Is an SGLT2 Inhibitor Right for Your Patient with Type 2 Diabetes?

Home , SGLT2 inhibitor

Katelin M. Lisenby, PharmD, Is an SGLT2 inhibitor right for BCPS; Allison Meyer, PharmD, BCACP; Nicole A. Slater, PharmD, BCACP your patient with type 2 diabetes? Department of Pharmacy Practice, Auburn University, Harrison School of Pharmacy, Metformin isn’t quite doing the job or is contraindicated? Alabama Here’s a look at the patients who may benefit from these [email protected]

The authors reported no agents and the monitoring required. potential conflict of interest relevant to this article.

CASE 1 u Joe S is a 41-year-old African-American man who PRACTICE comes to your clinic after his employee health screening re- RECOMMENDATIONS vealed elevated triglycerides. The patient has a 3-year history ❯ Consider sodium-glucose of type 2 diabetes mellitus (T2DM); he also has a history of cotransporter 2 (SGLT2) hypertension, gastroesophageal reflux disease, and obstruc- inhibitors as second-line agents in patients with type tive sleep apnea. Mr. S tells you he takes metformin 1000 mg 2 diabetes mellitus who twice daily, but stopped taking his glipizide because he didn’t need mild hemoglobin A1c think it was helping his blood sugar. His last hemoglobin (Hb) reductions (≤1%) and who A1c result was 8.8%, and he is very resistant to starting insulin would benefit from mild to therapy. modest weight and blood The patient’s other medications include enalapril 10 mg/d, pressure reductions. A atorvastatin 10 mg/d, and omeprazole 20 mg/d. Mr. S weighs ❯ Avoid using SGLT2 255.6 lbs (body mass index=34.7), his BP is 140/88 mm Hg, and inhibitors in patients with a his heart rate is 82 beats per minute. Laboratory values include: history of recurrent genital serum creatinine, 1.01 mg/dL; estimated glomerular filtration mycotic or urinary tract rate (eGFR) >100 mL/min/1.73 m2; potassium (K), 4.3 mmol/L; infections. B serum phosphorous (Phos), 2.8 mg/dL; magnesium (Mg), ❯ Use SGLT2 inhibitors with 1.9 mg/dL; total cholesterol, 167 mg/dL; low-density lipoprotein caution in patients at risk (LDL), 78 mg/dL; high-density lipoprotein (HDL), 38 mg/dL; and for volume-related adverse triglycerides, 256 mg/dL. effects (dizziness and hypotension), such as the CASE 2 u Susan R, a 68-year-old Caucasian woman, returns to elderly, those with moderate your clinic for a follow-up visit 3 months after you prescribed renal dysfunction, and those dapagliflozin 10 mg/d for her T2DM. Her glucose levels have taking concomitant diuretic improved, but she complains of vaginal pruritus and is worried therapy. C that she has a yeast infection. Strength of recommendation (SOR) You diagnose vulvovaginal candidiasis in this patient and A Good-quality patient-oriented evidence prescribe a single dose of fluconazole 150 mg. After review- B Inconsistent or limited-quality ing her laboratory test results, you notice that since starting patient-oriented evidence the dapagliflozin, her HbA1c level has improved slightly from C Consensus, usual practice, 9.8% to 9.3%, but is still not where it needs to be. Her eGFR is opinion, disease-oriented evidence, case series 49 mL/min/1.73 m2. What would you recommend to improve control of these patients’ blood glucose levels?

