A Focus on Diabetic Ketoacidosis Ashley M

PHARMACY AND THERAPEUTICS CARE INNOVATIONS

A Review of the Efficacy and Safety of Sodium– Glucose Cotransporter 2 Inhibitors: A Focus on Diabetic Ketoacidosis Ashley M. Zurek,1 Raghunandan Yendapally,2 and Elizabeth M. Urteaga2

iabetes is a complex, chronic empagliflozin are the currently avail- medical condition affecting able SGLT2 inhibitors in the United D29.1 million people in the States (2,3). United States (9.3% of the popula- Mechanism of Action tion) and is projected to affect one Sodium–glucose cotransporter 1 in three Americans by 2050 if the (SGLT1) is predominantly locat- current trend continues (1). Diabetes ed in the small intestine, but is also management can be challenging, expressed in the kidneys, trachea, often requiring multiple therapeu- heart, and colon (4,5). In the kidneys, tic agents as the disease progresses. SGLT1 is primarily located in the S3 Current guidelines recommend met- segment of the proximal convoluted formin as first-line pharmacological tubule (PCT) (4). SGLT2 is expressed therapy for the treatment of type 2 in the kidneys and primarily located diabetes. Multiple second-line opin the S1 and S2 segments of the PCT tions are available for patients whose (4,5). In normoglycemic adults, about A1C goal is not achieved with mono- 180 g of glucose (Figure 1) is filtered therapy, and selection should be based per day in the glomerulus, and most on patient- and drug-specific fac- is reabsorbed (4,6). In people with di- tors. Sodium–glucose cotransporter abetes, reabsorption of glucose is in- 2 (SGLT2) inhibitors, the newest creased compared to people without U.S. Food and Drug Administration diabetes (7,8). SGLT1 and SGLT2 are (FDA)–approved oral antidiabet- located in the apical membrane and ic agents, are among these options facilitate the transport of glucose with for patients with type 2 diabetes. sodium from the renal tubular lumen Canagliflozin, dapagliflozin, and into the cells (Figure 2) (4).

1San Antonio Military Medical Center, Fort Sam Houston, TX 2Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX Corresponding author: Ashley M. Zurek, [email protected]

https://doi.org/10.2337/ds16-0030

©2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http:// ■ FIGURE 1. Structures of glucose, phlorizin, canagliflozin, dapagliflozin, and creativecommons.org/licenses/by-nc-nd/3.0 empagliflozin. for details.

