Sodium-glucose cotransporter-2 (SGLT2) inhibitors are newer agents available for the treatment of type 2 diabetes mellitus (T2DM).1 There are two types of SGLTs: SGLT2 (a high-capacity, low-affinity transporter found in the early portion of the renal tubule) and SGLT1 (a low-capacity, high-affinity transporter located in the distal part of the proximal tubule).2
The mechanism of action of SGLT2 inhibitors involves reduction of glucose absorption in the kidney, which results in excreting excess glucose in the urine, thereby lowering hyperglycemia.3 SGLT2 inhibitors act independently of pancreatic beta cell function and are thus suitable at all stages of T2DM.4 However, SGLT2 inhibitors are dependent on kidney function, and their glycemic efficacy will decline with decreasing glomerular filtration rate (GFR).4
When blood glucose is normal, SGLT2 is responsible for about 90% of glucose reabsorption; SGLT1 mediates the remaining 10%. Approximately 180 g of glucose is filtered daily in healthy adults; most is reabsorbed by the SGLTs, and less than 1% is excreted in the urine.2 Glucose handling in the kidney is altered in patients with T2DM. Urinary glucose excretion (UGE) occurs at plasma glucose levels that are roughly 20% higher than levels in healthy individuals.2
Expression of SGLT2 is upregulated, resulting in enhanced glucose reabsorption and worsening hyperglycemia. SGLT2 inhibitors produce a shift in the relationship between plasma glucose and UGE, thus reducing the renal threshold for glucose.5 However, SGLT2 inhibition reduces only 30% to 50% of the glucose load, and it has been speculated that this is due to increased compensatory SGLT1 activity.6
SGLT2 inhibitors: Clinical trials
Efficacy. Currently, three SGLT2 inhibitors are approved in the United States: canagliflozin, dapagliflozin, and empagliflozin. In clinical studies, SGLT2 inhibitor monotherapy has been shown to reduce hemoglobin A1C (A1C) by approximately 0.54% to 1.45% compared with placebo/active treatment (baseline A1C, 7.9% to 9.1%).5
A recent review showed that when an SGLT2 inhibitor was added to background metformin therapy, reductions in A1C versus placebo were 0.54% to 0.77% (baseline A1C, 7.9% to 8.2%).5 When the SGLT2 inhibitor was added to metformin and compared with a sulfonylurea or a dipeptidyl peptidase-4 (DPP-4) inhibitor, the changes were similar to those seen with the comparator.5
Further glucose lowering was achieved with SGLT2 inhibitors in combination with insulin (0.39% to 1.27%; baseline A1C, 8.3% to 8.5%).5
In clinical studies, the risk of hypoglycemia with SGLT2 inhibitor therapy is low unless combined with insulin or insulin secretagogues.7-9 Studies also show modest decreases in systolic BP (3 mm Hg to 5 mm Hg) and diastolic BP (approximately 2 mm Hg) without a compensatory increase in heart rate.10
In addition, treatment with an SGLT2 inhibitor provides moderate placebo-corrected weight loss of 2% to 5%.5,11-14 Small increases in both high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C), without a change in the HDL-C/LDL-C ratio as well as reductions in urinary albumin excretion, have been reported.15-17 Taken together, these changes address a number of unmet needs in patients with T2DM.
The CANagliflozin cardioVascular Assessment Study (CANVAS) has recently completed, and the results have been combined with those of the CANVAS-RENAL (CANVAS-R) study to generate a larger number of outcome events for analysis.18 This integrated analysis of the CANVAS program included data from 10,142 patients who were randomized in both trials to receive canagliflozin (100 mg or 300 mg daily) versus placebo in addition to standard of care and who were followed for a mean of 188.2 weeks.18 Patients had T2DM and were either age 30 or older with T2DM and had previous cardiovascular disease (CVD) or age 50 or older with two or more risk factors for CVD.
The primary 3-point major adverse cardiovascular event (MACE) outcome occurred in 26.9 versus 31.5 participants per 1,000 patient-years; hazard ratio (HR), 0.86; 95% confidence interval (CI), 0.75 to 0.97; P < 0.001 for noninferiority; P = 0.02 for superiority. This is a 14% significant relative risk reduction (RR) in overall MACE. The treatment effects for the individual MACE components showed point estimates that suggested benefit; however, the individual effects did not reach statistical significance.18
The Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) study is an ongoing, prospective cardiovascular outcomes trial that will compare the effect of dapagliflozin 10 mg versus placebo on the composite endpoint of cardiovascular death, myocardial infarction (MI), or ischemic stroke in approximately 17,000 patients age 40 or older with T2DM and either known CVD (secondary prevention cohort) or two or more cardiovascular risk factors (primary prevention cohort). This study is scheduled to conclude in April 2019.
The EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial demonstrated outcome improvement with a glucose-lowering agent added to the standard-of-care therapy.19 The primary outcome (3-point MACE: death from cardiovascular causes, nonfatal MI, or nonfatal stroke) occurred in 10.5% of patients in the empagliflozin group (combining the 10 mg and 25 mg doses); it occurred in 12.1% of patients in the placebo group (HR, 0.86; 95% CI, 0.74 to 0.99; P < 0.001 for noninferiority and P = 0.04 for superiority), resulting in a 14% reduction in risk of the 3-point MACE.
In secondary analyses, empagliflozin treatment resulted in a 38% RR reduction in cardiovascular death and also improved overall survival with a 32% RR reduction in all-cause mortality. In addition, hospitalization for heart failure or cardiovascular death (excluding fatal stroke) occurred in a significantly lower percentage of patients treated with empagliflozin than with placebo (5.7% versus 8.5%; HR, 0.66; 95% CI, 0.55 to 0.79; P < 0.001). The risk reduction was consistent in patients with versus without heart failure at baseline.20 As a result, the FDA has updated the indication for empagliflozin to include the reduction of cardiovascular death risk in adult patients with T2DM and established CVD.
Safety and tolerability profile
Hypoglycemia. The mechanism of action (MOA) of SGLT2 inhibitors does not interfere with normal endogenous glucose production in response to hypoglycemia and does not stimulate insulin release; thus, the risk of hypoglycemia is low when given as monotherapy.21 However, the risk of hypoglycemia is increased when coadministered with insulin or insulin secretagogues.8,22,23
Genital mycotic infections. Hyperglycemia creates an environment conducive to genital infections by encouraging fungal growth, impairing neutrophils, and promoting virulent yeast strains.24,25 Women with T2DM have a predisposition for genital mycotic infections (GMIs) and have 81% higher risk of vulvovaginal candidiasis than healthy women.25
In clinical trials of SGLT2 inhibitors, GMIs were reported more frequently among individuals receiving any SGLT2 inhibitors than with placebo or active comparators.26-28 In a meta-analysis of 10 trials involving 6,701 patients with T2DM, GMIs occurred more frequently with canagliflozin compared with placebo (RR, 3.76; 95% CI, 2.23 to 6.35; P < 0.00001) and active comparators (sitagliptin or glimepiride; RR, 4.95; 95% CI, 3.25 to 7.52; P < 0.00001).8 Overall, about 10% of women in canagliflozin trials reported GMIs, compared with 3% of women on placebo; GMIs were generally reported during the first 3 to 6 months of treatment, and the risk declined over time.25
In a pooled analysis of 12 dapagliflozin trials, the rates of GMIs in all patients were higher with dapagliflozin than with placebo (5.1% versus 0.9%).23 Pooled data from 17 empagliflozin studies showed that the incidence of GMIs was higher in patients treated with empagliflozin than placebo (4.7/100 patient-years, 5.0/100 patient-years, and 1.3/100 patient-years for empagliflozin 10 mg, 25 mg, or placebo, respectively).22
In all of the aforementioned analyses, most events were mild to moderate in intensity, and the incidence of GMIs was higher in women than in men. In phase III studies, a higher incidence of balanitis (inflammation of the glans penis) and balanoposthitis (inflammation of the glans penis and foreskin) was observed in men receiving SGLT2 inhibitors versus placebo.8,9,16,22,25
Urinary tract infections (UTIs). Approximately 50% of women will have at least one UTI in their lifetime.29 T2DM is an independent risk factor for UTIs, as are older age, poor glycemic control, recurring UTI episodes, and diabetic kidney disease.29 In clinical trials, no significant difference in UTI incidence was observed between canagliflozin and placebo (RR, 1.19; 95% CI, 0.82 to 1.73; P = 0.36) or other comparators (RR, 1.18; 95% CI, 0.84 to 1.64; P = 0.34).8 The occurrence of UTIs was slightly higher in patients receiving dapagliflozin than in those receiving placebo (4.8% versus 3.7%) and was higher in women and patients with a history of recurrent UTIs. Long-term analyses showed that UTIs were more likely to occur in the first 2 months of treatment.23
In a pooled analysis of empagliflozin clinical studies, the incidence of events consistent with UTIs was similar with placebo and empagliflozin (11.3/100 patient-years, 10.4/100 patient-years, and 9.4/100 patient-years for placebo, empagliflozin 10 mg, or 25 mg, respectively).22 Although serious UTIs have been rare in clinical trials, postmarketing reports of such occurrences (pyelonephritis, urosepsis) have led to a warning added to U.S. labels.26-28,30 In addition, following reports of acute kidney injury with SGLT2 inhibitor therapy from postmarketing surveillance, existing warnings on this risk were strengthened, and recommendations to minimize the risk were added to U.S. labels.
