Abstract
Purpose
Diabetes is a chronic metabolic disorder characterized by hyperglycemia that results
from insulin resistance, diminished or absent insulin secretion, or both. Approximately
one-half of patients with diabetes fail to achieve acceptable glycemic control. Consequently,
morbidity and mortality associated with diabetes is high, resulting from complications
such as cardiovascular disease and nephropathy. The sodium-glucose co-transporter
2 (SGLT2) inhibitors are a new class of medications for the treatment of type 2 diabetes.
This article provides an overview of efficacy and safety data for the SGLT2 inhibitors
and outlines their role in the management of diabetes.
Methods
Relevant articles were identified through searches of PubMed and International Pharmaceutical
Abstracts by using the key terms canagliflozin, dapagliflozin, empagliflozin, and sodium-glucose co-transporter 2 inhibitor. A review of bibliographies of retrieved articles was also performed to identify
additional references. All identified trials published in English and that involved
the efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes were
reviewed.
Findings
The SGLT2 inhibitors improve glucose control by increasing urinary glucose excretion.
Effectiveness is decreased in the presence of renal dysfunction. These agents are
efficacious as monotherapy and add-on therapy for patients with type 2 diabetes uncontrolled
on metformin, sulfonylureas, insulin, and other antihyperglycemic combinations. The
SGLT2 inhibitors lower glycosylated hemoglobin by 0.5% to 1% and fasting plasma glucose
by ~15 to 35 mg/dL, depending on the agent and the dosage used, and are also associated
with modest reductions in weight (−1.5 to −3.5 kg) and systolic blood pressure (−3
to −5 mm Hg). Genital mycotic infections and increased urination, owing to the mechanism
of action, are the most common adverse effects. In general, the class is well tolerated,
and the risk of hypoglycemia is low.
Implications
With their unique mechanism of action and good safety and tolerability profiles, the
SGLT2 inhibitors are an important addition to existing treatments for type 2 diabetes.
Because of the lack of data with this class of drugs when current treatment guidelines
for diabetes were published, the SGLT2 inhibitors are recommended as second- or third-line
therapies for diabetes. Forthcoming data on the long-term efficacy and safety profile
of these agents should help to solidify the role of SGLT2 inhibitors in the management
of diabetes.
Key words
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
Diabetes fact sheet. World Health Organization website. http://www.who.int/mediacentre/factsheets/fs312/en/. Accessed November 26, 2014.
Statistics about diabetes. American Diabetes Association website. http://www.diabetes.org/diabetes-basics/statistics/?loc=db-slabnav. Accessed November 26, 2014.
Heart disease. American Diabetes Association website. http://www.diabetes.org/living-with-diabetes/complications/heart-disease/. Accessed November 26, 2014.
- The effect of intensive treatment of diabetes on the development of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group.N Engl J Med. 1993; 329: 977-986
- 10-year follow-up of intensive glucose control in type 2 diabetes.N Engl J Med. 2008; 359: 1577-1589
- Approaches to glycemic treatment.Diabetes Care. 2015; 38: S41-S48
- The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1988–2010.Diabetes Care. 2013; 36: 2271-2279
Invokana [package insert]. Janssen Pharmaceuticals, Inc. http://www.invokanahcp.com/prescribing-information.pdf. Accessed November 19, 2014.
Farxiga [package insert]. Bristol-Myers Squibb Company. http://www.azpicentral.com/farxiga/pi_farxiga.pdf#page=1. Accessed November 19, 2014.
Jardiance [package insert]. Boehringer Ingelheim Pharmaceuticals, Inc. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Jardiance/jardiance.pdf. Accessed November 19, 2014.
- Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications.Diabet Med. 2010; 27: 136-142
- Sodium-glucose co-transport inhibitors: progress and therapeutic potential in type 2 diabetes mellitus.Drugs. 2010; 70: 377-385
- 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
- Canagliflozin lowers postprandial glucose and insulin by delaying intestinal glucose absorption in addition to increasing urinary glucose excretion: results of a randomized, placebo-controlled study.Diabetes Care. 2013; 36: 2154-2161
- SGLT2 inhibitors in the treatment of type 2 diabetes.Diabetes Res Clin Pract. 2014; 104: 297-322
- Lack of pharmacokinetic interaction between dapagliflozin, a novel sodium-glucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects.Diabetes Obes Metab. 2011; 13: 47-54
- Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial.Diabetes Obes Metab. 2011; 13: 928-938
- Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, and metformin following co-administration in healthy volunteers.Int J Clin Pharmacol Ther. 2013; 51: 132-140
- Pharmacokinetics of empagliflozin, a sodium glucose 2 cotransporter-2 inhibitor, and glimepiride following co-administration in healthy volunteers: a randomized, open-label, crossover study.Diab Res Clin Metab. 2012; 1: 1-7
- Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT2) inhibitor, coadministered with sitagliptin in healthy volunteers.Adv Ther. 2012; 29: 889-899
- 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
- Lack of pharmacokinetic interactions between dapagliflozin and simvastatin, valsartan, warfarin, or digoxin.Adv Ther. 2012; 29: 163-177
- Lack of drug-drug interactions between empagliflozin, a sodium glucose cotransporter-2 inhibitor, and warfarin in healthy volunteers.Diabetes Obes Metab. 2013; 15: 316-323