CONTINUED

JFPONLINE.COM VOL 65, NO 9 | SEPTEMBER 2016 | THE JOURNAL OF FAMILY PRACTICE 587 agents may be used at any stage of the diabetes continuum. When to consider an SGLT2 inhibitor SGLT2 agents as monotherapy, Consider therapy with SGLT2 inhibitors in adult patients with T2DM who:3-9,13-15,17-24 or as add-on therapy All SGLT2 agents have been studied as • have an HbA1c between 7% and 9% monotherapy accompanied by diet and ex- • would benefit from weight and/or ercise and shown to produce HbA1c reduc- blood pressure reductions tions of 0.34% to 1.11%.3-6 In trials, the effect • have metabolic syndrome was similar regardless of study duration (18-104 weeks); generally, higher doses cor- • have adequate means to pay for the 3-6 medication (ie, prescription coverage responded with larger HbA1c reductions. or the ability to afford it). SGLT2 inhibitors have also been studied as add-on therapy to several oral agents In addition, consider an SGLT2 inhibitor including metformin, sulfonylureas, thia- as initial monotherapy if metformin is zolidinediones (TZDs), and the combination contraindicated or not tolerated, or as add-on therapy to metformin, sulfonyl- of metformin plus sulfonylureas or TZDs or 1 ureas, thiazolidinediones, dipeptidyl dipeptidyl peptidase IV (DPP-IV) inhibitors. Used as peptidase IV inhibitors, or insulin. When used in any of these combinations, monotherapy, each SGLT2 agent demonstrated a consistent SGLT2 inhibitors HbA1c lowering effect of 0.62% to 1.19%.7-14 produce HbA1c Additionally, SGLT2 inhibitors have reductions of as odium-glucose cotransporter 2 (SGLT2) been studied in combination with insu- much as 1.11%. inhibitors are the newest class of agents lin therapy (median or mean daily doses S to enter the T2DM management arena. >60 units), which yielded further reductions They act in the proximal renal tubules to de- in HbA1c of 0.58% to 1.02% without signifi- crease the reabsorption of glucose by targeting cant insulin adjustments or an increase in the SGLT2 transmembrane protein, which re- major hypoglycemia events.15-17 Patients re- absorbs about 90% of the body’s glucose.1,2 The ceiving insulin and an SGLT2 inhibitor had class is currently made up of 3 agents—cana- lower insulin doses and more weight loss gliflozin, dapagliflozin, and empagliflozin—all compared to placebo groups. of which are approved by the US Food and Drug Administration (FDA) for the treatment SGLT2 inhibitors offer of T2DM (TABLE 1).2 additional benefits The American Diabetes Association and Secondary analyses of most studies of SGLT2 the European Association for the Study of inhibitors include changes in BP and weight Diabetes published updated guidelines for from baseline as well as minor changes T2DM management in 2015.1 In addition to (some positive, some not) in several lipid pa- lifestyle modifications, the guidelines rec- rameters.3-5,7-9,13-15,17-24 In general, these effects ommend the use of metformin as first-line do not appear to be dose-dependent (with therapy unless it is contraindicated or pa- the exception of canagliflozin and its associ- tients are unable to tolerate it (eg, because ated lipid effects25) and are similar among the of gastrointestinal adverse effects). They rec- 3 medications.3-5,7-9,13-15,17-24 (For more on who ommend other pharmacologic therapies as would benefit from these agents, see “When second-line options based on specific patient to consider an SGLT2 inhibitor” above.) characteristics. Thus, SGLT2 inhibitors may ❚ BP reduction. Although the mean base- be used as add-on therapy after metformin, line BP was controlled in most studies, SGLT2 or as a first-line option if metformin is con- inhibitors have been shown to significantly traindicated or not tolerated. Because the reduce BP. Reductions in BP with all 3 SGLT2 mechanism of action of SGLT2 inhibitors medications range from approximately 2 to is independent of insulin secretion, these 5 mm Hg systolic and 0.5 to 2.5 mm Hg dia-

