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Q&A: A closer look at class effects of SGLT2 inhibitors on CV outcomes in diabetes

Photo of Darren McGuire
Darren K. McGuire

An expert consensus decision pathway recently published by the American College of Cardiology highlights studies that show SGLT2 inhibitors significantly improve CV outcomes in patients with type 2 diabetes and atherosclerotic CVD.

Research presented at the 2018 American Heart Association Scientific Sessions further demonstrates the favorable CV effects of these antihyperglycemic agents. In particular, results from the DECLARE-TIMI 58 trial have implications for a broader patient population, according to Darren K. McGuire, MD, MHSc, Distinguished Teaching Professor of internal medicine at the University of Texas Southwestern Medical Center.

“These agents primarily reduce the risk for CV death and hospitalization for HF,” he told Cardiology Today. “Given the observed benefits, we are trying internationally to engage cardiologists to embrace these medications.”

To learn more about SGLT2 inhibitors, Cardiology Today asked McGuire about the indications and mechanisms of action of the agents, how they compare with similar drug classes, and the clinical implications of new findings from DECLARE-TIMI 58 and other trials presented at the AHA Scientific Sessions.

What SGLT2 inhibitors are currently available in the United States and what characteristics distinguish them within the class?

There are four SGLT2 inhibitors available in the U.S.: empagliflozin (Jardiance, Boehringer Ingelheim), canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca) and ertugliflozin (Steglatro, Merck).

There are some slight differences in their selectivity for SGLT2. Empagliflozin and ertugliflozin are both highly selective for SGLT2. There is another glucose cotransporter known as SGLT1. Dapagliflozin has intermediate spillover in SGLT1 activity. Canagliflozin has the most SGLT1 inhibition.

Whether the inhibition of SGLT1 will be incrementally beneficial or not remains to be seen. SGLT1 is in the GI tract, so inhibiting it impedes glucose absorption from food intake. There is a dual SGLT1/2 antagonist that is in development called sotagliflozin. It has been developed first for type 1 diabetes (FDA application pending) and is now being tested in large-scale trials assessing CV outcomes in type 2 diabetes.

Empagliflozin was tested in the EMPA-REG trial, which was specific to patients with atherosclerotic vascular disease. CANVAS, which evaluated canagliflozin, and the DECLARE-TIMI 58 trial, which evaluated dapagliflozin, included patients with risk factors, but no evident atherosclerotic vascular disease in addition to those with CVD. However, this subset of patients represented only about one-third of the trial population in CANVAS, whereas the majority of patients in DECLARE-TIMI 58 — about 60% — were in the high-risk primary prevention population.

Canagliflozin and empagliflozin have been proven not only to be safe, but beneficial for CV outcomes. Both have FDA product labels with an indication to reduce CV risk. For empagliflozin, that indication is unique to CV death risk reduction. Canagliflozin has an indication to reduce the composite outcome of CV death, MI and stroke. The two FDA indications are limited to patients with type 2 diabetes who also have atherosclerotic vascular disease. The SGLT2 inhibitors appear to be particularly beneficial in that subpopulation of patients. In DECLARE-TIMI 58, dapagliflozin was shown to be safe but not incrementally beneficial for the outcome of CV death, MI and stroke, while the composite of CV death and hospitalization for HF was significantly improved with dapagliflozin, overall and in the subsets with CV disease and with multiple risk factors. The FDA has not yet considered a labeled indication based on these more recent trial findings.

Discuss the safety profile of SGLT2 inhibitors.

They are really quite safe and well tolerated. There are some common side effects that are seen across the class, including increased risk for genitourinary yeast infections. Other than that, there is not a lot of risk. They are diuretics, and so there is a very small signal of increased risk for hypovolemic events such as orthostatic hypotension and dizziness; however, these are uncommon and rarely severe. One safety signal that appears to be unique to canagliflozin is an increased risk for amputation, which is about a 0.3% absolute increased risk, representing a doubling of risk that was statistically significant. This has not been seen with the other SGLT2 inhibitors.

What other drug classes have a CV indication for patients with diabetes? How do these compare to SGLT2 inhibitors?

There is one other drug class that has a member with CV indication for this patient population: GLP-1 receptor agonists. One drug in that class, liraglutide (Victoza, Novo Nordisk), has an FDA product label indication that is similar to the indication for canagliflozin in patients with type 2 diabetes and atherosclerotic vascular disease, which is that it reduces the risk for the composite outcome of CV death, MI and stroke. So, canagliflozin and liraglutide are more similar than different with regards to their effects on CV risk, but neither one robustly reduces death. In contrast, empagliflozin uniquely and robustly reduces the risk for CV death. In the LEADER trial, liraglutide was associated with a statistically significant reduction in CV death, but the magnitude of that effect was smaller than with empagliflozin and it was not sufficiently robust to support an FDA indication in and of itself.

