US Pharm. 2019;44(2):HS9-HS12.
ABSTRACT: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to confer benefits in diabetic patients with heart failure, cardiovascular disease, and renal disease. This drug class has also been associated with major adverse events, including diabetic ketoacidosis in type 1 diabetes patients and limb amputations and genital and urinary tract infections in type 2 diabetes patients. Although oral antidiabetic medications are often discontinued in the hospital setting, it is important to understand their role in certain comorbid conditions. The use of SGLT2 inhibitors in type 1 diabetes is still being debated, but their use in type 2 diabetes patients with cardiovascular disease, renal disease, or heart failure has been established in several large trials.
Type 2 diabetes, which affects more than 415 million adults globally, is a major risk factor for cardiovascular disease.1 Patients with type 2 diabetes have an increased risk of atherosclerotic cardiovascular disease, heart failure, renal disease, and death.2 Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of diabetes medication approved for treating type 2 diabetes. The drugs in this class (the oral tablets empagliflozin, canagliflozin, and dapagliflozin) have gained traction as preferred agents for type 2 diabetes owing to the recent discovery that they offer cardiovascular and renal protection in these patients. SGLT2 inhibitors have also been used in patients with type 1 diabetes, but multiple studies have shown that they confer an increased risk of diabetic ketoacidosis.3
SGLT2 inhibitors, which have been termed glucosuretics, have multiple mechanisms that reduce glomerular hyperfiltration, blood pressure, fluid retention, body weight, and blood glucose.4 SGLT2 inhibitors block sodium-glucose cotransporters in the proximal convoluted tubule in the kidney, lowering the glucose threshold of the kidney and thereby decreasing renal glucose reabsorption. Therefore, unlike other diabetic medications, such as insulin, SGLT2 inhibitors are dependent on blood glucose levels; this reduces the likelihood of hypoglycemia. This drug class has pleiotropic mechanisms of action: Blood pressure reduction occurs initially through osmotic diuresis, but when the agent is used chronically, it takes place via inhibition of the renin-angiotensin system. Additionally, sodium-glucose transporters located outside the kidney contribute to the pleiotropic effects.5 Recent studies have established that SGLT2 inhibitors offer a benefit in cardiovascular disease, chronic kidney disease (CKD), and heart failure.1,5-7
Increased reports of severe adverse events have occurred in the major adverse cardiovascular events (MACE) trials of SGLT2 inhibitors and in additional postmarketing analysis. Of concern are the increased risks of lower-limb amputation and bone fracture, diabetic ketoacidosis, acute kidney injury (AKI), serious urinary tract infections, and—more recently—Fournier gangrene (necrotizing fasciitis of the perineum).7-10 Patients taking SGLT2 inhibitors who experience AKI often have fluid or electrolyte abnormalities, particularly dehydration. Therefore, in order to limit the risk of AKI, SGLT2 inhibitors should be withheld in patients who are dehydrated or have poor nutritional or hydration status. Although these medications are often discontinued upon hospital admission, it is important to understand the adverse effects of these medications.
Several large MACE trials of SGLT2 inhibitors have been conducted: EMPA-REG, the CANVAS Program, and DECLARE-TIMI 58.1,6,7 EMPA-REG was a large multicenter, randomized, double-blind, placebo-controlled trial in type 2 diabetes patients receiving empagliflozin 10 mg daily, empagliflozin 25 mg daily, or placebo.6 Empagliflozin patients had a significantly lower incidence of the composite primary outcome, which was cardiovascular mortality, nonfatal myocardial infarction (MI), or nonfatal stroke versus placebo. Patients also had significantly lower all-cause mortality, cardiovascular mortality, or heart failure hospitalization as individual endpoints.6
The CANVAS Program was a large, multicenter, randomized, double-blind, placebo-controlled trial in type 2 diabetes patients receiving canagliflozin 300 mg daily, canagliflozin 100 mg daily, or placebo.7 Canagliflozin patients had a significantly lower composite outcome of cardiovascular mortality, nonfatal MI, or nonfatal stroke compared with placebo. Patients receiving canagliflozin also had significantly fewer hospitalizations for heart failure.7
The largest of the MACE trials, DECLARE-TIMI 58, reported results similar to those for EMPA-REG and the CANVAS Program.1 This multicenter, randomized, double-blind, placebo-controlled trial was conducted in patients with type 2 diabetes who received either dapagliflozin 10 mg daily or placebo. Although patients had similar MACE outcomes, dapagliflozin patients had significantly lower rates of cardiovascular death or hospitalization for heart failure compared with placebo patients.1
A secondary analysis of EMPA-REG found, in addition to cardiovascular benefit, a decreased rate of all-cause hospitalization compared with placebo.6 Although the CANVAS Program did not demonstrate a significant MACE benefit, there was a trend toward cardiovascular protection, and more recent studies have shown a cardiovascular benefit for canagliflozin. The cardiovascular benefit of SGLT2 inhibitors has made them a key second-line agent in the treatment of type 2 diabetes. Recently, Persson and colleagues published a multinational observational study that compared the cardiovascular benefit of dapagliflozin versus dipeptidyl peptidase-4 (DPP-4) inhibitor therapy.11 Dapagliflozin was associated with lower risks of MACE, heart failure hospitalization, and all-cause mortality compared with DPP-4 inhibitors. Hazard ratios for individual components of MACE (myocardial infarction, stroke, and cardiovascular mortality) were numerically lower in the dapagliflozin group, but not significantly so.11