Osmotic-diuretic effects. The osmotic-diuretic effect of SGLT2 inhibition related to glucosuria may lead to increased urinary frequency and urinary volume, especially within the first 6 weeks of treatment. Osmotic diuresis results in intravascular volume contraction and adverse reactions consistent with volume depletion.8,9,22 In clinical trials, volume-related adverse reactions were generally higher with SGLT2 inhibitors than with placebo/active comparators.5 These agents could therefore increase the risk of volume-associated events in high-risk groups, such as older adults.5,29-31
In pooled analyses, volume-related adverse reactions were similar in the canagliflozin and placebo/active comparator groups.8 Similarly, hypotension, dehydration, and hypovolemia were reported infrequently with dapagliflozin and empagliflozin, with the exception of patients on loop diuretics who experienced more volume-related events with SGLT2 inhibitors than with placebo.22,23
There was a slight increase in the incidence of bladder cancer with dapagliflozin treatment versus placebo/comparator across 22 clinical studies; however, there were too few cases to determine causality, and there are insufficient data to determine whether dapagliflozin has any effect on preexisting bladder tumors. Therefore, until additional data become available, dapagliflozin should not be used in patients with known bladder cancer.26
Lipid changes. Both elevated LDL-C levels and decreased HDL-C levels are risk factors for CVD.31 SGLT2 inhibitor therapy is associated with small increases in LDL-C and HDL-C.5 Long-term data have shown placebo-subtracted increases in LDL-C with canagliflozin, dapagliflozin, and empagliflozin of approximately 3, 5, and 6 mg/dL in patients with baseline LDL-C of approximately 103, 93, and 92 mg/dL, respectively. For HDL-C, the placebo-corrected increases were approximately 1.0, 3.5, and 0.6 mg/dL from a baseline of 47 mg/dL for canagliflozin, dapagliflozin, and empagliflozin, respectively.5,26-28 These changes had no impact on the HDL-C/LDL-C ratio.8,9,11,22 Increases in both parameters suggest these effects may be related to changes in hemoconcentration.
Diabetic ketoacidosis (DKA). A well-known complication of type 1 diabetes mellitus (T1DM), DKA is typically defined based on the presence of hyperglycemia (greater than 250 mg/dL), anion-gap acidosis, and increased plasma ketones.32 Euglycemic ketoacidosis is considered rare, but recent cases have surfaced both in patients with T1DM and T2DM treated with SGLT2 inhibitors (although these agents are not approved for use in T1DM).32-35
A number of these cases were atypical, with patients having only moderately raised blood glucose levels. The identified precipitating factors included conditions that restricted food intake or led to severe dehydration, reductions in insulin dose, increased requirements for insulin due to illness, surgery, and alcohol overuse.30 Potential mechanisms that may increase susceptibility to ketoacidosis with SGLT2 inhibitors include an increase in glucagon-to-insulin ratio, increased free fatty acids, a shift in substrate use from carbohydrate to fat, and reductions in ketone body clearance.36
Bone. Inhibition of SGLT2 can interfere with calcium and phosphorus reabsorption and may also decrease mean concentrations of 1,25-dihydroxyvitamin D.37 These metabolic changes have the potential to adversely affect skeletal structure and increase bone fracture risk in patients with T2DM.37 This is of particular concern in older adults with T2DM, including postmenopausal women who are at increased risk for osteoporosis.31 In clinical studies with canagliflozin, 2 years of treatment resulted in small but statistically significant decreases compared with placebo in bone mineral density in the total hip in older patients with T2DM; nonsignificant changes were also observed in the lumbar spine.35,38
In a pooled analysis of eight non-CANVAS canagliflozin studies, the incidence of bone fractures was similar between patients receiving canagliflozin (1.7%) or placebo/active comparators (1.5%).35 In the CANVAS trial, canagliflozin was associated with an increased bone fracture risk in patients with T2DM and a history of CVD or at least two risk factors for cardiovascular events.18 Interestingly, in the CANVAS-R trial, the risk of fractures was numerically lower with canagliflozin compared with placebo in a similar patient population.18 The population in CANVAS was older, had a history of CVD, and lower baseline estimated GFR (eGFR) than patients in the pooled analysis; therefore, the increase in fractures was potentially related to volume-depletion–related adverse reactions, such as postural dizziness and increasing susceptibility to falls. In pooled studies of dapagliflozin or empagliflozin, the incidence of bone fractures was similar between drug and placebo groups.26
