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The Cardiovascular and Renal Benefits of SGLT2 Inhibitors

Wednesday, December 4, 2019  
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Jessica Marie Fraone, Doctor of Pharmacy Candidate 2020 Philadelphia College of Pharmacy

Benjamin Pullinger, PharmD, BCPS, Assistant Professor of Clinical Pharmacy, Philadelphia College of Pharmacy

 

In the last decade, diabetes treatment has undergone a paradigm shift. Since the FDA mandated phase IV cardiovascular (CV) outcome trials for antidiabetic agents, there has been considerable excitement about the potential for new agents to not only provide additional glycemic control but reduce hard endpoints such as major cardiovascular events (MACE). Recently, several trials have investigated the role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing both MACE and the progression of diabetic nephropathy. SGLT2 is a high capacity and low affinity glucose transporter expressed in the proximal tubule. By blocking this transporter, SGLT2 inhibitors lower the renal glucose threshold, inhibit glucose reabsorption, and induce urinary glucose elimination with concomitant natriuresis and osmotic diuresis.1

For several years we’ve known about the CV and renal benefits of SGLT2 inhibitors from the EMPA-REG OUTCOME2 and CANVAS3 trials. In the EMPA-REG OUTCOME trial, the effects of empagliflozin were compared with placebo for cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (T2DM) at high-risk for cardiovascular events. For the primary composite outcome, empagliflozin was associated with a 14% reduction in CV death, MI, or stroke and a 32% reduction in all-cause mortality, which was driven by a 38% decrease in CV death (refer to Table 1). For the secondary outcome, there was a 35% decrease in hospitalizations for heart failure (HF) with empagliflozin and for the renal outcome there was a reduction of new or worsening nephropathy.4 The CANVAS program evaluated two trials (CANVAS and CANVAS-R) in order to see the effects of canagliflozin on cardiovascular, renal, and safety outcomes. Canagliflozin was compared to placebo and 72% of patients enrolled had established atherosclerotic cardiovascular disease (ASCVD). Canagliflozin was associated with a 14% reduction in the primary MACE outcome and a 33% reduction in HF hospitalizations (refer to Table 1).5 In the canagliflozin arm, the progression of albuminuria occurred less frequently and the renal composite outcome of reduction in estimated glomerular filtration rate (eGFR), renal replacement therapy, or renal death was decreased by 40%. These results are largely in concordance with the results in the more recent SGLT2 trials, CREDENCE6 and DECLARE-TIMI 587 trials.

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was a double-blind, multi-site, placebo-controlled randomized trial that assessed the effects of canagliflozin on renal outcomes in 4401 patients with T2DM. The trial was stopped early due to observed benefit after a planned interim analysis: there was a 30% lower relative risk of the primary outcome in the canagliflozin arm. In the canagliflozin group the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34%, and 32% lower for the relative risk of end stage kidney disease (refer to Table 1). One of the strengths of this study was that the majority of patients had moderate CKD: the mean eGFR was 56 mL/min/1.73m2, and 29% and 27% of the study population had an eGFR from ≥45 to <60 mL/min/1.73m2 or from ≥30 to <45 mL/min/1.73 m2, respectively —However, when applying this trial, it should be noted that non-albuminuric patients and patients with severe renal disease (eGFR <30 mL/min/1.73m2) were excluded. Additionally, early termination of the trial may have limited the power of some secondary outcomes and have increased the risk of overestimating effect size. This was the first SGLT2 trial evaluating renal outcomes as a primary outcome and showed that canagliflozin was the first drug since ACEi/ARBs to be disease modifying for diabetic nephropathy.  

 The Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) was a randomized, double-blind, multinational, placebo-controlled trial that evaluated the effects of dapagliflozin on CV and renal outcomes in 17,160 patients who had or were at risk for ASCVD (refer to Table 1). There was a 27% reduction in HF hospitalizations in the dapagliflozin group, but no change in MACE, however, this should not be considered as a weakness because in another SGLT2 trial EMPA-REG OUTCOME, there was a higher overall mortality rate in their secondary patient population, which could have been why they met superiority. Dapagliflozin was not shown to be superior with respect to MACE which is different than the results of EMAPA-REG OUTCOME, however it should be noted that EMPA-REG OUTCOME included a secondary prevention population and had an increased mortality rate which is why it was easy to explain a MACE benefit in this trial. Some limitations in DECLARE are that they excluded patients with an eGFR <60 mL/min/1.73 m2, which allowed for a lower renal risk population. Patients also needed to have ASCVD risk factors or established ASCVD in order to be included and that lead to lower rates of a CV risk population, 40.6% of the patients had established ASCVD and 59.4% had multiple risk factors for ASCVD.

