The goal of this study was to investigate the pharmacodynamic effects of co-administration of empagliflozin, a sodium glucose cotransporter 2 inhibitor, with diuretic agents.
In a randomized, open-label cross-over study, 22 patients with type 2 diabetes mellitus received empagliflozin 25 mg for 5 days and either hydrochlorothiazide 25 mg for 4 days followed by hydrochlorothiazide 25 mg plus empagliflozin 25 mg for 5 days, or torasemide 5 mg for 4 days followed by torasemide 5 mg plus empagliflozin 25 mg for 5 days; 20 completed treatment. Food, fluid, and sodium intake were standardized for 3 days before and during treatment.
At baseline, the median age of the treated patients was 56 years (range, 40–65 years), body mass index was 26.8 kg/m2 (range, 20.1–34.4 kg/m2), fasting plasma glucose was 8.6 mmol/L (range, 6.0–12.9 mmol/L), and glycosylated hemoglobin level was 7.6% (range, 7%–10%). Empagliflozin significantly increased 24-hour urinary glucose excretion and reduced fasting serum glucose levels. These effects were maintained after co-administration with either diuretic. Urinary sodium excretion did not significantly change with empagliflozin or diuretic administration alone, but seemed to increase compared with either diuretic alone when empagliflozin was co-administered with either diuretic. Plasma renin and serum aldosterone levels were unaltered with empagliflozin or torasemide alone, but tended to increase with hydrochlorothiazide alone, and tended to increase when empagliflozin was co-administered with a diuretic compared with either diuretic alone. Urinary volume did not increase with empagliflozin or diuretics alone, but increased when empagliflozin was co-administered with either diuretic.
Empagliflozin alone for 5 days increased urinary glucose excretion but did not seem to have a relevant impact on urine volume or electrolytes. When empagliflozin was co-administered with a diuretic agent, urinary glucose excretion remained increased, and the renin-angiotensin system was activated. Clinicaltrials.gov identifier: NCT01276288.
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- Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors.Diabetes Obes Metab. 2012; 14: 83-90
- Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial.Diabetes Care. 2014; 37: 1650-1659
- Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week randomized, double-blind, placebo-controlled trial.Diabetes Care. 2013; 36: 3396-3404
- Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial.Diabetes Obes Metab. 2013; 16: 147-158
- 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
- Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds.Expert Opin Drug Saf. 2010; 9: 243-257
- World Health Organization equations have shortcomings for predicting resting energy expenditure in persons from a modern, affluent population: generation of a new reference standard from a retrospective analysis of a German database of resting energy expenditure.Am J Clin Nutr. 2004; 80: 1379-1390
- Assessing pharmacokinetic interactions between the sodium glucose cotransporter 2 inhibitor empagliflozin and hydrochlorothiazide or torasemide in patients with type 2 diabetes mellitus: a randomized, open-label, crossover study.Clin Ther. 2015; 37: 793-803
- Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).Arch Intern Med. 2006; 166: 2191-2201
- Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study.N Engl J Med. 2000; 342: 905-912
- Effects of low-dose thiazide diuretics on fasting plasma glucose and serum potassium—a meta-analysis.J Am Soc Hypertens. 2013; 7: 454-466
- The effects of antihypertensive drugs on glucose intolerance in hypertensive nondiabetics and diabetics.Am Heart J. 1988; 115: 640-656
- Diuretic resistance: physiology and therapeutics.Semin Nephrol. 1999; 19: 581-597
- Clinical pharmacokinetics and pharmacodynamics of torasemide.Clin Pharmacokinet. 1998; 34: 1-24
- KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.Kidney Inter Suppl. 2013; 3: 1-150
- 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC).Eur Heart J. 2016; 37: 2129-2200
- Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128
- Empagliflozin and progression of kidney disease in type 2 diabetes.N Engl J Med. 2016; 375: 323-334
- SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice.Am J Physiol Renal Physiol. 2014; 306: F194-F204
- Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus.Circulation. 2014; 129: 587-597
- Increased glomerular filtration rate after withdrawal of long-term antihypertensive treatment in diabetic nephropathy.Kidney Int. 1995; 47: 1726-1731
- A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function.Kidney Int. 1997; 51: 793-797
- Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration.J Clin Invest. 1987; 80: 670-674
- Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial.Lancet Diabetes Endocrinol. 2014; 2: 691-700
- Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis.J Am Soc Hypertens. 2014; 8: 262-275
- The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus.Cardiovasc Diabetol. 2014; 13: 28
- Torasemide. An update of its pharmacological properties and therapeutic efficacy.Drugs. 1995; 49: 121-142
- Factors affecting potassium balance during frusemide administration.Clin Sci (Lond). 1984; 67: 195-203
- Metabolic complications associated with use of diuretics.Semin Nephrol. 2011; 31: 542-552
- Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus.Am J Physiol Renal Physiol. 2015; 308: F77-83
- 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
- Thiazide and loop diuretics.J Clin Hypertens. 2011; 13: 639-643
- Effect of allopurinol in chronic kidney disease progression and cardiovascular risk.Clin J Am Soc Nephrol. 2010; 5: 1388-1393
- Allopurinol and progression of CKD and cardiovascular events: long-term follow-up of a randomized clinical trial.Am J Kidney Dis. 2015; 65: 543-549
- Uric acid and cardiovascular events: a mendelian randomization study.J Am Soc Nephrol. 2015; 26: 2831-2838
- Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts.BMJ. 2013; 347: f4262
- Energy balance following sodium-glucose co-transporter-2 inhibition.Diabetes Care. 2015; 38: 1730-1735
Published online: September 22, 2016
Accepted: August 18, 2016
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