Type 2 diabetes mellitus (T2DM) is a complex disease characterized by elevated blood glucose levels due to progressive loss of pancreatic β-cell function and insulin resistance in peripheral tissues, such as the muscle, liver, and adipose tissue.

Glycemic control is a critical component of reducing the risk of diabetes-associated complications, such as chronic kidney disease (CKD); lowering hemoglobin A1c levels by 1% reduces the risk of microvascular complications by 30% to 40%.1

Most glucose-lowering therapies target insulin production and metabolism. However, as T2DM progresses, insulin secretion and sensitivity continue to decline, and therapies that rely on these mechanisms can have reduced efficacy.

The kidney is the main site of glucose reabsorption in the body. Thus, targeting the kidney presents a novel, insulin-independent mechanism for managing hyperglycemia. In healthy individuals, virtually all glucose filtered by the glomeruli is reabsorbed by sodium-dependent glucose co-transporters (SGLTs) in the proximal renal tubule.2

SGLT-2 accounts for approximately 90% of glucose reabsorption by the kidney, and SGLT-1 accounts for the remaining 10%.2 SGLT-1 is an undesirablethe drug target because it is abundantly expressed in the gastrointestinal tract, where inhibition could lead to symptoms such as diarrhea.2 Inhibition of SGLT-2 provides a kidney-specific mechanism of lowering blood glucose levels by inhibiting the majority of glucose reabsorption and increasing urinary glucose excretion.

Benefits of SGLT-2 inhibitors

SGLT-2 inhibitors are a new and effective class of glucose-lowering drugs that also produce nonglycemic benefits. The US Food and Drug Administration (FDA) has approved 3 SGLT-2 inhibitors for use in the treatment of T2DM (Table 1). Meta-analyses have found that, on average, these agents reduce A1c by 0.5% to 1.0% compared with placebo, and they appear to have similar efficacy when compared with most standard oral agents, such as sulfonylureas and dipeptidyl peptidase 4 (DPP-4) inhibitors.3,4 Since the mechanism of action of SGLT-2 inhibitors is independent of insulin secretion, the risk of hypoglycemia is low.

SGLT-2 inhibitors may be used at any stage of T2DM, as monotherapy or in combination with other agents. They have demonstrated efficacy as add-on therapy to metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, and insulin.2,5

The potential nonglycemic benefits of SGLT-2 inhibitor therapy include weight loss and reduction in blood pressure.2 Urinary glucose excretion is associated with a net caloric loss of 200 to 300 kilocalories per day, which leads to modest weight loss (~2 to 3 kg).6 Weight loss tends to plateau after approximately 3 to 6 months of treatment, though the reasons for this are not completely understood.6

SGLT-2 inhibitor therapy is associated with reductions in systolic and diastolic blood pressure (~2 to 5 mm Hg) with no compensatory increases in heart rate.3,6 These effects may be particularly beneficial to patients with T2DM because they often have additional cardiovascular risk factors such as obesity and hypertension.

Changes in lipid profile are neutral, with small increases in both low-density-lipoprotein cholesterol (LDL-C) and high-density-lipoprotein cholesterol (HDL-C).2

New findings: Cardiovascular benefits and safety of empagliflozin

Due to the increased risk of cardiovascular events in patients with T2DM, the results of cardiovascular outcomes trials are important to consider when weighing the risks and benefits of antihyperglycemic agents.

While SGLT-2 inhibitors produce favorable reductions in hyperglycemia, body weight, and blood pressure, there has been concern that changes in lipid profile may offset any potential cardiovascular benefits.6 Pooled analyses of clinical trial data have not shown any increase in cardiovascular risk with SGLT-2 inhibitor use, but the trials were not designed to assess cardiovascular safety or benefit.6

Several cardiovascular outcomes trials to assess the safety of SGLT-2 inhibitors are ongoing, with one recently completed. The EMPA-REG OUTCOME trial examined the effects of empagliflozin on cardiovascular morbidity and mortality in 7020 patients with T2DM and established cardiovascular disease. While there were no differences between groups in the rates of myocardial infarction or stroke, the rate of death from cardiovascular causes was 38% lower in the empagliflozin group compared to the placebo group.7 The rate of hospitalization for heart failure was 35% lower in the empagliflozin group, and the rate of death from any cause was 32% lower.7

Safety outcomes were also assessed. As expected, rates of genital infections were higher with empagliflozin treatment. The proportion of patients experiencing acute renal failure, diabetic ketoacidosis, bone fractures, thromboembolic events, and events consistent with volume depletion were similar in the 2 groups.7