In addition, based on data from the CANVAS and CANVAS-R trials, canagliflozin was associated with an increased risk of leg and foot amputations (mostly of the toe and middle of the foot) in high-risk patients with T2DM, specifically those with a history of amputation or peripheral vascular disease.18 As a result, the FDA has issued a boxed warning for all U.S. canagliflozin labels; such an increase was not observed in 12 other completed canagliflozin trials.28,39 No increased risk of lower limb amputation has been reported in pooled clinical trial data for empagliflozin or adverse event reporting data for dapagliflozin.34,40
Using SGLT2 inhibitors in clinical practice
Place in therapy. The most recent American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) consensus statement and American Diabetes Association (ADA) position statement emphasize a comprehensive approach to treating T2DM, which includes individualizing glycemic targets.31,41 The ADA/European Association for the Study of Diabetes position statement recommends that SGLT2 inhibitors can be used at any stage of T2DM in dual or triple combination with other oral and injectable glucose-lowering agents.42
Metformin remains the recommended first-line agent. The AACE/ACE algorithm provides the following hierarchy of seven agents that may be considered first-line monotherapy for patients with T2DM and A1C less than 7.5%: metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, thiazolidinediones, alpha-glucosidase inhibitors, and sulfonylureas/glinides.41 AACE/ACE notes that treatment should be individualized and suggests using alpha-glucosidase inhibitors, sulfonylureas, and glinides for select patients as is clinically appropriate.
For patients with A1C baseline levels 7.5% or greater, combination therapy with metformin and a second agent with a complementary mechanism of action and a low propensity for hypoglycemia (GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors) is preferred.41 However, other combinations may be used for those not tolerating metformin.
Patients who would potentially benefit from SGLT2 inhibitors therapy include those with a high CVD risk already taking multiple medications. Recent data from CANVAS have demonstrated a significant 14% RR reduction in overall MACE with canagliflozin in patients with T2DM and preexisting CVD.18 In comparison, the EMPA-REG OUTCOME study has shown a significant 14% RR reduction in the composite endpoint of death from cardiovascular causes, MI, or stroke by 14%, and a significant 38% RR reduction in cardiovascular death.19 Whether empagliflozin has a similar effect on cardiovascular disease mortality in low-risk patients with T2DM is currently unknown.
Because of their MOA via the kidney, SGLT2 inhibitors have reduced glycemic efficacy in patients with declining kidney function and are contraindicated in those with severe kidney impairment, end-stage renal disease, or on dialysis.26-28 SGLT2 inhibitors require dosing adjustments for patients with reduced eGFR. Based on U.S. labeling, canagliflozin and empagliflozin are not recommended when eGFR is less than 45 mL/min/1.73 m2, and dapagliflozin should not be used when eGFR is less than 60 mL/min/1.73 m2.26-28
However, there is also evidence that inhibition of SGLT2 may have renoprotective effects. Results from animal studies suggest that SGLT2 inhibitors suppress renal hyperfiltration (a condition conveying significant risk of diabetic kidney disease) independent of glucose-lowering effects in addition to limiting expression of markers of kidney growth, inflammation, and albuminuria through reductions in blood glucose.43 In a recent open-label study in 40 patients with T1DM, empagliflozin 25 mg attenuated renal hyperfiltration, most likely by affecting the tubular-glomerular feedback mechanism.44,45
The patient visit
Setting expectations. It is important for patients to understand what percentage decrease in A1C can be expected from their medications. Data from clinical trials of SGLT2 therapy have reported A1C decreases from approximately 0.5% to 1.5% when used as monotherapy.5 If patients are treatment-naive or have a higher baseline A1C value, reductions may be larger than observed in clinical trials.
For many patients, even a 0.7% decrease in A1C can provide motivation, especially if coupled with weight loss. Many patients will already be on other oral glucose-lowering agents, in which case SGLT2 inhibitors can provide additional glycemic benefits without an increase in hypoglycemia risk or weight.