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is an ongoing randomized, double-blind, placebo-controlled trial studying the effect of canagliflozin on cardiovascular outcomes and death in patients with uncontrolled type 2 diabetes and a history of cardiovascular events (23). DECLARE-TIMI 58 is an ongoing randomized, double-blind, placebo-controlled trial investigating the effect of dapagliflozin on cardiovascular death, ■ FIGURE 2. Cotransport of glucose and sodium by SGLT1 and SGLT2 in the PCT. myocardial infarction, and stroke in patients ≥40 years of age with type 2 Phlorizin (Figure 1), an O-glucose and 1–2 mmHg, respectively, as a diabetes (24). These trials will provide derivative/O-glycoside, was discov- result of their osmotic diuretic effect more insight regarding the cardiovas- ered in 1835 from apple tree bark (12,17). Weight loss of ~2 kg has been cular effects of SGLT2 inhibitors. (9,10). Phlorizin is a dual SGLT observed with SGLT2 inhibitors as a Safety inhibitor, inhibiting both SGLT1 result of their glucosuric effect, and SGLT2 inhibitors are generally well and SGLT2 (10). Canagliflozin, even greater weight reductions have tolerated, but some disadvantages dapagliflozin, and empagliflozin been observed in patients with a are associated with this therapy. An are C-glucose derivatives and selec- higher baseline BMI (14,18). increase in urogenital infections has tively inhibit SGLT2 (11). SGLT2 As with many other antidia- been observed because of their ef- inhibitors are structurally similar to betic agents, data on microvascular fect on increased urinary glucose. A glucose, as shown in Figure 1, and outcomes with SGLT2 inhibitors pooled analysis of clinical trials found thereby competitively inhibit glucose, are lacking. However, macrovas- 11 and 4% increased risks of genital leading to increased levels of glucose cular and mortality outcomes with mycotic infection in women and in the urine (5,6). Clinically available empagliflozin are now available, men, respectively, compared to pla- SGLT2 inhibitors block ~30–50% of and cardiovascular and mortality cebo. Events were generally mild to filtered glucose (6). trials of canagliflozin and dapagliflozin are underway. EMPA-REG moderate in severity and responded to Efficacy OUTCOME, a 3-year trial in standard therapy (25). The FDA has The efficacy of SGLT2 inhibitors as patients with type 2 diabetes and since issued a warning regarding the monotherapy, dual and triple oral high cardiovascular risk, found that risk of urinary tract infections leading therapy, and in combination with in- empagliflozin significantly decreased to urosepsis and pyelonephritis with sulin has been established in random- the primary composite outcome SGLT2 inhibitors (26). Health care ized, controlled trials. A1C reduction with a number needed to treat of 63, providers should ask whether patients associated with SGLT2 inhibitors driven by a reduction in cardiovas- have a history of urogenital infections ranges from 0.5–1% and varies based cular death (19). Neither myocardial before initiating SGLT2 inhibitor on dose, severity of diabetes, and oth- infarction, stroke, nor hospitalization therapy. er patient-specific factors (12–15). for unstable angina was reduced com- SGLT2 inhibitors are also associ- Because of the insulin-independent pared to placebo. Hospitalization for ated with a small, reversible decrease mechanism of action of SGLT2 heart failure was 2.7% with empagli- in estimated glomerular filtration inhibitors, they may be used at all flozin compared to 4.1% with placebo rate (eGFR), thereby decreasing the stages of type 2 diabetes, including (P = 0.002) (19). Although the precise magnitude of their effect on glucose more severe stages, in which endog- explanation for empagliflozin’s bene- excretion and thus their efficacy as enous insulin secretion has declined ficial clinical outcomes is unknown, renal function declines (21,22,27). significantly. This mechanism it is likely multifactorial. Potential Hence, canagliflozin, dapagliflozin, explains why the risk of hypoglyce- reasons include the agent’s effects on and empagliflozin have variable dos- mia is rare, although it may still occur arterial stiffness, cardiac function, ing adjustments and restrictions based when an SGLT2 inhibitor is used in and cardiorenal function (19,20). on eGFR. The FDA strengthened a combination with an insulin secre- Empagliflozin’s ability to reduce warning on the labels of canagliflozin tagogue or exogenous insulin (16). albuminuria, uric acid, body weight, and dapagliflozin in June 2016 after SGLT2 inhibitors are also associated visceral adipose tissue, and blood receiving 101 case reports of acute with a consistent reduction of systolic pressure may provide additional kidney injury and recommends and diastolic blood pressure by 2–4 mechanisms (19,21,22). CANVAS considering predisposing factors