588 THE JOURNAL OF FAMILY PRACTICE | SEPTEMBER 2016 | VOL 65, NO 9 SGLT2 INHIBITORS

TABLE 1 FDA-approved SGLT2 inhibitors2

Generic agent (brand) Canagliflozin (Invokana) Dapagliflozin (Farxiga) Empagliflozin (Jardiance) Initial dose 100 mg/d if eGFR is 45 to <60 and 5 mg/d (10 mg/d) 10 mg/d (25 mg/d) (maximum dose) 300 mg/d if eGFR ≥60 Renal dosage adjustments Discontinue if eGFR is persistently Do not administer/discontinue Do not initiate/discontinue <45 (Contraindicated if eGFR <30) with eGFR <60 with eGFR persistently <45 (Contraindicated if eGFR <30) Hepatic dosage No adjustment for mild to moderate impairment; not recommended None to note adjustments in severe impairment (has not been studied) Drug interactions If receiving concurrent UGT None to note enzyme inducers and eGFR is 45 to <60, consider alternative antihyperglycemic therapy Administration Administer prior to first meal Administer in the morning without regard to food Common adverse effects Genital mycotic infections, urinary tract infections, volume-related effects such as dizziness and hypotension Available combination canagliflozin + metformin dapagliflozin + metformin ER empagliflozin + metformin products, generic (brand) (Invokamet) (Xigduo) (Synjardy) empagliflozin + linagliptan (Glyxambi) eGFR, estimated glomerular filtration rate (reported in mL/minute/1.73 2m ); UGT, uridine 5’-diphospho-glucuronosyltransferase enzyme inducers (eg, rifampin, phenytoin, phenobarbital, ritonavir). stolic, which may be due to weight loss and doses of empagliflozin.13 Additionally, mod- diuresis.4-8,10-16,20-23 While the reductions were est reductions in triglycerides and increases modest at best, one study involving empa- in HDL across all doses of canagliflozin, gliflozin reported that more than one-quarter dapagliflozin, and empagliflozin have been of patients with uncontrolled BP at baseline seen.8,9,13,15,19 While the clinical relevance of achieved a BP <130/80 mm Hg 24 weeks these lipid changes is unknown, monitoring later.5 While these agents should not be used is recommended.2 solely for their BP lowering effects, they may help a small number of patients with mildly elevated BP achieve their goal without an ad- These agents ditional antihypertensive agent. are well tolerated ❚ Weight reduction. Modest weight SGLT2 inhibitors were generally well toler- loss, likely due to the loss of calories through ated in studies. The most common adverse urine, was seen with SGLT2 inhibitors in effects include mycotic infections (2.4%- most studies, with reductions persisting be- 21.6%) and urinary tract infections (UTIs) yond one year of use. In most studies, in- (4.0%-19.6%) (both with higher incidences cluding those involving obese patients on in females); volume-related effects such insulin therapy,15,17,21 patients’ body weights as dizziness and hypotension (0.3%-8.3%); were reduced by approximately 2 to 4 kg from and nasopharyngitis (5.4%-18.3%).4-14,16-23,26-28 baseline.3-16,18,21-23,26 Hypoglycemia was observed more often ❚ Lipid effects. Although the mecha- when an SGLT2 inhibitor was used in com- nism is unclear, use of SGLT2 inhibitors can bination with a sulfonylurea or insulin ther- have varying effects on lipid panels. In most apy.4-14,16-23,26-28 The number of times adverse studies, total and LDL cholesterol levels events led to discontinuation was low and were increased with elevations ranging from similar to that in control groups.4-14,16-23,26-28 0.7 to 10 mg/dL.3,7,8,18,19,22,23 Conversely, at least Mycotic and urinary infections should be one study demonstrated mild reductions in diagnosed and treated according to current total and LDL cholesterol levels with higher standards of care and do not require discon-

JFPONLINE.COM VOL 65, NO 9 | SEPTEMBER 2016 | THE JOURNAL OF FAMILY PRACTICE 589 tinuation of the SGLT2 inhibitor. Canagli- Over a 2-year period, canagliflozin also flozin therapy was associated with electrolyte significantly decreased BMD in the hip and abnormalities including hyperkalemia, hy- lower spine compared to placebo.31 Patients permagnesemia, and hyperphosphatemia.25 should be evaluated for additional risk fac- Thus, levels should be monitored periodi- tors for fracture before taking canagliflozin.31 cally, especially in patients predisposed The FDA is continuing to evaluate whether to elevations due to other conditions or the other approved SGLT2 inhibitors are as- medications.25 sociated with an increased risk for fractures.

