Sodium-Glucose Co-Transporter-2 Inhibitors: An Update on the Evidence for Treatment of Type 2 Diabetes
Sodium-glucose co-transporter-2 inhibitors are a class of antihyperglycemic agents that can be used to improve glycemic control in the treatment of type 2 diabetes.
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a class of antihyperglycemic agents that can be used to improve glycemic control in the treatment of type 2 diabetes (T2D). SGLT-2 inhibitors block SGLT-2—mediated reabsorption of glucose into circulation. By this mechanism, plasma glucose levels are reduced and glucose is excreted in the urine. Not only do SGLT-2 inhibitors have glucose-lowering effects, but their efficacy in nonglycemic clinical parameters, such as lowering blood pressure and helping in weight loss, may be beneficial for patients with T2D.1
Within the family of sodium-dependent glucose transporters, sodium-glucose co-transporter-1 (SGLT-1) and SGLT-2 transporters are key regulators of glucose reabsorption filtered by the kidney, with expression on 2 regions of the renal proximal convoluted tubule. The majority of glucose reabsorption (90%) is attributed to SGLT-2 within the S1 segment, and the SGLT-1 receptor aids in glucose reabsorption downstream from SGLT-2 in the S3 segment.2 In patients with T2D, an increased filtered load of glucose increases its reabsorption through the SGLT-2 transporters of the kidney. Instead of excreting excess filtered glucose in urine, increased reabsorption causes elevated plasma glucose, thereby leading to the hyperglycemic state.
The American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) currently recommend that an SGLT-2 inhibitor may be used as first-line therapy in the management of T2D for patients with glycated hemoglobin (A1C) <7.5%, although stronger levels of evidence exist for using an SGLT-2 inhibitor for both dual and triple therapy for patients with A1C >7.5%.3 Similarly, the American Diabetes Association recommends an SGLT-2 inhibitor as dual or triple therapy.4 Currently, 3 oral SGLT-2 inhibitors are indicated for the treatment of T2D as an adjunct to diet and exercise: empagliflozin, canagliflozin, and dapagliflozin.5 This article will discuss the recent updates in evidence relating to the clinical concerns and monitoring parameters of available SGLT-2 inhibitors, including cardiovascular benefits, the risk of amputations, acute kidney injury, euglycemic diabetic ketoacidosis (euDKA), and genitourinary infections.
Evidence supports the efficacy of canagliflozin and empagliflozin use in patients with T2D and established cardiovascular disease (CVD). Although empagliflozin has the most cardiovascular data, dapagliflozin and canagliflozin trial results also show decreases in systolic blood pressure, with evidence-based benefits ranging from decreased systolic blood pressure to decreased morbidity and mortality.
In the phase 3 EMPA-REG Outcome trial, treatment with empagliflozin significantly decreased the risk of the composite clinical cardiovascular outcome of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke compared with placebo treatment in patients with T2D and high risk for cardiovascular events/established CVD (HR, 0.86; 95% CI, 0.74-0.99; P <.0001, for noninferiority).6 Empagliflozin was also associated with a significantly lower risk of all-cause death (HR, 0.68; 95% CI, 0.57 to 0.82; P <.001) and hospitalization for heart failure (HF) compared with placebo (HR, 0.65; 95% CI, 0.50-0.85; P = .002).6
The CANVAS trial was recently completed, and results regarding the safety and efficacy of canagliflozin in patients with T2D and high risk of cardiovascular events/established CVD were published. Compared with placebo, canagliflozin significantly lowered the risk of death from cardiovascular causes, nonfatal MI, or nonfatal stroke (HR, 0.86; 95% CI, 0.75-0.97; P <.001, for noninferiority).7 Fewer patients treated with canagliflozin experienced events of all-cause death and hospitalization for HF compared with placebo; however, the results were not statistically significant.7
The CVD-REAL Nordic trial investigated the real-world clinical outcomes of initial treatment with dapagliflozin in patients with T2D compared with initiation of insulin. Dapagliflozin significantly decreased the risk for all-cause mortality (HR, 0.44; 95% CI, 0.28-0.70; P <.001) and of CVD (HR, 0.51; 95% CI, 0.30-0.86; P = .011)8; however, the majority of patients (24%) did not have CVD at baseline. Dapagliflozin is currently under investigation in the phase 3 DECLARE-TIMI58 trial to demonstrate cardiovascular outcomes in patients with T2D and CVD; results are expected in 2018.9
