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DRUG RECORD

 

SODIUM GLUCOSE COTRANSPORTER-2 INHIBITORS
(SGLT-2 INHIBITORS)
CANAGLIFLOZIN, DAPAGLIFLOZIN, EMPAGLIFLOZIN

OVERVIEW
SGLT-2 Inhibitors

 

Introduction

The sodium glucose cotransporter 2 (SGLT-2) inhibitors are diabetic agents that act by inhibiting the reabsorption of glucose in the proximal renal tubule, resulting in loss of glucose in the urine and reduction in serum levels.  SGLT-2 is the major enzyme responsible for glucose reabsorption in the kidney and its inhibition causes a reduction in the threshold for glucose loss in urine.  The excess loss of glucose causes a loss of calories, reduction in serum glucose and mild osmotic diuresis.  The SGLT-2 inhibitors also cause a modest weight loss, which may contribute to their beneficial effects.  Three specific SGLT-2 inhibitors, canagliflozin, dapagliflozin and empagliflozin, have been shown to result in improvements in glycemic control in type 2 diabetes and introduced into clinical use.  In prelicensure studies, none of the three agents was reported to be associated with increases in serum aminotransferase or alkaline phosphatase levels and, since licensure, there have been only very rare reports of clinically apparent liver injury associated with their use.

 

Background

Canagliflozin (kan" a gli floe' zin) is a specific SGLT-2 inhibitor that in clinical trials was shown to result in a reduction in serum HbA1c levels and improved glycemic control in type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate control on diet and exercise) or in combination with insulin, metformin and/or sulfonylureas.  Canagliflozin was approved for use in the United States in 2013 and current indications are for management of hyperglycemia in patients with type 2 diabetes in conjunction with diet and exercise and with or without other antidiabetic medications.  Canagliflozin is available in tablets of 100 and 300 mg under the brand name Invokana, the recommended dose being 100 to 300 mg once daily.  Combinations of canaglifozin with metformin are also available (Invokamet).  Common side effects include symptoms of thirst, urinary tract infections and mycotic genital infections.  Less common side effects are hypoglycemia, dehydration, hypovolemia and serum creatinine elevations.

 

Dapagliflozin (cap' a gli floe' zin) is a specific SGLT-2 inhibitor that has been shown to result in a reduction in serum HgbA1c levels and better control of type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate glycemic control on diet and exercise) or in combination with insulin, metformin and or sulfonylureas.  Dapagliflozin was approved for use in the United States in 2014 and current indications are for management of hyperglycemia in patients with type 2 diabetes in conjunction with diet and exercise with or without other antidiabetic medications.  Dapagliflozin is available in tablets of 5 and 10 mg under the brand name Farxiga, the recommended dose being 5 to 10 mg once daily.  Fixed extended release combinations of dapaglifozin with metformin are also available (Zigduo XR). Common side effects include symptoms of thirst, urinary tract infections and mycotic genital infections.  Less common side effects are hypoglycemia, dehydration, hypovolemia and serum cholesterol and creatinine elevations.

 

Empagliflozin (em" pa gli floe' zin) is a specific SGLT-2 inhibitor that in clinical trials was shown to result in a reduction in serum HbA1c levels and better glycemic control in type 2 diabetes, both as monotherapy (in patients who failed to achieve adequate control on diet and exercise) or in combination with insulin, metformin and or sulfonylureas.  Empagliflozin was approved for use in the United States in 2014 and current indications are for management of hyperglycemia in patients with type 2 diabetes in conjunction with diet and exercise and with or without other antidiabetic medications.  Empagliflozin is available in tablets of 10 and 25 mg under the brand name Jardiance, the recommended initial dose being 10 mg once daily, which can be increased to 25 mg daily.  Fixed e combinations of empaglifozin with metformin (Synjardy) and with liraglutide (Glyxambi) are also available.  Common side effects include symptoms of thirst, urinary tract infections and mycotic genital infections.  Less common side effects are hypoglycemia, dehydration, hypovolemia, and serum creatinine elevations.

 

Hepatotoxicity

In multiple large randomized controlled trials, canagliflozin, dapagliflozin and empagliflozin were not associated with serum enzyme elevations during therapy.  Indeed, in retrospective analyses, therapy with SGLT-2 inhibitors was associated with improvements in ALT levels, probably as a result of concurrent improvements in fatty liver disease due to improved glycemic control or weight loss or both.  During prelicensure studies, no instances of clinically apparent acute liver injury were convincingly linked to use of the SGLT-2 inhibitors and serum enzyme elevations accompanied by jaundice occurred equally in the actively treated and placebo groups.  Since their approval and more wide spead use, at least one report of liver injury possibly due to has been published.  A woman with nonalcoholic fatty liver disease and cirrhosis developed decompensation with jaundice, ascites and encephalopathy 10 weeks after starting dapagliflozin.  She improved somewhat after stopping therapy but ultimately required liver transplantation several months later.  Thus, hepatotoxicity from canagliflozin, dapagliflozin and empagliflozin is quite rare, if it occurs at all.  

 

Canagliflozin likelihood score: E* (Unproven but suspected cause of clinically apparent liver injury).