Two additional warnings are worth noting Drug interactions: Diabetic ketoacidosis (DKA) has been re- Proceed carefully with diuretics ported with all 3 agents, and bone fractures The number of drugs that interact with SGLT2 have been reported with canagliflozin. inhibitors is minimal. Because these agents The FDA issued a warning in May can cause volume-related effects such as hy- 2015 regarding the increased risk of DKA potension, dizziness, and osmotic diuresis, with the use of SGLT2 inhibitor single and patients—particularly the elderly and those combination products.29 This warning was with renal impairment—taking concomitant prompted by several case reports of DKA diuretics, especially loop diuretics, may be at SGLT2 inhibitors with uncharacteristically mild to moder- increased risk for these effects and should be can reduce ate glucose elevations in patients with monitored accordingly.2,25 BP by about type 1 diabetes mellitus (T1DM) and T2DM Canagliflozin is primarily metabolized via 2 to 5 mm Hg, who were taking an SGLT2 inhibitor. The ab- glucuronidation by the uridine 5'-diphospho- systolic, and 0.5 sence of significant hyperglycemia delayed glucuronosyltransferase (UGT) enzymes. to 2.5 mm Hg, diagnosis in many cases. Therefore, patients Therefore, UGT enzyme inducers (eg, ri- diastolic. should be counseled on the signs and symp- fampin, phenytoin, phenobarbital, rito- toms of DKA, as well as when to seek medical navir) decrease canagliflozin’s serum attention. concentration. If a patient has an eGFR Patients with diabetes and symptoms of >60 mL/min/1.73 m2 and is tolerating a dose ketoacidosis (eg, difficulty breathing, nau- of 100 mg/d, consider increasing the dose to sea, vomiting, abdominal pain, confusion, 300 mg/d during concomitant treatment. and fatigue) should be evaluated regardless In addition, researchers have found of current blood glucose levels, and SGLT2 that canagliflozin increases serum levels of inhibitors should be discontinued if acidosis digoxin by between 20% and 36%.25 Experts sus- is confirmed. Identified potential triggers in- pect this occurs because canagliflozin inhib- clude illness, reduced food and fluid intake, its P-glycoprotein efflux of digoxin. Although reduced insulin dose, and history of alcohol monitoring of digoxin levels is recommended, intake. Use of SGLT2 inhibitors should be this interaction is considered to be minor.25 avoided in patients with T1DM until safety and efficacy are established in large randomized controlled trials. The European Cost consideration: SGLT2 inhibitors Medicines Agency announced that a thor- are more expensive ough review of all currently approved SGLT2 The SGLT2 inhibitors are available only as agents is underway to evaluate the risk for brand name products and are more expen- DKA.30 sive than agents that have generic options In addition, the FDA called for a revi- (eg, metformin, sulfonylureas, TZDs). The sion of the label of canagliflozin to reflect a average wholesale cost is approximately strengthened warning about an increased risk $400 for a 30-day supply of all SGLT2 agents.32 of bone fractures and decreased bone min- When considering an SGLT2 inhibitor, the eral density (BMD).31 Fractures can occur as patient should ideally have medication pre- early as 12 weeks after initiating treatment scription coverage. Depending on the spe- and with only minor trauma.31 cific insurance plan, these agents are clas-