The mechanism of SGLT-2 inhibition and cardiovascular effects is not fully understood, but is theorized to stem from increased diuresis, natriuresis, weight loss, and decreases in blood pressure, oxidative stress, and triglyceride production.9,10 Another proposed mechanism suggests that SGLT-2 inhibition may shift the myocardial cells’ metabolism from primarily free fatty acids to ketones, which the cells can use more efficiently.10 Lastly, results from multiple trials with SGLT-2 inhibitors have shown an increase in both hemoglobin and hematocrit, which may also contribute to improved HF status and risk of death.10
In May 2017, the FDA issued a safety announcement regarding the increased risk of leg and foot amputations with canagliflozin treatment in patients with T2D and CVD.11 A black box warning was added to all canagliflozin drug labels, and health care providers were urged to consider all risk factors for amputations prior to initiating canagliflozin therapy.11 The CANVAS and CANVAS-R trial results demonstrated the safety risk associated with canagliflozin treatment: canagliflozin significantly increased the risk of leg and foot amputations compared with placebo (HR, 1.97; 95% CI, 1.41-2.75; P <.0001).7 In addition to canagliflozin treatment as an independent risk factor, the CANVAS program demonstrated that patients at high risk for amputations with canagliflozin treatment include those with prior amputations, peripheral vascular disease, neuropathy, and diabetic foot ulcers. The FDA reported the CANVAS trial results showed the risk of amputation to be 5.9 of every 1000 patients treated with canagliflozin compared with 2.8 of every 1000 patients treated with placebo.11 The CANVAS-R trial supplemented this data, with evidence again supporting the risk of amputation: 7.5 of every 1000 patients treated with canagliflozin compared with 4.2 of every 1000 patients treated with placebo.11 Most amputations (71%) reported during the CANVAS and CANVAS-R trials involved the toe or metatarsal; however, more proximal amputations of the leg are possible.7
he mechanism by which canagliflozin increases risk of amputation is unknown at this time, and there is no current evidence to suggest that other members of the SGLT-2 inhibitor class, such as empagliflozin and dapagliflozin, pose the same risk.12 Health care providers should educate patients to perform daily foot exams, to stay adequately hydrated, and to contact their health care provider if they develop any ulceration, discoloration, or new pain/tenderness in their feet.12
Acute Kidney Injury
In June 2016, the FDA strengthened a pre-existing warning regarding the incidence and severity of acute kidney injury (AKI) with canagliflozin and dapagliflozin use, as current evidence suggests that empagliflozin has renoprotective properties.13,14 The FDA updated this warning based on evidence from more than 100 case reports of AKI in patients treated with SGLT-2 inhibitors, some of which required hospitalization and dialysis.13
Although the mechanism by which SGLT-2 inhibition mediates AKI is not completely understood, 3 proposed mechanisms may provide insight into the risk of AKI in patients with T2D treated with an SGLT-2 inhibitor. As SGLT-2 inhibition leads to osmotic diuresis, increased urinary excretion of sodium and glucose results in excessive volume depletion and dehydration.15 This elevated urinary glucose may trigger an imbalance in glucose-uric acid exchange by glucose transporters located on the proximal tubules. Uricosuria, or elevated uric acid in the urine, may induce local tubular injury leading to AKI.15 SGLT-2 inhibition blocks glucose reabsorption in the S1 segment of the proximal tubule; however, this may channel glucose delivery to the S3 segment where SGLT-1—mediated glucose uptake is stimulated. Alterations in gene expression patterns involving fructose generation and metabolism lead to downstream intratubular oxidative stress, uric acid generation, local inflammation, and local tubular injury and the generation of AKI.15 Health care providers should beware of any other nephrotoxic medications or disease states that may increase a patient’s risk for developing AKI and should recommend that patients stay adequately hydrated. Patients should contact their health care provider if they experience decreased urine output or any lower extremity swelling.