 

Dapagliflozin likelihood score:  D (Rare possible cause of clinically apparent liver injury).

 

Empagliflozin likelhood score:  E* (Unproven but suspected cause of clinically apparent liver injury).

 

Mechanism of Injury

The relative lack of hepatototoxicity of the SGLT-2 inhibitors may relate to their minimal hepatic metabolism which is largely via UDP-glucuronylsyltransferase (UGT-1A9 and 2B4 among others).

 

Outcome and Management

Liver injury from the SGLT-2 inhibitors is rare and they have not been associated with acute liver failure, vanishing bile duct syndrome or chronic hepatitis.  The similarity of structure and function of the SGLT-2 inhibitors suggests that there may be some degree of cross sensitivity to their adverse events.


Drug Class:  Antidiabetic Agents

 

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PRODUCT INFORMATION
SGLT-2 Inhibitors

 

REPRESENTATIVE TRADE NAMES
Canagliflozin – Invokana®
Dapagliflozin – Farxiga®
Empagliflozin – Jardiance®

 

DRUG CLASS
Antidiabetic Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NO. MOLECULAR FORMULA STRUCTURE
Canagliflozin 928672-86-0 C24-H25-F-O5-S.1/2H2-O Canagliflozin Chemical Structure
Dapagliflozin 461432-26-8 C21-H25-Cl-O6 Dapagliflozin Chemical Structure
Empagliflozin 864070-44-0 C23-H27-Cl-O7 Empagliflozin Chemical Structure

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REFERENCES
SGLT-2 Inhibitors

 

References updated: 12 January 2017

  1. Zimmerman HJ. Oral hypoglycemic agents and other diabetes therapy. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 575-9.  (Textbook of hepatotoxicity published in 1999 and before the availability of SGLT2 inhibitors).

  2. De Marzio DH, Navarro VJ. Antidiabetic drugs. Hepatotoxicity of cardiovascular and antidiabetic drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 528-32.  (Review of hepatotoxicity of drugs for diabetes, does not discuss the SGLT-2 inhibitors).

  3. Powers AC, D'Alessio D. Therapy of diabetes. Endocrine pancreas and pharmacotherapy of diabetes mellitus and hypoglycemia. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1248-67.  (Textbook of pharmacology and therapeutics).

  4. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver injury in the US collected from 2004 to 2008, none were attributed SGLT-2 inhibitors, which were rarely used during the period of this study).

  5. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. 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: 2217-24. PubMed Citation  (Among 485 patients with type 2 diabetes who were not adequately controlled on diet and exercise advice were treated with one of 3 doses of dapagliflozin or placebo for 24 weeks, there was an increased incidence of signs and symptoms of urinary tract and genital infections on dapagliflozin; no mention of ALT levels of clinically apparent liver injury).

  6. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; Dapagliflozin 006 Study Group. 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: 405-15. PubMed Citation  (Among 805 patients with type 2 diabetes on insulin treated with dapagliflozin or placebo, those on dapagliflozin had higher rates of hypoglycemia episodes, genital and urinary tract infections, and weight loss [1.0-1.5 kg]; no discussion of ALT results or hepatotoxicity).

  7. Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol 2013; 1: 140-151. PubMed Citation  (Review of mechanisms of action, structure, pharmacokinetics, efficacy and safety of the SGLT inhibitors; no mention or discussion of ALT elevations or hepatotoxicity).

  8. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159: 262-74. PubMed Citation  (Metaanalysis of publications on the safety and efficacy of the SGLT-2 inhibitors states that: “regarding liver related adverse events, regulatory authorities’ reports concluded that slight imbalance among patients treated with dapagliflozin or canagliflozin and control groups were probably not associated with the study drug”).

  9. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Kawaguchi M, et al. 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: 2508-15. PubMed Citation  (Among 756 patients on treated with the addition of either canagliflozin or sitagliptin to stable therapy for 52 weeks, adverse events rates were similar in the two groups, except for higher rates of genital mycotic infections and small to moderate decreases in ALT, GGT and weight loss in the canagliflozin treated patients; no liver related serious adverse events in either group).

  10. Stenlöf K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, Canovatchel W, et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013; 15: 372-82. PubMed Citation  (Among 584 patients with type 2 diabetes treated with canagliflozin [200 or 300 mg] or placebo for 26 weeks, there were increased rates of urinary tract and genital infections and were modest improvements in ALT and Alk P levels).

  11. Canagliflozin (Invokana) for type 2 diabetes. Med Lett Drugs Ther 2013; 55 (1416): 37-9. PubMed Citation  (Concise overview on the use of canagliflozin in diabetes shortly after its approval for use in the US mentions side effects of genital mycotic infections [10-15%], urinary tract infections [5%] and serum cholesterol elevations; no mention of hepatotoxicity or changes in serum ALT levels).

  12. Dapagliflozin(Farxiga) for type 2 diabetes. Med Lett Drugs Ther 2014; 56 (1436): 13-5. PubMed Citation  (Concise overview on the use of dapagliflozin in diabetes shortly after its approval for use in the US mentions increased risk of mycotic genital infections and urinary tract infections, and its potential to cause hypovolemia and cholesterol elevations; no discussion of hepatotoxicity or serum ALT elevations).

