–756.
   PubMed Web of Science ®Google Scholar
• Yoon K-H, Lee J-H, Kim J-W, et al. Epidemic obesity and type 2 diabetes in Asia. Lancet. 2006;368:1681–1688.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Kyrou I, Georgousopoulou EN, et al. Modeling anthropometric indices in relation to 10-year (2002-2012) incidence of cardiovascular disease, among apparently healthy individuals: the ATTICA study. Diabetes Metab Syndr. 2017;11:S789-S795.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Panagiotakos DB, Georgousopoulou EN, et al. Mediterranean diet and 10-year (2002-2012) incidence of diabetes and cardiovascular disease in participants with prediabetes: the ATTICA study. Rev Diabet Stud. 2016;13:226–235.
   PubMedGoogle Scholar
• Cowie CC, Rust KF, Byrd-Holt DD, et al. Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health and Nutrition Examination Survey 1999–2002. Diabetes Care. 2006;29:1263–1268.
   PubMed Web of Science ®Google Scholar
• King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998;21:1414–1431.
   PubMed Web of Science ®Google Scholar
• Hurst RT, Lee RW. Increased incidence of coronary atherosclerosis in type 2 diabetes mellitus: mechanisms and management. Ann Intern Med. 2003;139:824–834.
   PubMed Web of Science ®Google Scholar
• Roper NA, Bilous RW, Kelly WF, et al. Excess mortality in a population with diabetes and the impact of material deprivation: longitudinal, population based study. BMJ. 2001;322:1389–1393.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Florentin M, Georgoula M, et al. Pharmacological management of diabetic dyslipidemia. Expert Rev Clin Pharmacol. 2017;10:187–200.
   PubMed Web of Science ®Google Scholar
• Filippatos T, Tsimihodimos V, Pappa E, et al. Pathophysiology of diabetic dyslipidaemia. Curr Vasc Pharmacol. 2017;15:566–575.
   Web of Science ®Google Scholar
• Scheen AJ. SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf. 2015;14:1879–1904.
   PubMed Web of Science ®Google Scholar
• Scheen AJ, Paquot N. Metabolic effects of SGLT-2 inhibitors beyond increased glucosuria: a review of the clinical evidence. Diabetes Metab. 2014;40:S4–S11.
   PubMed Web of Science ®Google Scholar
• Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297:127–136.
   PubMed Web of Science ®Google Scholar
• American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment. Diabetes Care. 2017;40:S64–S74.
   PubMed Web of Science ®Google Scholar
• Bell DS. Combine and conquer: advantages and disadvantages of fixed-dose combination therapy. Diabetes Obes Metab. 2013;15:291–300.
   PubMed Web of Science ®Google Scholar
• Hutchins V, Zhang B, Fleurence RL, et al. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin. 2011;27:1157–1168.
   PubMed Web of Science ®Google Scholar
• Friedrich C, Metzmann K, Rose P, et al. A randomized, open-label, crossover study to evaluate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy male volunteers. Clin Ther. 2013;35:A33–A42.
   PubMed Web of Science ®Google Scholar
• Glund S, Mattheus M, Runge F, et al. Relative bioavailability of an empagliflozin 25-mg/linagliptin 5-mg fixed-dose combination tablet. Int J Clin Pharmacol Ther. 2017;55:355–367.
   PubMed Web of Science ®Google Scholar
• Roden M, Weng J, Eilbracht J, et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 2013;1:208–219.
   PubMed Web of Science ®Google Scholar
• Merker L, Häring H-U, Christiansen AV, et al. Empagliflozin as add-on to metformin in people with type 2 diabetes. Diabet Med. 2015;32:1555–1567.
   PubMed Web of Science ®Google Scholar
• Kovacs CS, Seshiah V, Merker L, et al. Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Clin Ther. 2015;37:1773–1788.e1.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care. 2014;37:1815–1823.
   PubMed Web of Science ®Google Scholar
• Ribola FA, Cançado FB, Schoueri JH, et al. Effects of SGLT2 inhibitors on weight loss in patients with type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci. 2017;21:199–211.
   PubMed Web of Science ®Google Scholar
• Mazidi M, Rezaie P, Gao H-K, et al. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6:e004007.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Tsimihodimos V, Elisaf MS. Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors. Expert Opin Pharmacother. 2016;17:1581–1583.
   PubMed Web of Science ®Google Scholar
• Wu AH, Gladden JD, Ahmed M, et al. Relation of serum uric acid to cardiovascular disease. Int J Cardiol. 2016;213:4–7.
   PubMed Web of Science ®Google Scholar
• Chino Y, Samukawa Y, Sakai S, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014;35:391–404.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Liberopoulos EN, Elisaf MS. Dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2015;6:29–41.
   PubMed Web of Science ®Google Scholar
• Tsimihodimos V, Filippatos TD, Elisaf MS. Effects of sodium-glucose co-transporter 2 inhibitors on metabolism: unanswered questions and controversies. Expert Opin Drug Metab Toxicol. 2017;13:399–408.