Euglycemic Diabetic Ketoacidosis
euDKA is defined as a ketoacidosis with a normal to slightly elevated plasma glucose level, usually less than 200 mg/dL.16 As a potential mechanism underlying euDKA following SGLT-2 inhibition, the inhibition of glucose reabsorption first leads to decreased plasma glucose levels. Clearance of plasma glucose reduces insulin production and secretion from pancreatic β-cells and stimulates free fatty acid production, which are converted to ketones in the liver through beta-oxidation.16 Increased glucagon secretion modulates the production of ketone bodies through effector molecules triggering beta-oxidation; SGLT-2 inhibitors increase glucagon either through direct SGLT-2 inhibition on α-pancreatic cells or as a secondary response due to decreased insulin secretion from the pancreatic β-cells.16
The incidence of diabetic ketoacidosis (DKA) in patients treated with SGLT-2 inhibitors is still under investigation at this time; however, the FDA issued a warning statement in May 2015 explaining the possible risk and subsequently updated SGLT-2 inhibitor package inserts to reflect this data.17 Due to the infrequent incidence of DKA in patients with T2D treated with SGLT-2 inhibitors as well as the clinical benefits offered, the AACE/ACE consensus does not recommend changes to the current recommendation of SGLT-2 inhibitor treatment.18 Patients with type 1 diabetes (T1D) have a higher risk of DKA compared with patients with T2D. As SGLT-2 inhibitors are not indicated for T1D, data regarding the risk of DKA with SGLT-2 inhibitor treatment in this population requires further investigation in clinical trials.18
Patients should be encouraged to contact their health care provider if experiencing any signs or symptoms of DKA, such as dyspnea, fatigue, nausea, vomiting, and abdominal pain. In any patient experiencing symptoms suggestive of DKA during therapy with SGLT-2 inhibitors, health care providers should measure arterial pH and serum ketone levels to confirm diagnosis.18 Patients with confirmed DKA should immediately cease treatment with SGLT-2 inhibitors and begin traditional DKA treatment.18 In order to limit the risk of DKA in patients treated with SGLT-2 inhibitors, health care providers also should educate patients to stop treatment at least 24 hours prior to elective surgery or an extremely strenuous exercise, such as a marathon.18
In December 2015, the FDA issued a warning regarding serious urinary tract infections (UTIs) associated with SGLT-2 inhibitor treatment due to safety data that demonstrated an increased incidence of life-threatening urosepsis and pyelonephritis from untreated UTIs.17 Both vulvovaginal candidiasis and UTIs have an increased incidence in patients treated with SGLT-2 inhibitors, and women and patients with a previous history of UTIs are more likely to experience them during SGLT-2 treatment.19 Current literature suggests a 4% to 9% UTI incidence rate, which is about 1% to 1.5% higher than that of placebo, and a 4% to 6% fungal infection incidence rate compared to 1% with placebo.19 The higher incidence of these infections stems from an increase in urine glucose concentration in the lower urinary tract, and the risk of developing such infections is consistent between SGLT-2 inhibitors.19
Patients treated with SGLT-2 inhibitors should be encouraged to contact their health care provider if they experience any signs or symptoms of UTIs, such as dysuria, urinary urgency and/or frequency, lower abdominal/pelvic pain, fever, or hematuria.17 If a UTI or fungal infection is suspected, patients should be treated with appropriate antibiotics or antifungals, and the SGLT-2-inhibitor may be continued.