Clinical trial data have shown that SGLT2 inhibitors cause moderate weight loss or ameliorate weight gain caused by other medications. Glucosuria creates a negative energy balance of 200 to 300 kilocalories per day. On average patients lost approximately 4.4 lb to 5.5 lb (approximately 2.0 kg to 2.5 kg) over a 1-year period followed by weight maintenance. More important, weight loss is associated with loss of abdominal visceral and subcutaneous fat, an important benefit, as visceral adiposity is associated with increased risk of T2DM, cardiovascular complications, and overall mortality.46,47
The effect of SGLT2 inhibitors on BP can be beneficial for patients who have not reached their BP goals. Small decreases of 3 to 5 mm Hg systolic BP and approximately 3 mm Hg diastolic BP have been observed in clinical trials.5 To avoid hypotension, before initiating SGLT2 inhibitor therapy, volume contraction should be assessed and corrected as appropriate in patients with kidney impairment, older adults, and those with low systolic BP as well as those on diuretics, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers.26-28
Managing adverse reactions. Glucosuria creates an environment conducive to vaginal mycotic infections in women. General risk factors include use of high-estrogen oral contraceptives, intrauterine devices, diaphragms with spermicide, and antibiotics.25 Women should be educated on the symptoms of vaginal yeast infections. Standard, over-the-counter (OTC) antifungal intravaginal azole agents are effective for vulvovaginal candidiasis. Those with recurrent infections may wish to consult with their healthcare provider for a definitive diagnosis. Women with severe infections or those with poor glycemic control may need a longer course of treatment with OTC topical azoles or may require a prescription for two doses of oral fluconazole treatment.29
Men may also experience mycotic infections, especially those who are uncircumcised and suffer from chronic recurrent infections. These patients need to be educated about the symptoms of balanitis and balanoposthitis. Proper hygiene should be encouraged (retracting the prepuce and washing it).48
Glucosuria also creates an environment conducive to UTI, especially in women. The risk of UTIs is increased in women with diabetes mellitus, with one epidemiological study showing the risk nearly doubled (RR, 1.8; 95% CI, 1.2 to 2.7), with the greatest increased risk in postmenopausal women who have had diabetes for over 10 years (RR, 2.6; 95% CI, 1.3 to 5.1) and insulin use (RR, 3.7; 95% CI, 1.8 to 7.3).49 Patients should be educated on the symptoms of UTIs and encouraged to call their healthcare providers so prompt treatment with antimicrobials can be initiated if necessary.
Patients should be warned to expect increases in urine volume as they initiate therapy and to maintain adequate levels of hydration. Patients should also be advised to rise slowly from a sitting to a standing position, particularly if they are at increased risk of volume-associated adverse reactions. Reducing or holding diuretics when initiating SGLT2 inhibitors may be warranted.
Dehydration may also predispose the patient to DKA. The possibility of DKA should be considered in patients taking SGLT2 inhibitors who have nonspecific symptoms such as nausea, vomiting, anorexia, abdominal pain, excessive thirst, difficulty breathing, confusion, unusual fatigue, or somnolence.50 Healthcare providers need to be aware of certain conditions that may predispose patients to DKA, including surgery, extreme exercise, reduced food and fluid intake, dehydration, infections, and reduced insulin doses; special caution should be exercised in insulinopenic patients.
For patients displaying symptoms of DKA, SGLT2 inhibitors should be discontinued immediately and not continued unless another precipitating factor for the condition has been identified. Routine measurement of blood ketones is not recommended during SGLT2 inhibitor therapy; however, because urine ketone measurement can be misleading, measurement of blood ketones is preferred for DKA diagnosis in symptomatic patients. Discontinuing SGLT2 inhibitors temporarily should be considered for patients undergoing major surgery or anticipating severe stressful physical activity (for example, running a marathon).51
When prescribing SGLT2 inhibitors, patient factors should be considered that may increase the risk of bone fractures (particularly with canagliflozin), such as falls secondary to hypovolemic hypotension. This risk should be discussed with patients including potential strategies to decrease fracture risk (see Key clinical considerations).
SGLT2 inhibitors are another option in treating patients with T2DM and have provided a paradigm shift in the management of T2DM, using glucosuria to lower plasma glucose levels. In addition, inhibition of SGLT2 leads to modest weight reduction, small decreases in BP, and a low propensity to cause hypoglycemia. Canagliflozin and empagliflozin have demonstrated a reduction in overall adverse cardiovascular outcomes when added to standard-of-care therapy in patients with high cardiovascular risk. Taken together, data from the integrated CANVAS program and EMPA-REG OUTCOME study suggest that the cardiovascular benefit with SGLT2 inhibitors is a class effect, but further trials are awaited and will also help determine whether it will extend to patients with lower cardiovascular risk.
Key clinical considerations
The following patient characteristics require caution when prescribing SGLT2 inhibitor therapy:
- High risk of volume-related adverse reactions, such as hypotension and dehydration
- Older adults
- Kidney impairment
- Low BP
- Diuretic use
- A history of recurring genital infections or UTIs
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