   PubMed Web of Science ®Google Scholar
• Tsimihodimos V, Filippatos TD, Filippas-Ntekouan S, et al. Renoprotective effects of SGLT2 inhibitors: beyond glucose reabsorption inhibition. Curr Vasc Pharmacol. 2017;15:96–102.
   PubMed Web of Science ®Google Scholar
• Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–334.
   PubMed Web of Science ®Google Scholar
• Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
   PubMed Web of Science ®Google Scholar
• Liakos A, Karagiannis T, Athanasiadou E, et al. Efficacy and safety of empagliflozin for type 2 diabetes: a systematic review and meta-analysis. Diabetes Obes Metab. 2014;16:984–993.
   PubMed Web of Science ®Google Scholar
• Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017;7:2824.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Tsimihodimos V, Liamis G, et al. SGLT2 inhibitors-induced electrolyte abnormalities: an analysis of the associated mechanisms. Diabetes Metab Syndr. 2017. [Epub ahead of print].
   Web of Science ®Google Scholar
• Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med. 2017;376:2300–2302.
   PubMed Web of Science ®Google Scholar
• Jensen ML, Persson F, Andersen GS, et al. Incidence of ketoacidosis in the Danish type 2 diabetes population before and after introduction of sodium-glucose cotransporter 2 inhibitors-a nationwide, retrospective cohort study, 1995-2014. Diabetes Care. 2017;40:e57–e58.
   PubMed Web of Science ®Google Scholar
• Filippatos T, Tzavella E, Rizos C, et al. Acid-base and electrolyte disorders associated with the use of antidiabetic drugs. Expert Opin Drug Saf. 2017;16:1121–1132.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–1642.
   PubMed Web of Science ®Google Scholar
• Hayami T, Kato Y, Kamiya H, et al. Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet. J Diabetes Investig. 2015;6:587–590.
   PubMed Web of Science ®Google Scholar
• McKeage K. Linagliptin: an update of its use in patients with type 2 diabetes mellitus. Drugs. 2014;74:1927–1946.
   PubMed Web of Science ®Google Scholar
• Barnett AH, Patel S, Harper R, et al. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: an 18-week randomized, double-blind, placebo-controlled phase III trial with a 34-week active-controlled extension. Diabetes Obes Metab. 2012;14:1145–1154.
   PubMed Web of Science ®Google Scholar
• Ross SA, Caballero AE, Del Prato S, et al. Linagliptin plus metformin in patients with newly diagnosed type 2 diabetes and marked hyperglycemia. Postgrad Med. 2016;128:747–754.
   PubMed Web of Science ®Google Scholar
• Sheu W-H-H, Park SW, Gong Y, et al. Linagliptin improves glycemic control after 1 year as add-on therapy to basal insulin in Asian patients with type 2 diabetes mellitus. Curr Med Res Opin. 2015;31:503–512.
   PubMed Web of Science ®Google Scholar
• Barnett AH, Huisman H, Jones R, et al. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet. 2013;382:1413–1423.
   PubMed Web of Science ®Google Scholar
• Groop P-H, Del Prato S, Taskinen M-R, et al. Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment. Diabetes Obes Metab. 2014;16:560–568.
   PubMed Web of Science ®Google Scholar
• Lajara R, Aguilar R, Hehnke U, et al. Efficacy and safety of linagliptin in subjects with long-standing type 2 diabetes mellitus (>10 years): evidence from pooled data of randomized, double-blind, placebo-controlled, phase III trials. Clin Ther. 2014;36:1595–1605.
   PubMed Web of Science ®Google Scholar
• Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–1326.
   PubMed Web of Science ®Google Scholar
• White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–1335.
   PubMed Web of Science ®Google Scholar
• Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–242.
   PubMed Web of Science ®Google Scholar
• Johansen OE, Neubacher D, Von Eynatten M, et al. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3.
   PubMed Web of Science ®Google Scholar
• Filippatos TD, Athyros VG, Elisaf MS. The pharmacokinetic considerations and adverse effects of DPP-4 inhibitors. Expert Opin Drug Metab Toxicol. 2014;10:787–812.
   PubMed Web of Science ®Google Scholar
• Lehrke M, Marx N, Patel S, et al. Safety and tolerability of linagliptin in patients with type 2 diabetes: a comprehensive pooled analysis of 22 placebo-controlled studies. Clin Ther. 2014;36:1130–1146.
   PubMed Web of Science ®Google Scholar
• Bajaj M, Gilman R, Patel S, et al. Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: a 24-week randomized, double-blind study. Diabet Med. 2014;31:1505–1514.
   PubMed Web of Science ®Google Scholar
• Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579–1588.
   PubMed Web of Science ®Google Scholar
• Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:689–697.
   PubMed Web of Science ®Google Scholar
• Clifton P. Do dipeptidyl peptidase IV (DPP-IV) inhibitors cause heart failure? Clin Ther. 2014;36:2072–2079.
   PubMed Web of Science ®Google Scholar
• Zannad F, Cannon CP, Cushman WC, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067–2076.
   PubMed Web of Science ®Google Scholar
• Lewin A, DeFronzo RA, Patel S, et al. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015;38:394–402.