Based on new evidence regarding risks and concerns with SGLT-2 inhibitors, it is crucial that health care providers properly screen each patient and perform a complete history and physical. With newer evidence for cardiovascular benefits with the SGLT-2 inhibitors, we can expect their use to increase. However, consideration must be given to risks associated with the therapy, including amputations, AKI, euDKA, and genitourinary infections. Monitoring parameters for patients on SGLT-2 inhibitors should include changes in patients’ feet to assess for risk of amputation and AKI, fluid status, and signs and/or symptoms of DKA for euDKA. Screening should also be performed for both vulvovaginal candidiasis and UTIs. See the Table5,17,19-21 for a quick reference guide for health care providers. After correct monitoring and screening is performed for patients on SGLT-2 inhibitors, the decision can be made to either start or continue this medication therapy.
AMANDA DANIELS, PHARMD, is a current PGY-2 pain and palliative care pharmacy resident at Hospice of Southern Illinois in Belleville, Illinois.JESSICA L. KERR, PHARMD, CDE, is assistant chair and associate professor in the department of pharmacy practice at the SIUE School of Pharmacy in Edwardsville, Illinois.
- Kalra S. Sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther. 2014;5(2):355-366. doi: 10.1007/s13300-014-0089-4.
- Harada N, Inagaki N. Role of sodium‐glucose transporters in glucose uptake of the intestine and kidney. J Diabetes Investig. 2012; 3(4): 352—353. doi: 10.1111/j.2040-1124.2012.00227.x.
- Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm — 2017 executive summary. Endocr Pract. 2017;23(2):207-238. doi: 10.4158/EP161682.CS.
- Standards of medical care in diabetes. Diabetes Care. 2017;40(suppl 1):S4-S5. doi: 10.2337/dc17-S003.
- Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squibb, Inc; 2014.
- Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2228. doi: 10.1056/NEJMoa1504720.
- Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi: 10.1056/NEJMoa1611925.
- Nyström T, Bodegard J, Nathanson D, Thuresson M, Norhammar A, Eriksson JW. Novel oral glucose-lowering drugs are associated with lower risk of all-cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes. Diabetes Obes Metab. 2017;19(6):831-841. doi: 10.1111/dom.12889.
- Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2):90-100. doi: 10.1177/1479164114559852.
- Neeland IJ, de Albuquerque Rocha N, McGuire DK. Cardiovascular effects of sodium glucose cotransporter 2 inhibitors: The search for the how and why. American College of Cardiology website. www.acc.org/latest-in-cardiology/articles/2016/06/29/13/48/cardiovascular-effects-of-sodium-glucose-cotransporter-2-inhibitors. Published July 1, 2016. Accessed August 21, 2017.
- FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). FDA website. www.fda.gov/Drugs/DrugSafety/ucm557507.htm. May 16, 2017. Accessed August 21, 2017.
- SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information. European Medicines Agency website. ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/SGLT2_inhibitors_(previously_Canagliflozin)/human_referral_prac_000059.jsp&mid=WC0b01ac05805c516f. Published August 5, 2017. Accessed August 15, 2017.
- FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). FDA website. www.fda.gov/Drugs/DrugSafety/ucm505860.htm. Published June 14, 2016. Accessed August 21, 2017.
- Heyman SN, Khamaisi M, Rosen S, Rosenberger C, Abassi Z. Potential hypoxic renal injury in patients with diabetes on SGLT2 inhibitors: caution regarding concomitant use of NSAIDs and iodinated contrast media. Diabetes Care. 2017;40(4):e40-e41. doi: 10.2337/dc16-2200.
- Hahn K, Johnson R, Lanaspa M, Lanaspa MA, Johnson RJ. Acute kidney injury from SGLT2 inhibitors: potential mechanisms. Nat Rev Nephrol. 2016;12(12):711-712. doi: 10.1038/nrneph.
- Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016;7(2):135-138. doi: 10.1111/jdi.12401.
- FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. FDA website. www.fda.gov/Drugs/DrugSafety/ucm475463.htm. December 4, 2015. Accessed August 21, 2017.
- Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the Association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract. 2016;22(6):753-762. doi: 10.4158/EP161292.PS.
- Chaplin S. SGLT2 inhibitors and risk of genitourinary infections. Prescriber. 2016;27(12):26-30. doi: 10.1002/psb.1521.
- Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2017.
- Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2016.