It is pretty clear that the mechanisms of CV benefit of SGLT2 inhibitors and GLP-1 receptor agonists, specifically liraglutide, are different and probably complimentary. The GLP-1 receptor agonists appear to modify atherosclerotic disease, whereas the SGLT2 inhibitors do not have much effect, if any, on atherosclerotic disease progression and complications, but clearly reduce the risk for CV death and hospitalization for HF.

How do the results of the DECLARE-TIMI 58 trial add to the growing body of evidence that SGLT2 inhibitors have a favorable class effect on CV outcomes in patients with type 2 diabetes?

DECLARE-TIMI 58 extends the observation of risk reductions in CV death and hospitalization for HF into a much broader patient population, including not only those with atherosclerotic vascular disease, but those with CVD risk factors. The importance of that is, in the United States, roughly 20% of patients with type 2 diabetes have atherosclerotic vascular disease, but probably 85% have risk factors for CVD.

DECLARE-TIMI 58 was the largest SGLT2 inhibitor-trial to assess these CV outcomes and the second-largest trial ever in type 2 diabetes, with more than 17,000 patients. The patients were followed for about 4 years, with a primary outcome of CV death, MI and stroke. The trial met the primary objective of noninferiority for dapagliflozin vs. placebo and additionally proved superiority for the composite outcome of CV death and hospitalization for HF.

In the context of the other trials, this reinforces the concept of how these drugs benefit patients and what has been observed with empagliflozin and canagliflozin. It looks like they benefit them by reducing CV death and hospitalization for HF.

Additional findings presented at the AHA Scientific Sessions showed that long-term canagliflozin use was associated with reduced body weight and a dose-dependent reduction in BP compared with placebo. Could this possibly explain the CV benefits?

All of the medications in this class reduce weight and BP. It is unknown how this contributes to the CV benefits of SGLT2 inhibitors. The CV benefits occur very quickly after the drugs are started — much faster than could be attributed to weight loss. The BP effects are modest. It is likely that over longer periods of time, the incremental benefit of the weight loss and BP may add to the observed benefits, but that is not certain.

These drugs have very complex physiology in the kidney. What I think is the leading hypothesis of the benefit is that they restore near-normal renal physiology. The kidney mediates a lot of vasoactivity/vascular tone, BP and volume status in the body. Inhibiting the cotransporter restores a lot of those abnormalities to normal, resulting in secondary benefits, so-called restoration of tubuloglomerular feedback.

There is another potential mechanism that is just now beginning to get attention. I have been very enamored by it. All of these drugs increase hematocrit. It was first thought that this was because these drugs are diuretics and lead to hemoconcentration. If fluid is lost but the red blood cell mass remains the same, hematocrit will increase due to the concentration of red blood cells. In fact, it appears the red blood cell mass is expanding through a simulation of the body’s internal mechanism of making red blood cells. It is a little bit like blood doping, which is what athletes use for competitive advantage. Increasing red blood cells increases oxygen-carrying capacity and oxygen delivered to the heart, kidney and other organs.

A third mechanism is that all of these drugs increase circulating ketone bodies, which are highly efficient metabolic substrates for the heart. It is possible that we are improving myocardial metabolism by providing extra highly-efficient metabolic fuel.

Among all of the proposed mechanisms, I do not think anyone believes that the benefit is due to glucose control. It is important to note that the indications for empagliflozin and canagliflozin for CV risk reduction are completely unlinked from glucose control in the product label.

References:

Das SR, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.09.020.

Khan MS, et al. Abstract 2303. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Wiviott SD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812389.

Wiviott SD, et al. LBS.02 – Late Breaking Clinical Trials: Novel Approaches to CV Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Zelniker TA, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)32590-X.

Disclosure: McGuire reports receiving fees for clinical trial leadership from AstraZeneca, Boehringer Ingelheim, Eisai Inc., Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co, Pfizer, Novo Nordisk and Sanofi-Aventis; and consultancy fees from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck & Co, Pfizer, Metavant, Novo Nordisk and Sanofi-Aventis.