Preventing Heart Failure Exacerbations and Hospitalizations
Hospitalizations for heart failure can lead to poor outcomes and are one of the leading healthcare expenditures. Heart failure hospitalizations are a burden for the patient and costly for the healthcare system.12 SGLT2 inhibitors have been shown to reduce blood pressure, BMI, and proteinuria; they also promote urination because lowering the glucose threshold in the kidney tubules can decrease fluid retention. EMPA-REG, the CANVAS Program, and DECLARE-TIMI 58 have shown that SGLT2 inhibitor use can significantly decrease hospitalizations for heart failure.1,6,7 Persson and colleagues’ study emphasized the benefit of SGLT2 inhibitors over other diabetes agents, including glucagon-like peptide-1 (GLP-1) agonists and DPP-4 inhibitors, in reducing heart failure hospitalizations in patients with type 2 diabetes.11
Renal Protection and AKI Risk
Based on a small observed initial estimated glomerular filtration rate (eGFR) reduction, SGLT2 inhibitors were initially expected to have the potential for harm and a risk of AKI in CKD patients.13 It was later shown that this medication class contributes to renal protection by reducing proteinuria, lowering blood pressure, and aiding in fluid removal. Although when used alone these agents may not show much benefit, when they are combined, they can have significant benefit in patients with CKD. The EMPA-REG OUTCOME trial revealed a significantly decreased incidence or worsening of nephropathy, progression of macroalbuminuria, doubling of serum creatinine level with an eGFR ≤45 mL/minute/1.73 m2, and composite renal outcome. The composite renal outcome was the doubling of serum creatinine level with an eGFR ≤45 mL/minute/1.73 m2, initiation of renal-replacement therapy, or death from renal disease.4 The CANVAS Program showed a decrease in the progression of albuminuria and a reduction in the composite outcome of 40% decrease in eGFR, need for renal-replacement therapy, or renal death.7,14 Significantly, DECLARE-TIMI 58 found a ≥40% decrease in eGFR to <60 mL/minute/1.73 m2, end-stage renal disease, or death from renal or cardiovascular cause.1 Renal benefit, or a trend toward it, has been shown with empagliflozin, canagliflozin, and dapagliflozin. This has even been demonstrated at a lower level of kidney functioning where the blood glucose–lowering benefit is not observed.15
In 2015, the FDA received reports of diabetic ketoacidosis (DKA) associated with the use of SGLT2 inhibitors.16 Subsequently, additional reports were made of patients developing euglycemic DKA (defined as blood glucose <200-250 mg/dL). There were also several reports of patients with type 1 diabetes developing euglycemic DKA, although the use of SGLT2 inhibitors is off-label in this population.17
To determine the relative risk of DKA in patients taking SGLT2 inhibitors, Blau and colleagues compared SGLT2-related DKA incidence in the FDA Adverse Event Reporting System to that for DPP-4 inhibitors.18 They found that the risk of developing DKA was approximately 14-fold higher for SGLT2 inhibitors, and 71% of these cases were euglycemic ketoacidosis.18 Similarly, in a register-based study using a propensity-matched cohort of more than 21,000 patients in Sweden and Denmark, Ueda and colleagues compared DKA incidence for SGLT2 inhibitors versus GLP-1 receptor agonists, and the risk of DKA was doubled in patients receiving SGLT2 inhibitors (0.6% vs. 1.3%).19 It is important for clinicians, especially those providing inpatient care, to be aware of this risk. Although these events occurred in a small percentage of patients receiving SGLT2 inhibitor therapy, the seriousness of DKA, as well as the potential for misdiagnosis, is high.
Recent trials have compared the effect of increasing doses of empagliflozin and dapagliflozin versus placebo on A1C reduction, weight loss, and risk of adverse outcomes—including DKA—in patients with type 1 diabetes. Notably, with increasing doses of SGLT2 inhibitors, both trials found a greater reduction in A1C, more weight loss, and a higher risk of DKA.20,21
Given the risk, the clinician must critically evaluate whether a patient is a candidate for SGLT2 inhibitor therapy. Individualizing pharmacotherapy is paramount and should be based on factors including the patient’s propensity for dehydration, reduced food and/or caloric intake, and future acute illnesses. A sociobehavioral consideration for pharmacotherapy was studied by Abdelgadir and colleagues in various Muslim countries during the month of Ramadan, when most Muslims abstain from eating and drinking for 14 to 16 hours per day; during this month, higher rates of DKA occurred regardless of medications prescribed, as well as higher rates of hypoglycemia in patients taking SGLT2 inhibitors, although no patient required hospitalization.22,23
SGLT2 inhibitors were deemed safe upon approval, but, increasingly, reports of serious adverse events continue to appear. The CANVAS Program revealed not only a decrease in all serious adverse events versus placebo, but also an increase in genital infections, osmotic diuresis, fractures, and lower-limb amputations. A twofold increase in lower-limb amputations has led to a black box warning for patients receiving canagliflozin. Amputations were more common in patients with a history of amputation and peripheral vascular disease.7 Peripheral vascular disease and a history of amputation are not uncommon in patients with type 2 diabetes.