These results provide strong evidence that empagliflozin reduces cardiovascular risk in patients with T2DM, with a favorable safety profile. Additional cardiovascular outcomes trials for other SGLT-2 inhibitors are planned to run through 2019 (Table 2).6

Potential renal benefits of SGLT-2 inhibitors

CKD is one of the most common long-term complications of T2DM and is marked by a persistent increase in urinary albumin excretion and a progressive decline in estimated glomerular filtration rate (eGFR).8 Increasing albuminuria or decreasing eGFR is associated with the development of comorbid conditions, increased risk of cardiovascular disease, and increased mortality rates.9,10

Experimental studies in animal models suggest SGLT-2 inhibitors may have renal benefits, including prevention of glomerular hyperfiltration, reductions in albuminuria, reduced kidney growth, and attenuation of inflammation. However, the clinical evidence was unclear until recently.11

Clinical trials of SGLT-2 inhibitors in patients with T2DM and CKD have observed reductions in urinary albumin excretion.12-14 However, it is unclear whether such reductions would translate into potential cardiovascular or renal benefits. All cardiovascular outcomes trials include prespecified renal secondary outcomes, and the results from current SGLT-2 trials are expected over the next few years.

New findings from the EMPA-REG Outcome trial demonstrated that empagliflozin used in conjunction with standard of care significantly improved renal outcomes in adults with type 2 diabetes who were at high risk for cardiovascular events. Compared with placebo, patients who received empagliflozin had a lower rate of the primary composite cardiovascular outcome and death from any cause.The benefits were consistent among patients with and without CKD at baseline.15

Another area of interest is whether SGLT-2 inhibitors can produce beneficial glomerular hemodynamic alterations. At the onset of T2DM, hyperglycemia is accompanied by an increase in GFR due to alterations in tubuloglomerular feedback mechanisms and neurohormonal/vascular factors.16 Chronic hyperglycemia causes increased SGLT-2 expression in the proximal tubule and, consequently, increased glucose and sodium reabsorption.11 This results in decreased sodium chloride delivery to the macula densa, alterations in tubuloglomerular feedback, and a supranormal GFR.16

The abnormal increase in GFR (hyperfiltration) is postulated to lead to glomerular injury and contribute to the progression of diabetic nephropathy.17 A mechanistic clinical study of patients with T1DM found that empagliflozin attenuated renal hyperfiltration, likely by affecting tubuloglomerular feedback mechanisms.18 This suggests that SGLT-2 inhibitors may be able to decrease the rate of progression of CKD while the EMPA-REG trial reports benefits, prospective clinical trials would be needed to determine whether the observed changes in renal hyperfiltration could translate into long-term renal protection.

To more directly assess the effects of SGLT-2 inhibitors on the progression of CKD, the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial was initiated in 2014.19 The study is a phase 3, randomized, double-blind, placebo-controlled trial that will enroll approximately 3700 patients with T2DM and CKD. Patients will receive standard of care, which consists of treatment with angiotensin-converting-enzyme inhibitors or angiotensin-receptor blockers, and either canagliflozin or placebo.19 Primary composite end point of the study includes occurrence of end-stage renal disease, doubling of serum creatinine, and renal or cardiovascular death.20 CREDENCE is expected to run through 2020.20

Recommendations for the use of SGLT-2 inhibitors: Renal considerations

Kidney function is a key consideration when deciding whether to initiate SGLT-2 inhibitor therapy, especially since CKD occurs in 20% to 40% of patients with T2DM. The ability of SGLT-2 inhibitors to increase urinary glucose excretion depends on the presence of a sufficient GFR, and their effectiveness would be expected to be lower in patients with CKD and a reduced GFR.

Clinical trials have evaluated the efficacy of SGLT-2 inhibitors in patients with mild to moderate renal impairment. Canagliflozin and empagliflozin have been shown to reduce Ap1c in patients with stage 3 CKD.12,14 Reductions in body weight and blood pressure were also observed. Both agents may be used in patients with eGFR ≥45 mL/min/1.73 m2.21,22 Dapagliflozin was not effective in reducing A1c in patients with stage 3 CKD; thus, it may only be used in patients with eGFR ≥60 mL/min/1.73 m2.13,23

Current FDA labeling states that the use of SGLT-2 inhibitors is contraindicated in patients with severe renal impairment, end-stage renal disease, or dialysis due to reduced efficacy in these groups rather than safety concerns.21-23

Potential renal and urogenital adverse reactions to SGLT-2 inhibitor use

The most common adverse reactions experienced with SGLT-2 inhibitor use are genital mycotic infections. These occur in 5% to 11% of women and 2% to 4% of men taking SGLT-2 inhibitors.21-23 Some studies have also shown a slight increase in the rate of urinary tract infections in patients taking SGLT-2 inhibitors.4 These events tend to be mild to moderate in severity and respond to routine management.2