Photo of Darren McGuire
Darren K. McGuire

An expert consensus decision pathway recently published by the American College of Cardiology highlights studies that show SGLT2 inhibitors significantly improve CV outcomes in patients with type 2 diabetes and atherosclerotic CVD.

Research presented at the 2018 American Heart Association Scientific Sessions further demonstrates the favorable CV effects of these antihyperglycemic agents. In particular, results from the DECLARE-TIMI 58 trial have implications for a broader patient population, according to Darren K. McGuire, MD, MHSc, Distinguished Teaching Professor of internal medicine at the University of Texas Southwestern Medical Center.

“These agents primarily reduce the risk for CV death and hospitalization for HF,” he told Cardiology Today. “Given the observed benefits, we are trying internationally to engage cardiologists to embrace these medications.”

To learn more about SGLT2 inhibitors, Cardiology Today asked McGuire about the indications and mechanisms of action of the agents, how they compare with similar drug classes, and the clinical implications of new findings from DECLARE-TIMI 58 and other trials presented at the AHA Scientific Sessions.

What SGLT2 inhibitors are currently available in the United States and what characteristics distinguish them within the class?

There are four SGLT2 inhibitors available in the U.S.: empagliflozin (Jardiance, Boehringer Ingelheim), canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca) and ertugliflozin (Steglatro, Merck).

There are some slight differences in their selectivity for SGLT2. Empagliflozin and ertugliflozin are both highly selective for SGLT2. There is another glucose cotransporter known as SGLT1. Dapagliflozin has intermediate spillover in SGLT1 activity. Canagliflozin has the most SGLT1 inhibition.

Whether the inhibition of SGLT1 will be incrementally beneficial or not remains to be seen. SGLT1 is in the GI tract, so inhibiting it impedes glucose absorption from food intake. There is a dual SGLT1/2 antagonist that is in development called sotagliflozin. It has been developed first for type 1 diabetes (FDA application pending) and is now being tested in large-scale trials assessing CV outcomes in type 2 diabetes.

Empagliflozin was tested in the EMPA-REG trial, which was specific to patients with atherosclerotic vascular disease. CANVAS, which evaluated canagliflozin, and the DECLARE-TIMI 58 trial, which evaluated dapagliflozin, included patients with risk factors, but no evident atherosclerotic vascular disease in addition to those with CVD. However, this subset of patients represented only about one-third of the trial population in CANVAS, whereas the majority of patients in DECLARE-TIMI 58 — about 60% — were in the high-risk primary prevention population.

PAGE BREAK

Canagliflozin and empagliflozin have been proven not only to be safe, but beneficial for CV outcomes. Both have FDA product labels with an indication to reduce CV risk. For empagliflozin, that indication is unique to CV death risk reduction. Canagliflozin has an indication to reduce the composite outcome of CV death, MI and stroke. The two FDA indications are limited to patients with type 2 diabetes who also have atherosclerotic vascular disease. The SGLT2 inhibitors appear to be particularly beneficial in that subpopulation of patients. In DECLARE-TIMI 58, dapagliflozin was shown to be safe but not incrementally beneficial for the outcome of CV death, MI and stroke, while the composite of CV death and hospitalization for HF was significantly improved with dapagliflozin, overall and in the subsets with CV disease and with multiple risk factors. The FDA has not yet considered a labeled indication based on these more recent trial findings.

Discuss the safety profile of SGLT2 inhibitors.

They are really quite safe and well tolerated. There are some common side effects that are seen across the class, including increased risk for genitourinary yeast infections. Other than that, there is not a lot of risk. They are diuretics, and so there is a very small signal of increased risk for hypovolemic events such as orthostatic hypotension and dizziness; however, these are uncommon and rarely severe. One safety signal that appears to be unique to canagliflozin is an increased risk for amputation, which is about a 0.3% absolute increased risk, representing a doubling of risk that was statistically significant. This has not been seen with the other SGLT2 inhibitors.

What other drug classes have a CV indication for patients with diabetes? How do these compare to SGLT2 inhibitors?

There is one other drug class that has a member with CV indication for this patient population: GLP-1 receptor agonists. One drug in that class, liraglutide (Victoza, Novo Nordisk), has an FDA product label indication that is similar to the indication for canagliflozin in patients with type 2 diabetes and atherosclerotic vascular disease, which is that it reduces the risk for the composite outcome of CV death, MI and stroke. So, canagliflozin and liraglutide are more similar than different with regards to their effects on CV risk, but neither one robustly reduces death. In contrast, empagliflozin uniquely and robustly reduces the risk for CV death. In the LEADER trial, liraglutide was associated with a statistically significant reduction in CV death, but the magnitude of that effect was smaller than with empagliflozin and it was not sufficiently robust to support an FDA indication in and of itself.