590 THE JOURNAL OF FAMILY PRACTICE | SEPTEMBER 2016 | VOL 65, NO 9 SGLT2 INHIBITORS

sified as tier 2 to 4, which is comparable to 2011, the FDA issued a request for further in- other oral brand name options. vestigation surrounding the risk of cancer associated with dapagliflozin.36 As of November 2013, 10 of 6045 patients treated with dapa- Research looks at CV outcomes gliflozin developed bladder cancer compared and cancer risk to 1 of 3512 controls.36 Furthermore, 9 of Cardiovascular (CV) risk reduction. To date, 2223 patients treated with dapagliflozin only one study evaluating the effect of SGLT2 developed breast cancer compared to 1 of inhibitors on CV outcomes is complete.33 Two 1053 controls.36 large randomized controlled trials involving Although the trials were not designed to canagliflozin and dapagliflozin designed to detect an increase in risk, the number of ob- evaluate treatment effects on major CV end- served cases warranted further investigation. points are ongoing.34,35 No official warning for breast cancer exists In the EMPA-REG OUTCOME trial,33 re- since the characteristics of the malignancies searchers found that empagliflozin had ben- led the FDA to believe dapagliflozin was un- eficial effects on CV outcomes, making it one likely the cause.36 of the only antidiabetic agents on the market Given what we know to date, it appears to have such benefits. The study, which in- to be prudent to avoid prescribing SGLT2 in- volved more than 7000 patients with a history hibitors in patients with active bladder can- of T2DM and existing cardiovascular disease cer, and to use them with caution in those When (CVD), found that 10.5% of patients in the with a history of the disease.2 considering an empagliflozin group vs 12.1% in the placebo ❚ Other studies. Initially, animal stud- SGLT2 inhibitor, group died from a CV cause or experienced a ies suggested an increased risk of various the patient nonfatal myocardial infarction or stroke over a malignancies associated with canagliflozin should ideally median of 3.1 years. Results were similar with use in rats,37 but consistent results were not have medication both doses (10 mg vs 25 mg) of empagliflozin. seen in human studies. Similarly, at least prescription The mechanisms behind the CV benefits are one study found that empagliflozin was as- coverage. likely multifactorial and may be related to re- sociated with lung cancer and melanoma, ductions in weight and BP,33 but additional re- but closer examination found that most search is needed to fully elucidate the role of patients who developed these cancers had empagliflozin in this population. risk factors.38 Large, long-term studies of Canagliflozin is being evaluated in the these agents in various populations are Canagliflozin Cardiovascular Assessment needed to thoroughly investigate possible Study (CANVAS) for its effect on major CV carcinogenicity. events—CV death, nonfatal myocardial infarction, and nonfatal stroke—in patients with Additional considerations: either a history of CVD or who are at increased kidney function, age, and pregnancy risk of CVD and have uncontrolled diabetes.34 Consider avoiding SGLT2 inhibitors in pa- The trial is expected to wrap up in June 2017. tients with moderate kidney dysfunction And dapagliflozin is being studied in the (eGFR 30-59 mL/min/1.73 m2). Studies have DECLARE-TIMI 58 trial (the Effect of Dapa- shown that SGLT2 inhibitors are not as ef- gliflozin on the Incidence of Cardiovascular fective at lowering blood glucose in those Events) in patients with T2DM and either with reduced eGFR, although adverse events known CVD or at least 2 risk factors for CVD.35 were similar to those in placebo groups.24,39,40 The study is designed to assess dapagliflozin’s Dapagliflozin is not recommended in pa- effect on the incidence of CV death, myocar- tients with an eGFR <60 mL/min/1.73 m2 dial infarction, and ischemic stroke and has due to lack of efficacy.2,24 Empagliflozin does an estimated completion date of April 2019, not require dose adjustments if eGFR is which will provide a median follow-up of ≥45 mL/min/1.73 m2. A lower dose of cana- 4.5 years. gliflozin (ie, 100 mg/d) is recommended in ❚ Cancer. All 3 agents have been exam- those with an eGFR of 45 to 59 mL/min/- ined for any possible carcinogenic links. In 1.73 m2.2 All agents are contraindicated in