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before initiating these therapies (28). evidence does not suggest a positive and reduced dose or discontinuation However, this warning does not apply link between SGLT2 inhibitor expo- of insulin or oral insulin secretagogue to empagliflozin, which recently was sure and cancer risk (41). Minimal therapy (26). The FDA has added this reported in a subanalysis of EMPA- increases in LDL cholesterol also have warning to the labels of all SGLT2 REG OUTCOME to be associated been noted with SGLT2 inhibitors, inhibitors, and post-marketing phar- with a slower progression of kid- potentially resulting from metabolic macovigilance studies are ongoing. ney disease compared to placebo in changes such as increased lipoprotein Possible Mechanisms of DKA patients with mild renal dysfunction lipase activity, but the exact mecha- (29). It is unknown whether this is a nism is unknown (22,42). Although the exact mechanism is not class effect. The concept of renal pro- fully understood, the following pro- FDA Warning for Ketoacidosis tection relates to SGLT2 inhibitors’ posed mechanisms may explain how ability to decrease uric acid levels, Diabetic ketoacidosis (DKA) is a SGLT2 inhibitors cause euDKA (46): tubular glucose toxicity, and diabetes- potentially life-threatening compli- 1. Reduced insulin levels and induced hyperfiltration (30). The cation in people with diabetes, pre- enhanced glucagon secretion. CREDENCE trial, now underway, dominantly those with type 1 diabe- SGLT2 inhibitors act by block- will shed light on whether canagli- tes. DKA typically is defined as the ing the reabsorption of filtered flozin has beneficial renal effects in triad of hyperglycemia (blood glucose glucose in the PCT, leading to an patients with type 2 diabetes and stage >250 mg/dL), anion gap metabolic increased excretion of glucose in 2 or 3 chronic kidney disease (31). acidosis, and the presence of urine the urine and decreased levels of Because of SGLT2 inhibitors’ or plasma ketones (43). Euglycemic glucose in the blood (47,48). The effects on blood pressure, their use DKA (euDKA) is rare and defined as lower blood glucose levels result may lead to postural hypotension DKA with a blood glucose level ≤250 in the reduced secretion of insu- and dizziness, particularly in elderly mg/dL. It may be precipitated by in- lin from the pancreatic β-cells. patients, those taking loop diuretics, complete DKA treatment or reduced This enhances the secretion of or those with tenuous intravascular insulin dose, food restriction, alcohol glucagon from the pancreatic consumption, or inhibition of gluco- volume. Therefore, caution and dose α-cells, which is referred to as neogenesis (44). Metabolic changes adjustments may be warranted in an indirect effect of SGLT2 during pregnancy may also predispose such patients (32,33). Pooled trial inhibitors on glucagon (49,50). patients to euDKA (45). data from long-term canagliflozin Additionally, in vitro human After reviewing FDA Adverse therapy showed an increase in bone and in vivo mice studies show fracture rates, leading the FDA to Event Reporting System database entries since the approval of canagli- that dapagliflozin directly acts on issue a new warning in September α flozin in March 2013, the FDA issued the pancreatic -cells and trig- 2015 for decreased bone mineral gers the secretion of glucagon, density and to strengthen its warn- a warning in May 2015 about the risk of DKA associated with SGLT2 providing evidence that SGLT2 ing about increased bone fracture inhibitors are indeed α-cell risk (34). SGLT2 inhibitors increase inhibitors. The report found 73 cases secretagogues (51). Eventually, serum phosphate levels, likely via of DKA in patients with type 1 dia- reduced insulin and increased tubular reabsorption, thereby increas- betes or type 2 diabetes treated with glucagon levels will initiate lip- ing both parathyroid hormone (PTH) SGLT2 inhibitors, specifically 44 and fibroblast growth factor (FGF) cases in type 2 diabetes, 16 in type olysis in adipose tissues and β 23. PTH and FGF 23 promote phos- 1 diabetes, 13 unspecified, and 1 in -oxidation of fatty acids, lead- phaturia and have opposite effects on a patient with latent autoimmune ing to the formation of ketone vitamin D metabolism, although diabetes in adults (LADA) (26). bodies in the liver and poten- evidence has shown that SGLT2 Canagliflozin, dapagliflozin, and tially causing euDKA (47,49). inhibitors decrease mean 1,25 dihy- empagliflozin were associated with Patients with reduced insulin droxyvitamin D levels (35). Neither 21, 4, and 4 DKA cases, respectively levels, whether from a reduction dapagliflozin nor empagliflozin carry (26). Concomitant dehydration, in insulin dose or an insulin defi- bone fracture risk warnings (36,37). infection, and changes in insulin dose ciency, may be at increased risk. There have also been concerns were reported in 73% of the cases. 2. Reduced renal clearance of of bladder and breast cancer with Management took place in emergency ketone bodies. SGLT2 inhibitors dapagliflozin because it was associ- departments or inpatient settings in also may contribute to decreased ated with a nonsignificant increase all of the cases, and the FDA iden- excretion of ketone bodies syn- in phase 2 and 3 trials. However, tified possible risk factors, including thesized in the body because this may be attributable to detection infection, low-carbohydrate diet or phlorizin decreases the renal bias (38–40). Molecular and animal reduced caloric intake, alcohol use, clearance of ketone bodies (46).