PAGE BREAK

It is pretty clear that the mechanisms of CV benefit of SGLT2 inhibitors and GLP-1 receptor agonists, specifically liraglutide, are different and probably complimentary. The GLP-1 receptor agonists appear to modify atherosclerotic disease, whereas the SGLT2 inhibitors do not have much effect, if any, on atherosclerotic disease progression and complications, but clearly reduce the risk for CV death and hospitalization for HF.

How do the results of the DECLARE-TIMI 58 trial add to the growing body of evidence that SGLT2 inhibitors have a favorable class effect on CV outcomes in patients with type 2 diabetes?

DECLARE-TIMI 58 extends the observation of risk reductions in CV death and hospitalization for HF into a much broader patient population, including not only those with atherosclerotic vascular disease, but those with CVD risk factors. The importance of that is, in the United States, roughly 20% of patients with type 2 diabetes have atherosclerotic vascular disease, but probably 85% have risk factors for CVD.

DECLARE-TIMI 58 was the largest SGLT2 inhibitor-trial to assess these CV outcomes and the second-largest trial ever in type 2 diabetes, with more than 17,000 patients. The patients were followed for about 4 years, with a primary outcome of CV death, MI and stroke. The trial met the primary objective of noninferiority for dapagliflozin vs. placebo and additionally proved superiority for the composite outcome of CV death and hospitalization for HF.

In the context of the other trials, this reinforces the concept of how these drugs benefit patients and what has been observed with empagliflozin and canagliflozin. It looks like they benefit them by reducing CV death and hospitalization for HF.

Additional findings presented at the AHA Scientific Sessions showed that long-term canagliflozin use was associated with reduced body weight and a dose-dependent reduction in BP compared with placebo. Could this possibly explain the CV benefits?

All of the medications in this class reduce weight and BP. It is unknown how this contributes to the CV benefits of SGLT2 inhibitors. The CV benefits occur very quickly after the drugs are started — much faster than could be attributed to weight loss. The BP effects are modest. It is likely that over longer periods of time, the incremental benefit of the weight loss and BP may add to the observed benefits, but that is not certain.

PAGE BREAK

These drugs have very complex physiology in the kidney. What I think is the leading hypothesis of the benefit is that they restore near-normal renal physiology. The kidney mediates a lot of vasoactivity/vascular tone, BP and volume status in the body. Inhibiting the cotransporter restores a lot of those abnormalities to normal, resulting in secondary benefits, so-called restoration of tubuloglomerular feedback.

There is another potential mechanism that is just now beginning to get attention. I have been very enamored by it. All of these drugs increase hematocrit. It was first thought that this was because these drugs are diuretics and lead to hemoconcentration. If fluid is lost but the red blood cell mass remains the same, hematocrit will increase due to the concentration of red blood cells. In fact, it appears the red blood cell mass is expanding through a simulation of the body’s internal mechanism of making red blood cells. It is a little bit like blood doping, which is what athletes use for competitive advantage. Increasing red blood cells increases oxygen-carrying capacity and oxygen delivered to the heart, kidney and other organs.

A third mechanism is that all of these drugs increase circulating ketone bodies, which are highly efficient metabolic substrates for the heart. It is possible that we are improving myocardial metabolism by providing extra highly-efficient metabolic fuel.

Among all of the proposed mechanisms, I do not think anyone believes that the benefit is due to glucose control. It is important to note that the indications for empagliflozin and canagliflozin for CV risk reduction are completely unlinked from glucose control in the product label.

References:

Das SR, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.09.020.

Khan MS, et al. Abstract 2303. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Wiviott SD, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812389.

Wiviott SD, et al. LBS.02 – Late Breaking Clinical Trials: Novel Approaches to CV Prevention. Presented at: American Heart Association Scientific Sessions; Nov. 10-12, 2018; Chicago.

Zelniker TA, et al. Lancet. 2018;doi:10.1016/S0140-6736(18)32590-X.

Disclosure: McGuire reports receiving fees for clinical trial leadership from AstraZeneca, Boehringer Ingelheim, Eisai Inc., Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck & Co, Pfizer, Novo Nordisk and Sanofi-Aventis; and consultancy fees from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck & Co, Pfizer, Metavant, Novo Nordisk and Sanofi-Aventis.

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