JFPONLINE.COM VOL 65, NO 9 | SEPTEMBER 2016 | THE JOURNAL OF FAMILY PRACTICE 591 patients with severe renal impairment (eGFR CORRESPONDENCE Katelin M. Lisenby, PharmD, BCPS, University of Alabama 2 <30 mL/min/1.73 m ). College of Community Health Sciences, University Medical Older patients are at higher risk for dehy- Center, Box 870374, Tuscaloosa, AL 35487; kmh0003@auburn. edu. dration, hypotension, and falls; therefore, SGLT2 inhibitors should be used with caution in this population. Similarly, they should not be used References in patients with T1DM and should be avoided 1. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach. in those with active, or a history of, DKA. Update to a position statement of the American Diabetes As- sociation (ADA) and the European Association for the Study of There are no data on the use of SGLT2 in- Diabetes (EASD). Diabetes Care. 2015;38:140-149. hibitors in pregnancy; thus, these agents should 2. Canagliflozin, dapagliflozin, empagliflozin. Lexicomp, Inc. (Lexi- be avoided unless the potential benefits out- Drugs®). Accessed October 12, 2015. 2 3. Stenlöf K, Cefalu WT, Kim KA, et al. Long-term efficacy and safety weigh the potential risks to the unborn fetus. of canagliflozin monotherapy in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise: find- ings from the 52-week CANTATA-M study. Curr Med Res Opin. CASE 1 u An SGLT2 inhibitor is an acceptable 2014;30:163-175. 4. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monother- option for Mr. S. Because he is resistant to apy in type 2 diabetic patients with inadequate glycemic control starting insulin therapy and his HbA1c is <9%, by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010:33:2217-2224. an additional oral medication is reasonable. 5. Roden M, Weng J, Eilbracht J, et al. Empagliﬂozin monotherapy Adding an SGLT2 inhibitor may reduce his with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase HbA1c up to ~1%, and education on lifestyle 3 trial. Lancet Diabetes Endocrinol. 2013;1:208-219. The FDA issued a modifications may help bring him to goal. An 6. Ferrannini E, Berk A, Hantel S, et al. Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: an active- warning in light SGLT2 inhibitor may also benefit his BP and controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care. of several case weight, both of which could be improved. 2013;36:4015-4021. reports of DKA Given the drugs he’s taking, drug inter- 7. Wilding JPH, Charpentier G, Hollander P, et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inad- with unusually actions should not be an issue, and his renal equately controlled with metformin and sulphonylurea: a ran- mild glucose function and pertinent labs (K, Phos, Mg) are domised trial. Int J Clin Pract. 2013;67:1267-1282. 8. Forst T, Guthrie R, Goldenberg R, et al. Efficacy and safety of elevations within normal limits. Nevertheless, monitor canagliflozin over 52 weeks in patients with type 2 diabetes on in patients these labs periodically and monitor Mr. S for background metformin and pioglitazone. Diabetes Obes Metab. 2014;16:467-477. taking an adverse effects, such as UTIs, although these 9. Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin com- SGLT2 inhibitor. are more common in women. Canagliflozin is pared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonyl- the preferred SGLT2 inhibitor on his insurance urea: a 52-week randomized trial. Diabetes Care. 2013;36:2508- formulary, so you could initiate therapy at 2515. 10. Bristol-Myers Squibb [press release]. New phase III data showed 100 mg/d, administered prior to the first meal, dapagliflozin significantly reduced HbA1c compared to placebo at 24 weeks in patients with type 2 diabetes inadequately con- and increase to 300 mg/d if needed. As an al- trolled with the combination of metformin plus sulfonylurea. ternative, consider prescribing the metformin/ Available at: http://news.bms.com/press-release/rd-news/new- phase-iii-data-showed-dapagliflozin-significantly-reduced- canagliflozin combination agent. hba1c-compared-p&t=635156160653787526. Accessed Septem- ber 17, 2015. 11. Jabbour SA, Hardy E, Sugg J, et al. Dapagliflozin is effective as CASE 2 u Ms. R is likely experiencing a yeast add-on therapy to sitagliptin with or without metformin: a 24- week, multicenter, randomized, double-blind, placebo-con- infection as an adverse effect of the dapa- trolled study. Diabetes Care. 2014;37:740-750. gliflozin. Although one yeast infection is in- 12. DeFronzo RA, Lewin A, Patel S, et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with sufficient grounds for discontinuation of the type 2 diabetes inadequately controlled on metformin. Diabetes drug, recurrent infections should prompt a Care. 2015;38:384-393. 13. Kovacs CS, Seshiah V, Merker L, et al. Empagliflozin as add-on risk-to-benefit analysis to determine whether therapy to pioglitazone with or without metformin in patients it’s worth continuing the medication. Her re- with type 2 diabetes mellitus. Clin Ther. 2015;37:1773-1788. 2 14. Haring HU, Merker L, Seewaldt-Becker E, et al. Empagliflozin as cent eGFR (<60 mL/min/1.73 m ) is, however add-on to metformin plus sulfonylurea in patients with type 2 di- a contraindication to dapagliflozin, and ther- abetes: a 24-week, randomized double-blind, placebo-controlled trial. Diabetes Care. 2013;36:3396-3404. apy should be discontinued. Canagliflozin 15. Neal B, Percovik V, de Zeeuw D, et al. Efficacy and safety of cana- and empagliflozin may be considered since gliflozin, an inhibitor of sodium–glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 2 her eGFR is >45 mL/min/1.73 m , but given diabetes. Diabetes Care. 2015;38:403-411. her current HbA1c and recent adverse drug 16. Wilding JPH, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiv- event, alternative therapies, such as basal ing high doses of insulin: a randomized trial. Ann Intern Med. insulin, are more appropriate treatment 2012;156:405-415. 17. Rosenstock J, Jelaska A, Frappin G, et al. Improved glucose con- choices. JFP trol with weight loss, lower insulin doses, and no increased hy-

