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Study Explores Mechanisms Behind Cardiovascular Benefits of SGLT2 inhibitors

Mar 17, 2018

Researchers complete examination of class of type 2 medication.

Recently many studies have come out that highlight the role of SGLT2 inhibitors in cardiovascular disease when used for treatment of type 2 diabetes. However, the mechanism by which this medication class leads to the beneficial cardiovascular outcomes is not yet completely understood, and therefore, the researchers in Australia aimed to complete a thorough examination of the multifactorial approach that ultimately leads to improved cardiovascular benefits in individuals who have type 2 diabetes.   Their findings have been published by Diabetes Research and Clinical Practice.


People who have T2D also have increased risk of both micro- and macrovascular complications. To diminish the risk, it is imperative to modify risk factors that are responsible for the development of the complications and optimization of blood pressure, blood lipids, and of course, blood sugars. Due to the excretion of excess glucose in urine and preventing its reabsorption, SGLT2 inhibitors use results in weight loss and subsequently reduction in blood pressure as well. Furthermore, some studies, such as EMPA-REG and CANVAS Program, have demonstrated a decrease in cardiovascular death, or cardiovascular death composite, which hints that the CV benefits may be consistent across the entire medication class. The EMPA-REG trial demonstrated a decrease in cardiovascular death, non-fatal MI, and stroke by 14% (p-value of 0.04) in individuals treated with empagliflozin when added on to standard antihyperglycemic therapy. The CANVAS trial produced similar results where people treated with canagliflozin experienced a significant reduction in cardiovascular composite outcomes. However, canagliflozin use produced a risk of toe amputations and bone fractures. The third trial, DECLARE, is currently underway to establish the superiority of dapagliflozin over placebo in the reduction of the composite cardiovascular endpoint mentioned above.

SGLT2 inhibitors are commonly used as second-line agents in type 2 diabetes in instances where metformin therapy is not sufficient to regulate the HbA1c levels. They can also be used as a third-line therapy, and even as an add-on to insulin to decrease the insulin daily dose and potentially reduce the body weight of individuals who are long-time insulin users. When compared to DPP4 inhibitors, SGLT2-i have shown dominance. Although the effect on A1c lowering is similar for both of the medication classes, SGLT2s provide further improvements, mainly in blood pressure lowering, stabilization of renal function, and greater weight loss. On the other hand, while some DPP4 inhibitors may bestow increased risk of heart failure, SGLT2 inhibitors cause dehydration and urinary tract infections in many cases.

As mentioned previously, insulin need is often decreased when used with SGLT2 inhibitors. But, it may be advantageous to reduce the insulin dose by 20% in all patients who are receiving both medication therapies due to an enhanced hypoglycemia risk; sulfonylurea dose should be decreased in individuals started on SGLT2 inhibitors for the same reason. When added to diuretics, such furosemide or hydrochlorothiazide, SGLT2 inhibitors produce a larger natriuretic effect and, therefore, increase the risk of dehydration and hypotension. The doses of diuretics should be adjusted depending on the patient’s intravascular volume status. Those individuals who are hypervolemic can continue without dose modification, while those individuals who are euvolemic may benefit from lowering of the diuretic doses. Risk of diabetic ketoacidosis was once thought to be great with the entire medication class of SGLT2, however, this was recently challenged as the risk was not broadly present clinically. Those individuals who are receiving an SGLT2 inhibitor are likely to experience a small decrease in their eGFR levels during the first couple of weeks following the initiation of therapy; the reduction is generally between 5 and 7 mL/min and does not afford any safety concerns.

In conclusion, SGLT2 inhibitors improve cardiovascular outcomes in patients with CV disease and type 2 diabetes while also having a positive influence on body weight, renal function, and blood pressure. No serious safety concerns have been identified with the use of these medications, save for the enhanced risk of genitourinary infections and increased risk of toe amputations with canagliflozin. Consider changing dosing regimens of insulin, sulfonylureas, thiazide, and loop diuretics when initiating SGLT2 inhibitors to minimize the certain events that can occur with combination therapies. The benefits that were demonstrated with empagliflozin and canagliflozin are feasibly class-wide effects that have the aptitude to cause clinically relevant changes in how we treat individuals with type 2 diabetes.

Practice Pearls:

  • SGLT 2 inhibitors provide cardiovascular benefits in patients with CV disease and T2DM.
  • Efficacy of loop and thiazide diuretics is increased when combined with SGLT2 inhibitors; monitor patient’s fluid status prior to initiation.
  • Risk of genitourinary infections is enhanced with use of this medication class.
  • Consider decreasing the doses of insulin and sulfonylureas when combining with SGLT2 inhibitors.


Michael d’Emden, John Amerena, Gary Deed.  “SGLT2 inhibitors with cardiovascular benefits: Transforming clinical care in Type 2 diabetes mellitus.”  Diabetes Research and Clinical Practice. 2018. http://www.diabetesresearchclinicalpractice.com/article/S0168-8227(17)31098-7/fulltext.  Accessed Jan 2018.

Bernard Zinman, Christoph Wanner, John Lachin, et al.  “Empagliflozin, Cardiovascular Outcomes and Mortality in Type 2 Diabetes.” New England Journal of Medicine. 2015. http://www.nejm.org/doi/full/10.1056/NEJMoa1504720.  Accessed Jan 2018.

Bruce Neal, Vlado Perkovic, Kenneth Mahaffey, et al. “Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.” New England Journal of Medicine. 2017.  http://www.nejm.org/doi/full/10.1056/NEJMoa1611925. Accessed Jan 2018.

Lamija Zimic, PharmD(c), University of South Florida College of Pharmacy