- Pharmacokinetics of empagliflozin, a sodium glucose cotransporter 2 inhibitor, and simvastatin following co-administration in healthy volunteers.Int J Clin Pharmacol Ther. 2014; 52: 973-980
- Lack of clinically relevant drug-drug interaction between empagliflozin, a sodium glucose cotransporter 2 inhibitor, and verapamil, ramipril, or digoxin in healthy volunteers.Clin Ther. 2013; 35: 226-235
- Effects of hydrochlorothiazide on the pharmacokinetics, pharmacodynamics, and tolerability of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in healthy participants.Clin Ther. 2014; 36: 698-710
- 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; ([Epub ahead of print])
- Effects of rifampin and mefenamic acid on the pharmacokinetics and pharmacodynamics of dapagliflozin.Diabetes Obes Metab. 2013; 15: 280-283
- Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus.Clin Pharmacokinet. 2014; 53: 295-304
- Pharmacokinetics and pharmacodynamics of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in subjects with type 2 diabetes mellitus.J Clin Pharmacol. 2013; 53: 601-610
- Effect of empagliflozin on the steady-state pharmacokinetics of ethinylestradiol and levonorgestrel in healthy female volunteers.Clin Drug Investig. 2013; 20: 351-357
- Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR).Curr Med Res Opin. 2014; 30: 1759-1768
- Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise.Diabetes Obes Metab. 2013; 15: 372-382
- Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study.Curr Med Res Opin. 2014; 30: 163-175
- Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomized trial.Diabetologia. 2013; 56: 2582-2592
- Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial.Lancet. 2013; 382: 941-950
- Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.Int J Clin Pract. 2013; 67: 1267-1282
- Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial.Diabetes Care. 2013; 36: 2508-2515
- Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone.Diabetes Obes Metab. 2014; 16: 467-477
- Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.Diabetes Care. 2010; 33: 2214-2224
- Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise.Diabetes Obes Metab. 2014; 16: 1102-1110
- Dapagliflozin monotherapy in drug-naïve patients with diabetes: a randomized-controlled trial of low-dose range.Diabetes Obes Metab. 2012; 14: 951-959
- Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial.Diabetes Care. 2011; 34: 2015-2022
- Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomized, double-blind, placebo controlled trial.Lancet. 2010; 375: 2223-2233
- Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy.Diabetes Care. 2012; 35: 1473-1478
- Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study.Diabetes Care. 2014; 37: 740-750
- Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial.Ann Intern Med. 2012; 156: 405-415
- Pharmacokinetics, pharmacodynamics, safety and tolerability of 4 weeks’ treatment with empagliflozin in Japanese patients with type 2 diabetes mellitus.J Diabetes Investig. 2013; 4: 613-617
- A phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes.Diabetes Obes Metab. 2013; 15: 721-728
- Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, 12-week, double-blind, placebo-controlled, phase II trial.Adv Ther. 2014; 31: 621-638
- Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycemia.Diabetes Obes Metab. 2013; 15: 1154-1160
- Empagliflozin as add-on to metformin plus sulfonyl - urea 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. 2014; 16: 147-158
- 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
- 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
Fulcher G, Matthews DR, Perkovic V, et al. Canagliflozin (CANA) in subjects with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea (SU) monotherapy: a CANVAS study. Abstract presented at 73rd Annual American Diabetes Association Scientific Sessions; June 21–25, 2013; Chicago, Ill. Abstract No. 1124-P.
- Efficacy and safety of canagliflozin (CANA), an inhibitor of sodium glucose co-transporter 2 (SGLT2), added-on to insulin therapy +/− oral agents in type 2 diabetes [abstract 764].Diabetologia. 2012; 55: S314
- SGLT inhibitors in management of diabetes.Lancet Diabetes Endocrinol. 2013; 1: 140-151
- Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis.Ann Int Med. 2013; 59: 262-274
- Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors.J Am Soc Hypertens. 2014; 8: 330-339
- SGLT-2 inhibitors and their potential in the treatment of diabetes.Diabetes Metab Syndr Obes. 2013; 6: 453-467
- Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)--a randomized placebo-controlled trial.Am Heart J. 2013; 166: 217-223
F.D.A. Briefing Document (NDA 204042) Invokana (canagliflozin) tablets. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334550.pdf. Accessed December 5, 2014.
- Dapagliflozin treatment for type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials.Diabetes Metab Res Rev. 2014; 30: 204-221
F.D.A. Briefing Document (NDA 202293) Dapagliflozin oral tablets, 5 and 10 mg. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf. Accessed December 4, 2014.
- Rationale, design, and baseline characteristics of a randomized, placebo-controlled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOMETM).Cardiovasc Diabetol. 2014; 13: 102
- Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes.Am J Health Syst Pharm. 2013; 70: 311-319
Meta-analysis in post-marketing surveillances for SGLT2 inhibitors in patients with type 2 diabetes mellitus. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02284269?term=empagliflozin+and+cancer&rank=1. Accessed January 27, 2015.
- AACE comprehensive diabetes management algorithm 2013.Endocr Pract. 2013; 19: 327-336
Article info
Publication history
Published online: April 16, 2015
Accepted:
March 5,
2015
Identification
Copyright
© 2015 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