592 THE JOURNAL OF FAMILY PRACTICE | SEPTEMBER 2016 | VOL 65, NO 9 SGLT2 INHIBITORS

poglycemia with empagliflozin added to titrated multiple daily 30. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: injections of insulin in obese inadequately controlled type 2 dia- a predictable, detectable, and preventable safety concern with betes. Diabetes Care. 2014;37:1815-1823. SGLT2 inhibitors. Diabetes Care. 2015;38:1638-1642. 18. Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of cana- 31. US Food and Drug Administration. FDA drug safety communica- gliflozin versus glimepiride in patients with type 2 diabetes in- tion: FDA revises label of diabetes drug canagliflozin (Invokana, adequately controlled with metformin (CANTATA-SU): 52 week Invokamet) to include updates on bone fracture risk and new results from a randomised, double-blind, phase 3 non-inferiority information on decreased bone mineral density. Available at: trial. Lancet. 2013;382:941-950. http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm. Acces- 19. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in sed July 11, 2016. patients with type 2 diabetes who have inadequate glycaemic 32. Canagliflozin, dapagliflozin, empagliflozin. In: RED BOOK [AUH- control with metformin: a randomised, double-blind, placebo- SOP intranet database]. Greenwood Village, CO: Truven Health controlled trial. Lancet. 2010:375:2223-2233. Analytics; [updated daily]. Available at: http://www.microme- 20. Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to dexsolutions.com/micromedex2/librarian/ND_T/evidenc- metformin in type 2 diabetes inadequately controlled with met- expert/ND_PR/evidencexpert/CS/BB1644/ND_AppProduct/ formin: a randomized, double-blind, placebo-controlled 102- evidencexpert/DUPLICATIONSHIELDSYNC/FAF693/ND_PG/ week trial. BMC Med. 2013;11:43. evidencexpert/ND_B/evidencexpert/ND_P/evidencexpert/ PFActionId/redbook.ShowProductSearchResults?SearchTerm=J 21. Rosenstock J, Vico M, Wei L, et al. Effects of dapagliflozin, an ARDIANCE&searchType=redbookProductName&searchTermId SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk =42798&searchContent=%24searchContent&searchFilterAD=fi in patients with type 2 diabetes inadequately controlled on piogli- lterADActive&searchFilterRepackager=filterExcludeRepackager tazone monotherapy. Diabetes Care. 2012;35:1473-1478. &searchPattern=%5Ejard. Accessed March 15, 2016. 22. Merker L, Häring HU, Christiansen AV, et al. Empagliflozin as add-on to metformin in people with type 2 diabetes. Diabet Med. 33. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovas- 2015;32:1555-1567. cular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128. 23. Ridderstråle M, Anderson KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in pa- 34. CANagliflozin cardioVascular Assessment Study (CANVAS). Avail- tients with type 2 diabetes: a 104-week randomised, active-con- able at: http://clinicaltrials.gov/show/NCT01032629. Accessed trolled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. October 12, 2015. 2014;2:691-700. 