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Cardiovascular and Renal Benefits of SGLT2 Inhibitors

Dec 3, 2019
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Onyi Ibeji, PharmD. Candidate, LECOM School of Pharmacy

Cardiovascular and renal benefits of SGLT2 inhibitors can help prevent the development of heart disease and reduce progression of renal impairment in patients with T2DM. 

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used antidiabetic drugs with glucose-lowering effects, cardiovascular benefits, and potential renoprotective effects leading to the reduction in the rate of progression of diabetic kidney disease. The sodium-glucose cotransporter 2 (SGLT2), as a transport protein, is responsible for the reabsorption of a greater percentage of filtered glucose, unlike sodium-glucose co-transporter 1 (SGLT1). Therefore, Inhibition of these SGLT2s results in a great reduction in renal capacity for glucose reabsorption in the proximal tubules, reducing hyperfiltration by increasing sodium delivery to the macula densa, which activates tubuloglomerular feedback (TGF). Activation of TGF leads to vasoconstriction afferent arteriolar and a further reduction in intraglomerular hyperfiltration. Also, reduced glucose reabsorption lowers glucotoxicity in the organs and kidneys, especially, leading to reduced renal growth, inflammation, and injury to the kidney. 

For cardiovascular benefits, inhibition of SGLT2 produces natriuresis since SGLT2 is co-expressed with the Na+/H+ exchanger 3 (NHE3) membrane protein in the early proximal tubule. This natriuresis is what contributes to reduced blood pressure, the decline in sodium and volume overload, leading to a reduced CV and renal burden.

So far, three recent trials done – CANVAS (Canagliflozin Cardiovascular Assessment Study); EMPA-REG (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) and DECLARE-TIMI-58 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction), tested the effectiveness of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) and produced results suggestive of great expectations for SGLT2-i by consistently evidencing positive effects on hyperglycemia control, beneficial cardiovascular and renoprotective outcome in patients with type 2 diabetes mellitus.

According to Clegg et al., empagliflozin and canagliflozin have been found in cardiovascular outcomes trials to reduce the incidence of major adverse cardiovascular events (MACE), all-cause mortality (ACM), and renal events, with evidence from real-world observational analyses suggesting class affect benefits that include dapagliflozin. They, therefore, decided to examine and determine whether the effects of dapagliflozin on MACE, ACM, and estimated glomerular filtration rate (eGFR) were consistent with the other medicines in the SGLT2-i class using a placebo arm of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL).

In their study, Clegg et al., assessed in a single trial the impact of dapagliflozin compared with other SGLT2-i on cardiovascular and renal outcomes, in a population spread across multiple regions and with varying cardiovascular risk. This study became necessary, given the numerous discrepancies among previous trial outcomes. Following observational real-world evidence analyses (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [CVD-REAL], Empagliflozin – Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]), (Canagliflozin Cardiovascular Assessment Study [CANVAS]/CANVAS-Renal [R]), Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World [EASEL] and the Birmingham study in The Health Improvement Network [THIN] cohort), there had been several questions about whether the benefits seen are drug-specific or an SGLT2-i class effect.

As specified in the EXSCEL protocol, a three-point MACE of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were examined for the adjudicated first EXSCEL primary endpoint; the first adjudicated ACM as a prespecified EXSCEL secondary endpoint time and a change over time in the local site-reported eGFR calculated using the MDRD equation. Also, exploratory time-to-event analyses were performed for peripheral artery disease, hospitalization for heart failure, cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and diabetic eye complications.

Consistent with empagliflozin and canagliflozin in their CVOTs, there was an overall significant reduction in albuminuria and improvement in eGFR slope with both SGLT2-i and dapagliflozin treatment which supports a similar renal benefit for dapagliflozin as shown for other medicines in the SGLT2-i class.

Also, the treatment effects of dapagliflozin on MACE, ACM, and eGFR were again numerically consistent with the SGLT2-i analysis. These results are supportive of consistency across SGLT2 Inhibitors class in the reduction of cardiovascular risk and improved estimated glomerular filtration rate to be a class-effect.

Practice Pearls:

  •  Having the same mechanism of action of reduction in renal capacity for glucose reabsorption, all SGLT2 inhibitors lead to reductions in blood glucose concentrations, with a modest natriuretic effect, conferring some cardiovascular benefits and protective effects on the kidney.
  •  The uniqueness of the mechanism of action of SGLT2 inhibitors, being independent of β-cell function and insulin secretion, makes SGLT2 inhibitors useful for patients with longstanding diabetes.
  •  In general, SGLT2 inhibitors play a very important role in the management of T2DM. Their pleiotropic effects can potentially produce benefits beyond blood glucose control and therefore require future clinical trials on different mechanisms of actions of SGLT2 inhibitors in patients with T2DM.

Reference for “Cardiovascular and Renal Benefits of SGLT2 Inhibitors”:
Clegg, Heerspink., et al. “Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL’’ Diabetes Care 2019 Feb; 42(2): 318-326.

Onyi Ibeji, PharmD. Candidate, LECOM School of Pharmacy