  13. Drugs for type 2 diabetes. Treat Guidel Med Lett 2014; 12(139): 17-24; PubMed Citation  (Concise overview and recommendations on the use of medications in diabetes; the SGLT-2 inhibitors can reduce HbA1c levels by 0.5-1.0% and cause mild weight loss).

  14. Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, Broedl UC; EMPA-REG MONO trial investigators. 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: 208-19. PubMed Citation  (Among 899 patients with diabetes treated with empagliflozin at 2 doses, or sitagliptin, or placebo for 24 weeks; empagliflozin treated patients had more weight loss and higher rates of urinary tract and mycotic genital infections; no mention of ALT levels or hepatotoxicity).

  15. Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, Hach T, Woerle HJ. 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: 1154-60. PubMed Citation  (Among 495 patients with diabetes inadequately controlled on metformin treated with one of 5 doses of empagliflozin or sitagliptin or placebo for 12 weeks, adverse events included genital mycotic infections, urinary tract infections and frequent urination; no mention of ALT elevations or hepatotoxicity).

  16. Häring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ; EMPA-REG MET Trial Investigators. 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: 1650-9. PubMed Citation  (Among 638 patients with diabetes inadequately controlled on metformin treated with 2 doses of empagliflozin or placebo for 24 weeks, adverse events with empagliflozin included hypoglycemia [1-2%], urinary tract infections [5-6%] and genital infections [12%]; no mention of ALT elevations or hepatotoxicity).

  17. Jahagirdar V, Barnett AH. Empagliflozin for the treatment of type 2 diabetes. Expert Opin Pharmacother 2014; 15: 2429-41. PubMed Citation  (Review of the safety and efficacy of empagliflozin based upon 2 published phase II and 4 phase III studies concluded that “empagliflozin was well tolerated”; no mention of ALT elevations or hepatotoxicity).

  18. Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC; EMPA-REG H2H-SU trial investigators. 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. PubMed Citation(1549 patients with diabetes inadequately controlled on metformin, were randomly assigned to be treated with the addition of empagliflozin or glimepiride for 2 years; improvements in HbA1c and adverse events were both similar in both groups; reasons for discontinuation of empagliflozin included one case each of hepatic failure, acute hepatitis and jaundice with no further details; no mention of change in ALT levels).

  19. Empagliflozin (Jardiance) for diabetes. Med Lett Drugs Ther 2014; 56 (1453): 99-100. PubMed Citation  (Concise review of the mechanism of action, efficacy, safety and cost of empagliflozin shortly after its approval for use in the US, states that adverse events include urinary tract and mycotic genital infections and dehydration; no mention of ALT elevations or hepatotoxicity). 

  20. Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf 2014; 37: 815-29. PubMed Citation  (In a pooled analysis of 8685 patients from 12 controlled trials of dapagliflozin in type 2 diabetes, rates of adverse events were 17% vs 13% with placebo, including genital infections [11% vs 1%], urinary tract infections [6% vs 4%], polyuria [3% vs 1.7%] and liver test elevations [4% vs 4%]; mean ALT values decreasing by 3.9 U/L vs 1.7 U/L while combined liver enzyme and bilirubiin elevations arose in 0.1% vs 0.2%).

  21. Leiter LA, Forst T, Polidori D, Balis DA, Xie J, Sha S. Effect of canagliflozin on liver function tests in patients with type 2 diabetes. Diabetes Metab 2016; 42: 25-32. PubMed Citation   (Among 2313 patients with type 2 diabetes treated with canalgifozin or placebo for 26 weeks in 4 controlled trials, ALT, AST and Alk P levels decreased more with canaglifozin than placebo, but the decreases correlated more with reductions in HbA1c levels and weight rather than canaglifozin).

  22. Storgaard H, Gluud LL, Bennett C, Grøndahl MF, Christensen MB, Knop FK, Vilsbøll T. Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One 2016; 11: e0166125. PubMed Citation  (Systematic review of 18 controlled trials of SGLT-2 inhibitors in type 2 diabetes found that SGLT-2 inhibitors reduced ALT levels compared to placebo by an average of 2.8 U/L).

  23. Levine JA, Ann Lo A, Wallia A, Rogers M, VanWagner LB. Dapagliflozin-Induced Acute-on-Chronic Liver Injury. ACG Case Rep J 2016; 3: e169. PubMed Citation  (A 48 year old woman with cirrhosis due to nonalcoholic steatohepatitis and type 2 diabetes developed jaundice and ascites 10 weeks after starting dapagliflozin [bilirubin 1.2 before treatment rising to 20 mg/dL, ALT 45 to 78 U/L, Alk P 220 to 188 U/L, INR 1.5, creatinine 0.8], improving somewhat when the drug was stopped, but qualifying for and then undergoing liver transplantation 4 months later).

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OTHER REFERENCE LINKS
SGLT-2 Inhibitors
  1. PubMed logoRecent References on SGLT-2 Inhibitors

  2. Clinical Trials logoTrials on SGLT-2 Inhibitors

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