There have been concerns regarding a possible link between SGLT-2 inhibitors and bladder cancer due to an imbalance in bladder cancers in clinical trials of dapagliflozin, but this link has not been borne out in subsequent studies. Across 22 clinical trials of dapagliflozin, newly diagnosed cases of bladder cancer were reported in 10 out of 6045 patients (0.17%) treated with dapagliflozin and in 1 out of 3512 patients (0.03%) treated with placebo or comparator.23 While there was a numerical difference in cases, the sample size was too small to statistically determine whether there is a relationship with dapagliflozin.

Preclinical studies indicated that neither dapagliflozin, its primary metabolite, nor glucosuria were carcinogenic.24 Currently, dapagliflozin carries an FDA warning that it should not be used in patients with active bladder cancer and should be used with caution in patients with a prior history of bladder cancer.23 Subsequent trials of canagliflozin and empagliflozin have not observed an increased risk of bladder cancer, suggesting that it is not a class effect of the SGLT-2 inhibitors.3

Another potential safety concern with SGLT-2 inhibitor use is changes in serum electrolytes. The labeling information for canagliflozin carries a warning that increased serum potassium levels (hyperkalemia) can occur during use. In a clinical trial of patients with moderate renal impairment, increases in serum potassium of greater than 5.4 mEq/L occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, canagliflozin 100 mg, and canagliflozin 300 mg, respectively.21 Hyperkalemia was more common in patients with elevated baseline potassium levels and in patients who were taking medications that reduce potassium excretion (eg, potassium-sparing diuretics, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers).20

Dose-related increases in serum magnesium and phosphate have also been observed with canagliflozin use.20 However, such changes in electrolyte balance have not been observed in trials of dapagliflozin or empagliflozin.7,13

Update on FDA warning that SGLT-2 inhibitor use may lead to diabetic ketoacidosis

In May 2015, the FDA issued a drug safety warning that SGLT-2 inhibitors may be linked to diabetic ketoacidosis. A search of the FDA Adverse Event Reporting System (FAERS) yielded 20 cases of diabetic ketoacidosis requiring hospitalization in patients treated with SGLT-2 inhibitors between March 2013 and June 2014.25

The cases reported in FAERS and others described in case series were not typical of diabetic ketoacidosis in that glucose levels were only mildly or moderately elevated (euglycemic ketoacidosis).25,26 Most cases involved potential diabetic ketoacidosis triggering factors, such as intercurrent illness, low caloric and fluid intake, reduced insulin doses, and a history of alcohol intake.27

Interestingly, many of the reported cases of euglycemic ketoacidosis occurred in patients with latent T1DM; at the present time, SGLT-2 inhibitors are only approved for use in patients with T2DM. This represents both off-label prescription by physicians and instances of apparent misdiagnosis of T2DM in patients who actually have latent autoimmune diabetes of adulthood or T1DM.27,28

The frequency of diabetic ketoacidosis in clinical trials of all 3 marketed SGLT-2 inhibitors (>40,000 patients with T2DM) bore no clear signal of diabetic ketoacidosis.27 Retrospective analysis of clinical trials with canagliflozin found that diabetic ketoacidosis and related events occurred at a rate of <0.1% (12 of 17,596 patients).28 Similarly low rates of diabetic ketoacidosis have been reported in the DECLARE and EMPA-REG OUTCOME trials, and there was no imbalance observed between empagliflozin and placebo in EMPA-REG OUTCOME.7,27

Despite the low frequency of diabetic ketoacidosis and related events, clinicians should be aware of this potentially life-threatening complication. The absence of significant hyperglycemia can delay the recognition of diabetic ketoacidosis by both patients and providers. Patients with T1DM or T2DM who are on SGLT-2 inhibitor therapy and present with nausea, vomiting, malaise, or metabolic acidosis should promptly be evaluated for the presence of serum and/or urine ketones.26

Appropriate patient selection

SGLT-2 inhibitors can primarily be used as an add-on therapy for the treatment of T2DM in combination with metformin, insulin, sulfonylureas, DPP-4 inhibitors, or thiazolidinediones.8

Their mechanism of action is independent of pancreatic β-cell function or insulin sensitivity, so they may be used at any stage of T2DM. SGLT-2 inhibitors may also be considered for monotherapy in patients with an entry A1c <7.5% who are unable to tolerate metformin.29 Nonglycemic benefits include modest weight loss and reductions in blood pressure, albumin/creatinine ratio, and uric acid.