   PubMed Web of Science ®Google Scholar
• DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care. 2015;38:384–393.
   PubMed Web of Science ®Google Scholar
• Søfteland E, Meier JJ, Vangen B, et al. Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately controlled with linagliptin and metformin: a 24-week randomized, double-blind, parallel-group trial. Diabetes Care. 2017;40:201–209.
   PubMed Web of Science ®Google Scholar
• Tinahones FJ, Gallwitz B, Nordaby M, et al. Linagliptin as add-on to empagliflozin and metformin in patients with type 2 diabetes: two 24-week randomized, double-blind, double-dummy, parallel-group trials. Diabetes Obes Metab. 2017;19:266–274.
   PubMed Web of Science ®Google Scholar
• Rizos CV, Kei A, Elisaf MS. The current role of thiazolidinediones in diabetes management. Arch Toxicol. 2016;90:1861–1881.
   PubMed Web of Science ®Google Scholar
• Rizos CV, Elisaf MS, Mikhailidis DP, et al. How safe is the use of thiazolidinediones in clinical practice? Expert Opin Drug Saf. 2009;8:15–32.
   PubMed Web of Science ®Google Scholar
• GLYXAMBI® (empagliflozin and linagliptin) tablets, summary of product characteristics. 2017 cited 2017 Aug 11. Available from: http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Glyxambi/Glyxambi.pdf
   Google Scholar
• Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509–514.
   PubMed Web of Science ®Google Scholar
• Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512–517.
   PubMed Web of Science ®Google Scholar
• Hare KJ, Vilsbøll T, Asmar M, et al. The glucagonostatic and insulinotropic effects of glucagon-like peptide 1 contribute equally to its glucose-lowering action. Diabetes. 2010;59:1765–1770.
   PubMed Web of Science ®Google Scholar
• Hansen L, Iqbal N, Ekholm E, et al. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy. Endocr Pract. 2014;20:1187–1197.
   PubMed Web of Science ®Google Scholar
• Takebayashi K, Inukai T. Effect of sodium glucose cotransporter 2 inhibitors with low SGLT2/SGLT1 selectivity on circulating glucagon-like peptide 1 levels in type 2 diabetes mellitus. J Clin Med Res. 2017;9:745–753.
   PubMedGoogle Scholar
• Oguma T, Kuriyama C, Nakayama K, et al. Changes in glucose-induced plasma active glucagon-like peptide-1 levels by co-administration of sodium-glucose cotransporter inhibitors with dipeptidyl peptidase-4 inhibitors in rodents. J Pharmacol Sci. 2016;132:255–261.
   PubMed Web of Science ®Google Scholar
• Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015;38:376–383.
   PubMed Web of Science ®Google Scholar
• Goldenberg RM, Verma S, Perkins BA, et al. Can the combination of incretin agents and sodium-glucose cotransporter 2 (SGLT2) inhibitors reconcile the Yin and Yang of glucagon? Can J Diabetes. 2017;41:6–9.
   PubMed Web of Science ®Google Scholar
• Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care. 2013;36:4015–4021.
   PubMed Web of Science ®Google Scholar
• Van Gaal L, Scheen A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care. 2015;38:1161–1172.
   PubMed Web of Science ®Google Scholar
• Arauz-Pacheco C, Parrott MA, Raskin P, et al. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003;26 Suppl 1:S80–S82.
   PubMedGoogle Scholar
• Seifalian AM, Filippatos TD, Joshi J, et al. Obesity and arterial compliance alterations. Curr Vasc Pharmacol. 2010;8:155–168.
   PubMed Web of Science ®Google Scholar
• Neeland IJ, McGuire DK, Chilton R, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2016;13:119–126.
   PubMed Web of Science ®Google Scholar
• Mancia G, Cannon CP, Tikkanen I, et al. Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication. Hypertension. 2016;68:1355–1364.
   PubMed Web of Science ®Google Scholar
• Musso G, Gambino R, Cassader M, et al. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med. 2012;44:375–393.
   PubMed Web of Science ®Google Scholar
• Fadini GP, Bonora BM, Mayur S, et al. Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab. 2017. [Epub ahead of print].
   Google Scholar
• Xia C, Goud A, D’Souza J, et al. DPP4 inhibitors and cardiovascular outcomes: safety on heart failure. Heart Fail Rev. 2017;22:299–304.
   PubMed Web of Science ®Google Scholar
• Lambers Heerspink HJ, De Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15:853–862.
   PubMed Web of Science ®Google Scholar
• Martens P, Mathieu C, Verbrugge FH. Promise of SGLT2 inhibitors in heart failure: diabetes and beyond. Curr Treat Options Cardiovasc Med. 2017;19:23.
   PubMedGoogle Scholar
• Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37:1526–1534.
   PubMed Web of Science ®Google Scholar
• Kohler S, Zeller C, Iliev H, et al. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34:1707–1726.
   PubMed Web of Science ®Google Scholar
• DeVries JH, Rosenstock J. DPP-4 inhibitor-related pancreatitis: rare but real! Diabetes Care. 2017;40:161–163.
   PubMed Web of Science ®Google Scholar