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TABLE 1. Case Reports of DKA in Patients With Type 2 Diabetes Receiving SGLT2 Inhibitor Therapy Case Report Patient Age SGLT2 Inhibitor Changes in Other Other Factors Event (Years), Sex (Days of Therapy Antidiabetic Agent(s) Before Event) (Days Before Event) Venkatesh et al. (52) 63, male Empagliflozin None Elective surgery euDKA (not provided) Storgaard et al. (53) 44, male Dapagliflozin (5) Discontinued insulin None DKA glargine (196) Hayami et al. (54) 32, female Ipragliflozin (13) Discontinued glimepiride, Low- euDKA metformin, and linagliptin carbohydrate (13) diet Roach and 64, female Empagliflozin (5) Discontinued NPH and One alcoholic euDKA Skierczynski (55) regular insulin (21) drink Peters et al. (56) 58, male Canagliflozin None Elective surgery euDKA (not provided) Peters et al. (56) 64, female Canagliflozin (>180) Discontinued insulin detemir Elective surgery euDKA (not provided)

DKA and SGLT2 Inhibitors: OUTCOME study conducted for 3 Conclusion Literature Review years with 7,020 patients found no SGLT2 inhibitors are a second-line DKA in People With Type 2 difference in the rate of DKA with or later therapy option for the man- Diabetes empagliflozin compared to placebo agement of type 2 diabetes. However, In people with type 2 diabetes, no (19). Based on >18,000 patients with a recent FDA warning regarding clear signal to suggest DKA was type 2 diabetes in randomized, con- SGLT2-associated DKA has raised noted in large clinical development trolled study programs, the frequency concerns. The proposed mechanism programs for any of the three mar- of DKA in those exposed to dapagli- relates to SGLT2 inhibitors’ indirect keted SGLT2 inhibitors. Several case flozin is <0.1% (44). effects on reducing endogenous insu- reports are now noted in the litera- lin levels and enhancing glucagon se- ture (Table 1) (52–56). As evidenced DKA in People With Type 1 cretion, while also reducing renal ke- by case reports, sudden withdrawal Diabetes tone clearance. Although case reports of insulin therapy or secretagogues Although SGLT2 inhibitors are not have demonstrated an increased risk during the initiation of SGLT2 inhib- FDA-approved for use in people with of DKA in both type 1 and type 2 di- itors may increase the risk of DKA. type 1 diabetes, they have been used abetes, larger randomized, controlled Additionally, patients following a off label in practice. An 18-week trials are expected to provide greater low-carbohydrate diet may be at risk, phase 2 study of 351 patients with understanding. Patients should be and ensuring appropriate hydration type 1 diabetes assessed the efficacy educated about the risks of DKA. is essential because dehydration may Interruption of SGLT2 inhibitor lead to acceleration of ketogenesis and safety of canagliflozin as add- on treatment to insulin (58). Twelve treatment may be warranted during (54). Two cases of euDKA developed periods of prolonged fasting due to in the postoperative period, and fur- patients in the canagliflozin group illness or surgery, low-carbohydrate ther research will be needed to pro- developed DKA that required hospi- diet, dehydration, stress, or chang- vide recommendations for SGLT2 talization. No patients in the placebo es in insulin or insulin secretagogue inhibitor therapy in the pre- and group experienced a ketone-related medications. postoperative periods (56). adverse effect. Five of the 12 patients Further information is available had a blood glucose level <250 mg/dL from trial data. Erondu et al. at the time of hospitalization (58). Duality of Interest (57) reviewed DKA events in the Additional cases of canagliflozin- No potential conflicts of interest relevant to canagliflozin type 2 diabetes clin- this article were reported. ical program. Twelve of the 17,596 associated euDKA in type 1 diabetes patients developed DKA or related have been reported in the literature References events while receiving canagliflozin. (56). Precipitating factors such as ill- 1. Centers for Disease Control and ness, change in diet, increased activi- Prevention. Diabetes 2014 report card However, half of the 12 patients [Internet]. Available from http://www.cdc. were reported to have type 1 dia- ty, and reduction or omission of insu- gov/diabetes/pdfs/library/diabetesreport- betes or LADA. The EMPA-REG lin led to the DKA episodes (56,58). card2014.pdf. Accessed 20 January 2016

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