How Well Do You Know Empagliflozin?

Test your knowledge of empagliflozin, the newest SGLT2 inhibitor on the market. (Find references on the last page.)

1. Phase III trials have shown that use of 10 mg and 25 mg empagliflozin monotherapy can result in how much weight loss over 24 weeks, compared to placebo?

A. 1.25-1.74 lbs

B. 2.25- 2.74 lbs

C. 3.25-3.74 lbs

D. 4.25-4.74 lbs

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Answer: D. 4.25-4.74 lbs

According to the EMPA-REG MONO trial, which looked at the efficacy and tolerability of empagliflozin monotherapy versus placebo and versus sitagliptin, patients lost about 4.25-4.74 pounds when they received empagliflozin 10 mg and 25 mg for 24 weeks.¹ Because SGLT2 inhibitors induce a mild diuresis, one question is whether this weight loss represents actual reduction in adipose tissue, or results from fluid loss. Longer-term results with dapagliflozin and canagliflozin have suggested that the weight loss results from reduction in fat mass caused by net calorie loss from urinary glucose excretion.^2,3

2. Which of the following could increase the risk of hypoglycemia when combined with empagliflozin?

A. Metformin

B. Glipizide

C. Pioglitazone

D. All of the above

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Answer: B. Glipizide

The type of glucose-lowering agent used in combination with empagliflozin appears to affect the risk of hypoglycemia. For example, phase III clinical trials have suggested that adding empagliflozin to metformin⁴ or pioglitazone⁵ does not appear to significantly increase the risk of hypoglycemia. However, when empagliflozin is added to an insulin secretagogue like the sulfonylurea glipizide, the risk of hypoglycemia seems to increase.⁶ For this reason, the prescribing information for empagliflozin recommends using a lower dose of a sulfonylurea or insulin when combining these agents with empagliflozin.

3. Which of the following agents has been linked to increased risk of bladder cancer?

A. Dapaglifozin

B. Canagliflozin

C. Empagliflozin

D. All of the above

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Answer: A. Dapaglifozin

A pooled analysis of dapagliflozin clinical trials has suggested an increased risk for bladder cancer with this agent.⁷ Although the case numbers were too low to establish whether this increased risk was caused by dapagliflozin treatment, US prescribing information warns against using dapagliflozin in patients with active bladder cancer, and advises cautious use in patients with a history of the disease. Analyses of canagliflozin⁸ and empagliflozin⁹ have not suggested an increased risk of bladder cancer with these agents.

4. According to phase III clinical trials, which of the following statements is true?

A. Bone fractures are more common in patients treated with empagliflozin, compared to placebo.

B. Bone fractures are more common in patients treated with dapagliflozin, compared to placebo.

C. Long-term use of empagliflozin has been linked to loss in bone mineral density.

D. A and C

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Answer: B. Bone fractures are more common in patients treated with dapagliflozin, compared to placebo

In a phase III clinical trial looking at long-term (2 years) treatment with dapagliflozin vs. placebo in patients with moderate renal impairment, 13 patients treated with dapagliflozin experienced bone fractures, compared to none with placebo.¹⁰ In contrast, studies to date have suggested that bone fractures are no more common in patients treated with empagliflozin compared to placebo, and that treatment with empagliflozin for up to 2 years is not linked to loss in bone mineral density.¹¹

5. Because empagliflozin may affect liver function, careful monitoring is advisable when prescribing this medication.

A. True

B. False

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Answer: A. True

A phase III clinical trial looking at empagliflozin in patients with hepatic impairment found increases in area under the curve and maximum concentration levels of this drug in patients with hepatic impairment, compared to patients with normal liver function.  Dose adjustments were not needed, however, because the increases in pharmacokinetic values were less than twofold those of patients with normal liver function.¹² There is limited evidence, though, for the use of empagliflozin in patients with severe hepatic impairment, and the drug is not currently recommended for such patients.  Monitoring liver function tests is advisable in patients on SGLT2 inhibitors.¹³

6. Which of the following statements is true?

A. For empagliflozin, no dosage adjustments are recommended based on age.

B. Empagliflozin is not recommended for patients aged 85 years and older.

C. Because of the risk of volume depletion, dosage adjustments are recommended based on age for patients treated with empagliflozin.

D. Both A and B

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Answer: D. Both A and B

The European Medicines Agency does not currently recommend dosage adjustments for empagliflozin based on age. However, no analyses about the use of empagliflozin in elderly patients have yet been reported. Because of limited therapeutic experience, empagliflozin is not recommended for patients aged 85 and older.¹⁴ Because of the risk of hypovolemia,  caution is advisable when prescribing the drug  to patients aged 75 and older.¹³

References:

1. 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 Nov;1(3):208-219. Epub 2013 Sep 9.

2. Cefalu WT, Leiter LA, Yoon KH, et al. 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 Sep 14;382(9896):941-950. Epub 2013 Jul 12.

3. Bolinder J, Ljunggren Ö, Johansson L, 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 Feb;16(2):159-169. Epub 2013 Aug 29.

4. Häring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care. 2014 Jun;37(6):1650-1659. Epub 2014 Apr 10.

5. Kovacs CS, Seshiah V, Swallow R, et al. 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 Feb;16(2):147-158. Epub 2013 Aug 22.

6. Häring HU, Merker L, Seewaldt-Becker E, et al. 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 Nov;36(11):3396-3404. Epub 2013 Aug 20.

7. US Food and Drug Administration.  Briefing document for dapagliflozin. December 2013. Accessed May 27 2015 at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM378076.pdf

8. US Food and Drug Adnministration.  Briefing document for canagliflozin.  Accessed May 27, 2015 at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM334550.pdf

9. European Medicines Agency. Empagliflozin CHMP Assessment Report. March 2014.  Accessed May 27, 2015 at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002677/WC500168594.pdf

10. Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014 Apr;85(4):962-971. Epub 2013 Sep 25.

11. European Medicines Agency.  Summary of risk management plan (RMP) for Jardiance. April 2014.  Accessed May 27, 2015 at:  http://www.fimea.fi/download/27456_Jardiance_RMP_summary-EN.pdf

12. Macha S, Rose P, Mattheus M, et al. Pharmacokinetics, safety and tolerability of empagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with hepatic impairment. Diabetes Obes Metab. 2014 Feb;16(2):118-123. Epub 2013 Aug 19.

13. Hinnen D. Short commentary on empagliflozin and its potential clinical impact. Ther Adv Endocrinol Metab. 2015 Apr;6(2):68-81.

14. European Medicines Agency.  Jardiance Summary of Product Characteristics.  Accessed May 27, 2015 at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002677/WC500168592.pdf