Due to the benefits of SGLT2 inhibitors, professional organizations have weighed in about the evidence-based use of these drugs. Canagliflozin and empagliflozin are the only SGLT2 inhibitors FDA approved for reducing cardiovascular death in patients with T2DM and established CV disease. The American Diabetes Association (ADA) recommends that patients with T2DM and established ASCVD use an SGLT2 inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist due to the cardiovascular benefits, and an SGLT2 inhibitor is preferred in patients that have ASCVD and established HF or at high-risk for HF.8 The ADA also recommends that patients with T2DM and CKD consider the use of an SGLT2 inhibitor or a GLP-1 receptor agonist to reduce the risk of CKD progression, CV events, or both. Metformin is still the preferred first-line oral agent in patients with T2DM. However, if a patient with T2DM and cardiovascular disease cannot tolerate metformin or the patient’s hemoglobin A1C is still above their goal, it is strongly suggested that an SGLT2 inhibitor be considered. The American College of Cardiology (ACC) recommends an SGLT2 inhibitor or GLP-1 agonist in patients with ASCVD but prefers an SGLT2 inhibitor to reduce MACE and HF hospitalizations.5  

When prescribing SGLT2 inhibitors, there are some practical considerations to keep in mind. In patients with CKD, SGLT2 inhibitors have been shown to prevent renal progression, but there are prespecified eGFR cut offs. Although clinical trials such as CREDENCE studied patients with eGFRs as low as 30 mL/min/1.73 m2, the FDA deems acceptable eGFR cutoffs for initiation as 60 mL/min/1.73 m2 (dapagliflozin) and 45 mL/min/1.73 m2 (canagliflozin, empagliflozin). It is important to note there is a modest eGFR decrease when first initiating these agents due to the diuretic effect as observed in CREDENCE. When initiating these agents, clinicians should evaluate concomitant diuretics as a decrease might be warranted in patients at risk for volume depletion. Due to the diuretic effect and direct effects on vascular function, SGLT2 inhibitors can cause a systolic blood pressure reduction of 4 to 6 mmHg.9 It is important to monitor patients for dehydration and orthostatic hypotension when starting these agents, especially among elderly patients. The increased risk of bone fractures observed in CANVAS (which was not confirmed in any other SGLT2 inhibitor trial) could in part have been caused by falls due to dehydration or orthostatic hypotension.10 Additionally, with respect to fracture risk, a recent observational study compared SGLT2 inhibitors to dipeptidyl peptidase-4 (DPP-4) inhibitors and found that the SGLT2 inhibitors (including canagliflozin) had a lower rate of fractures.10 CANVAS was also the only trial that exhibited an increased risk of amputations primarily at the level of the toe or metatarsal. This has not been established as a class wide effect, but patients taking SGLT2 inhibitors should be educated on conducting regular foot exams and reporting new lesions. It should be noted that patients at the highest risk for amputations in CANVAS were those with prior amputations or peripheral artery disease. The rate of genital mycotic infections has been repeatedly shown to be higher with SGLT2 inhibitors, but rates of UTIs were no different than placebo in clinical trials. The FDA added a warning label to the SGLT2 inhibitors for Fournier’s gangrene (FG) due to post surveillance monitoring, but this finding may be interpreted with some caution due to a potential risk of reporting bias with novel medications. In DECLARE there were six cases of FG, one in the dapagliflozin group and five in the placebo group. In general, diabetes is a risk factor for FG, and patients taking these medications should be instructed to report any redness or lesions in perineal and genital regions. Euglycemic diabetic ketoacidosis (DKA) has also been reported with these agents; DECLARE and CREDENCE confirmed higher incidence of DKA with SGLT2 inhibitors than placebo, although overall rates were low. In these trials, most of the patients that experienced DKA were using insulin at baseline. It is important to counsel patients to monitor for signs and symptoms of DKA, and patients should temporarily discontinue SGLT2 inhibitors if they become acutely ill, dehydrated, or have decreased oral intake.

 

There is mounting evidence that SGLT2 inhibitors are beneficial in patients with T2DM who have or are at risk for ASCVD or diabetic nephropathy. The evidence for CV benefit is most convincing for secondary ASCVD prevention, and they should be a preferred antidiabetic agent in patients with ASCVD and HF (assuming metformin as background therapy if no contraindications are present). They should also be a preferred antidiabetic agent in patients with proteinuric diabetic nephropathy. Although a couple alarming adverse effects have been reported – albeit inconsistently – we believe that careful initiation, monitoring, and patient education can mitigate these risks, making these drugs valuable agents for both glycemic control and cardiovascular risk reduction.

 

 

References 

1. Gomez-Peralta F, Abreu C, Lecube A, et al. Practical Approach to Initiating SGLT2 Inhibitors in Type 2 Diabetes. Diabetes Ther. 2017 Oct;8(5):953-962.

2. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.

3. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657.

4. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016 Jul 28;375(4):323-34.

5. Das SR, Everett BM, Birtcher KK, et al. 2018 ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018 Dec 18;72(24):3200-3223.

6. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019 Jan 24;380(4):347-357.

7. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019 Jun 13;380(24):2295-2306.

8. American Diabetes Association. Standards of Medical Care in Diabetes-2019 Abridged for Primary Care Providers. Clin Diabetes. 2019 Jan;37(1):11-34.

9. Vardeny O, Vaduganathan M. Practical Guide to Prescribing Sodium-Glucose Cotransporter 2 Inhibitors for Cardiologists. JACC Heart Fail. 2019 Feb;7(2):169-172.

10. Abrahami D, Douros A, Yin H, Yu OHY, Azoulay L. Sodium-Glucose Cotransporter 2 Inhibitors and the Risk of Fractures Among Patients With Type 2 Diabetes. Diabetes Care. 2019 Jul 11.


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