SGLT-2 inhibitors are generally well tolerated, but there are some precautions to consider prior to use. Renal function must be assessed before initiating therapy, as SGLT-2 inhibitors are contraindicated in patients with severe renal impairment due to reduced efficacy (Table 1). Risk of hypoglycemia is low unless SGLT-2 inhibitors are combined with insulin or an insulin secretagogue. If patients are being treated with a sulfonylurea or insulin, the dosage of these medications may need to be lowered when an SGLT-2 inhibitor is added.

Before initiating therapy, consider whether the patient is predisposed to urinary tract infections or genital mycotic infections. Patients with a history of chronic or recurrent genital mycotic infections or urinary tract infections are more likely to develop these types of infections when treated with SGLT-2 inhibitors.

SGLT-2 inhibitors cause intravascular volume contraction, so there is also some risk of hypotension in patients with renal impairment, elderly patients, patients on diuretics, and patients with low systolic blood pressure. Prior to initiating therapy, these groups of patients should be assessed for volume contraction, and volume status should be corrected if indicated.

Counseling patients on the use of SGLT-2 inhibitors

Initial discussions with patients about SGLT-2 inhibitor use should focus on proper administration and identification of potential adverse effects. SGLT-2 inhibitors should be taken daily in the morning with or without food; the prescribing information for canagliflozin specifically recommends taking the medication prior to the first meal of the day.21-23

Patients should continue to adhere to any dietary instructions, regular physical activity, and regular blood glucose monitoring and A1c testing. Patients should be advised that their urine will test positive for glucose. SGLT-2 inhibitors can cause dehydration in some patients, so it is important for patients to maintain an adequate fluid intake, especially under conditions that contract effective circulating volume.

Patients should be counseled about the potential for genital mycotic infections and urinary tract infections. Female patients should be informed that vaginal infections may occur and that symptoms include vaginal odor, white or yellowish vaginal discharge, and/or vaginal itching.21-23 Male patients should be informed that yeast infections of the penis may occur, especially in uncircumcised men, and that symptoms include redness, itching, or swelling of the penis; foul-smelling discharge; and/or pain in the skin around the penis.21-23

All patients should be counseled on the symptoms of a urinary tract infection, including a strong, persistent urge to urinate; a burning sensation during urination; passing frequent small amounts of urine; and urine that is cloudy, red or pink in color, or strong-smelling. Advise patients to seek medical advice if they experience symptoms of a yeast infection or urinary tract infection.

Patients should be advised to seek medical advice promptly if they become ill and discuss with their clinician whether to discontinue medication use.21-23 This is especially important during periods of stress, such as those associated with fever, trauma, infection, or surgery. These types of stressful events can lead to deterioration in glycemic control and precipitate life-threatening conditions such as diabetic ketoacidosis or a nonketotic hyperosmolar state.8

Ongoing monitoring

Patients should continue with self-monitoring of blood glucose and A1c should be tested approximately every 3 months.8 Baseline assessment of renal function is required prior to initiating SGLT-2 inhibitor therapy, and renal function should be monitored periodically thereafter.21-23

SGLT-2 inhibitors are associated with small decreases in eGFR at the start of therapy, but these reductions are reversible when the medication is stopped.14 Monitor patients for symptoms of hypotension, hypoglycemia, genital mycotic infections, urinary tract infections, and increased LDL-C and treat as appropriate.21-23

Summary

SGLT-2 inhibitors are a relatively new class of glucose-lowering drugs that specifically target the kidney, and nephrologists and urologists should be aware of their potential risks and benefits. These agents improve glycemic control when used alone or in combination with other antihyperglycemic therapies.

SGLT-2 inhibitors may be beneficial for patients with cardiovascular risk factors such as obesity or hypertension because they produce modest weight loss and reductions in blood pressure. Recent trials have shown a reduction in the risk of death from cardiovascular causes with SGLT-2 inhibitor therapy, and more trials are under way to further assess cardiovascular safety and possible renal benefits.6,7

Clinicians should be aware that the efficacy of SGLT-2 inhibitors depends on renal function; therefore, renal function must be assessed prior to use and monitored periodically throughout treatment. The most common adverse events with SGLT-2 inhibitor therapy are genital mycotic infections and urinary tract infections, and patients should be counseled on their signs and symptoms.

SGLT-2 inhibitors should be used with caution in elderly patients or patients already on a diuretic, due to risk of intravascular volume depletion. SGLT-2 inhibitors are a promising new option for treatment of T2DM, and clinical trials currently in progress will shed further light on their effects on macrovascular and microvascular outcomes.


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