Ueda and colleagues’ register-based cohort study compared adverse events in patients who were recently started on SGLT2 inhibitors or GLP-1 receptor agonists.19 These are the only drug classes that are FDA approved for reduction of cardiovascular events in patients with type 2 diabetes, which has made them an attractive option for second-line therapy in patients with these two conditions. In Ueda and colleagues’ study, significantly more patients taking GLP-1 receptor agonists underwent lower-limb amputation (hazard ratio [HR] 2.32; 95% CI, 1.37-3.91) and experienced DKA (HR 2.12; 95% CI, 1.01-4.52).19 Incidences of AKI, bone fracture, serious urinary tract infections, venous thromboembolism, and acute pancreatitis were similar between groups. Most patients (61%) received dapagliflozin, and the least-used SGLT2 inhibitor was canagliflozin (1%).19
Under the appropriate conditions, type 1 and type 2 diabetes patients have the potential to benefit from SGLT2 inhibitors. These medications have been shown to improve hospitalizations for heart failure, cardiovascular disease, and renal disease in patients with type 2 diabetes.1,6,7 Some exceptions include poor hydration status, a history of amputations, and peripheral vascular disease. Patients with a history of dehydration, amputation, or peripheral vascular disease may experience increased adverse events, and these factors should be taken into account when initiation or continuation of an SGLT2 inhibitor is being considered.1,6,7,22,23 SGLT2 inhibitors are not currently recommended for patients with type 1 diabetes, and these agents confer a higher risk of DKA.16,18,19
1. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2018:1-12.
2. Emerging Risk Factors Collaboration, Di Angelantonio E, Kaptoge S, et al. Association of cardiometabolic multimorbidity with mortality. JAMA. 2015;314:52-60.
3. Chen J, Fan F, Wang JY, et al. The efficacy and safety of SGLT2 inhibitors for adjunctive treatment of type 1 diabetes: a systematic review and meta-analysis. Sci Rep. 2017;7:44128.
4. Kalra S. Erratum to: sodium glucose co-transporter-2 (SGLT2) inhibitors: a review of their basic and clinical pharmacology. Diabetes Ther. 2015;6(1):95.
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6. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117-2128.
7. Neal B, Perkovic V, Mahaffrey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657.
8. Invokana (canagliflozin) package insert. Titusville, NJ: Janssen Pharmaceuticals, Inc; October 2018.
9. FDA. FDA drug safety communication: FDA confirms increased risk of leg and foot amputations with the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). www.fda.gov/Drugs/DrugSafety/ucm557507.htm. Accessed November 29, 2018.
10. FDA. FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes. www.fda.gov/Drugs/DrugSafety/ucm617360.htm. Accessed November 29, 2018.
11. Persson F, Nyström T, Jorgensen ME, et al. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: a multinational observational study. Diabetes Obes Metab. 2018;20(2):344-351.
12. Parissis J, Athanasakis K, Farmakis D, et al. Determinants of the direct cost of heart failure hospitalization in a public tertiary hospital. Int J Cardiol. 2015;180:46-49.
13. Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6(6).
14. Heerspink HJL, Desai M, Jardine M, et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2017;28(1):368-375.
15. Vlotides G, Mertens PR. Sodium-glucose cotransport inhibitors: mechanisms, metabolic effects and implications for the treatment of diabetic patients with chronic kidney disease. Nephrol Dial Transplant. 2015;30(8):1272-1276.
16. FDA. Drug safety communications. FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood. www.fda.gov/Drugs/DrugSafety/ucm446845.htm. Accessed November 29, 2018.
17. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687-1693.
18. Blau JE, Tella SH, Taylor SI, Rother KI. Ketoacidosis associated with SGLT2 inhibitor treatment: analysis of FAERS data. Diabetes Metab Res Rev. 2017;33(8):e2924.
19. Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018;363:k4365.
20. Rosenstock J, Marquard J, Laffel LM, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care. 2018;41(12):2560-2569.
21. Dandona P, Mathieu C, Phillip M, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: the DEPICT-1 52-week study. Diabetes Care. 2018;41(12):2552-2559.
22. Abdelgadir EI, Hassanein MM, Bashier AM, et al. A prospective multi-country trial to compare the incidences of diabetic ketoacidosis in the month of Ramadan, the preceding month, and the following month (DKAR international). J Diabetes Metab Disord. 2016;15:50.
23. Bashier A, Khalifa AA, Abdelgadir EI, et al. Safety of sodium-glucose cotransporter 2 inhibitors (SGLT2-I) during the month of Ramadan in Muslim patients with type 2 diabetes. Oman Med J. 2018;33(2):104-110.
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