35. Multicenter trial to evaluate the effect of dapagliflozin on the inci- 24. Kohan DE, Fioretto P, Tang W, et al. Long-term study of patients dence of cardiovascular events (DECLARE-TIMI 58). Available at: with type 2 diabetes and moderate renal impairment shows that http://clinicaltrials.gov/show/NCT01730534. Accessed October dapagliflozin reduces weight and blood pressure but does not im- 12, 2015. Use SGLT2 prove glycemic control. Kidney Int. 2014;85:962-971. 36. FDA background document. BMS-512148 NDA 202293. In: inhibitors with 25. Invokana (canagliflozin) tablets [product information]. Titusville, Proceedings of the US Food and Drug Administration Endocri- NJ: Janssen Pharmaceuticals Inc. Available at: https://www.invo- nologic & Metabolic Drug Advisory Committee Meeting, 2013. caution in older kana.com. Accessed March 15, 2013. Available at: http://www.fda.gov/downloads/drugs/endocrino- logicandmetabolicdrugsadvisorycommittee/ucm378079.pdf. patients because 26. Lavalle-González FJ, Januszewicz A, Davidson J, et al. Efficacy and Accessed October 12, 2015. safety of canagliflozin compared with placebo and sitagliptin in they are at patients with type 2 diabetes on background metformin mono- 37. Lin HW, Tseng CH. A review of the relationship between therapy: a randomised trial. Diabetologia. 2013;56:2582-2592. SGLT2 inhibitors and cancer. Int J Endocrinol. 2014;2014: higher risk 719578. 27. Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in for dehydration, patients with type 2 diabetes who have inadequate glycaemic 38. Center for Drug Evaluation and Research. Risk assessment control with glimepiride: a randomized, 24-week, double-blind, and risk mitigation review(s). July 28, 2014. Available at: hypotension, placebo-controlled trial. Diabetes Obes Metab. 2011;13:928-938. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/ and falls. 28. Leiter LA, Yoon KH, Arias P, et al. Canagliflozin provides du- 204629Orig1s000RiskR.pdf. Accessed September 21, 2015. rable glycemic improvements and body weight reduction over 39. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of cana- 104 weeks versus glimepiride in patients with type 2 diabetes on gliflozin over 52 weeks in patients with type 2 diabetes mellitus metformin: a randomized, double-blind, phase 3 study. Diabetes and chronic kidney disease. Diabetes Obes Metab. 2014;16:1016- Care. 2015;38:355-364. 1027. 29. US Food and Drug Administration. FDA drug safety communica- 40. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of tion: FDA warns that SGLT2 inhibitors for diabetes may result in empagliflozin added to existing antidiabetes treatment in pa- a serious condition of too much acid in the blood. Available at: tients with type 2 diabetes and chronic kidney disease: a ran- http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Acces- domised, double-blind, placebo-controlled trial. Lancet Diabetes sed July 11, 2016. Endocrinol. 2014;2: 369-384. Residents’ Rapid Review

Residents: Are you getting ready for your family medicine certification exam?

Then check out our monthly Residents’ Rapid Review quizzes, featuring prep questions written by the faculty of the National Family Medicine Board Review course.

This month’s questions can be found at www.jfponline.com

JFPONLINE.COMRegistration is required. If you are not alreadyVOL 65, registered, NO 9 |go SEPTEMBER to: jfponline.com/residents_reg 2016 | THE JOURNAL OF FAMILY PRACTICE 593