Is Empagliflozin a Diabetes 'Game Changer'?

Matthew L. Mintz, MD


March 02, 2016

Do Prescribing Trends Foretell the Future?

When a new version of inhaled insulin was approved less than 2 years ago, it had the potential to become a major component of diabetes treatment. However, given the recent announcement that pharmaceutical giant Sanofi will stop distributing Afrezza® after a year of poor sales, it is unlikely that the product developed by Mannkind will change the diabetes landscape.

Another diabetes treatment has received even more fanfare lately, and one must wonder if it will be a true "game changer" this time around. Last fall, clinicians enthusiastically received news that the glucose-lowering drug empagliflozin significantly reduced the relative risk for both cardiovascular mortality and all-cause mortality in patients with type 2 diabetes, according to the EMPA-REG OUTCOME trial.[1]

The study was viewed as so important that in a recent Medscape survey, almost two thirds of physicians stated that they are prescribing empagliflozin for more patients with diabetes since EMPA-REG was published, and almost three fourths said that they planned to increase their prescribing of empagliflozin. Increased adoption was much more significant among endocrinologists, who represented more than two thirds of the nearly 700 physicians who responded, compared with primary care physicians (PCPs). Similarly, understanding of the EMPA-REG study was higher among endocrinologists than among PCPs, and endocrinologists represent only a small fraction of those writing prescriptions for type 2 diabetes.

So, based on the study's impressive results as well as relative physician awareness, it appears that empagliflozin could radically change the way type 2 diabetes is managed, or... the drug could go the way of inhaled insulin. Multiple factors will influence the fate of empagliflozin and, in fact, the class of drugs to which it belongs: the sodium glucose cotransporter 2 (SGLT2) inhibitors. Some of these factors are scientific, some are behavioral, and some are financial.

Was It Glucose Reduction or Something Else?

Improving cardiovascular outcomes (myocardial infarction, stroke, or death by either) has been studied extensively in very large, multicenter, randomized clinical trials sponsored by both industry and governments. While the evidence for improvements in microvascular outcomes has been substantial, no prior study had ever shown a difference in these macrovascular outcomes, even when tight glycemic control was attempted.

One likely reason for this is that while diabetes is strongly correlated with cardiovascular risk, factors other than hyperglycemia may play a more important role in cardiovascular outcomes. For example, there is clear evidence that statin use in this high-risk population improves cardiovascular outcomes. Yet, it would be unethical to perform cardiovascular outcome studies in patients with diabetes and not give them statins. Thus, any advantage of glucose lowering as it relates to macrovascular outcomes could be masked by the statin effect.

What is different about the SGLT2 inhibitors is that the glucosuria caused by the medicine not only lowers serum glucose, it also acts as a diuretic, leading to lower blood pressure as well as causing a reduction in weight. In the EMPA-REG trial, the empagliflozin group had small but significant reductions in weight, waist circumference, and systolic and diastolic blood pressure. Multiple large, randomized controlled trials have shown that even a small decrease in blood pressure can improve cardiovascular outcomes. If the same result could be achieved with a combination of metformin and a thiazide diuretic—a cheaper combination of pills that should achieve those same effects—empagliflozin may not be that radical after all.

Is the Effect Specific to Empagliflozin, or Is It Class Wide?

The SGLT2 inhibitors act by inhibiting a protein on the kidney that is important for glucose reabsorption. By decreasing reuptake of glucose by the kidney, glucosuria ensues, which lowers serum glucose, decreases blood pressure, and lowers body weight. In the United States, there are two other SGLT2 inhibitors approved for the treatment of type 2 diabetes in addition to empagliflozin (Jardiance®, Boehringer Ingelheim/Lilly): dapagliflozin (Farxiga™, Astra Zeneca) and canagliflozin (Invokana®, Janssen).

We have not had any head-to-head studies comparing these medications, but their mechanism of action and changes in glucose, blood pressure, and weight are all similar. Thus, there is no reason to believe that the cardiovascular outcomes seen with empagliflozin would not also be seen with the others.

That said, the makers of empagliflozin recently filed a supplemental new drug application with the US Food and Drug Administration (FDA) based on the cardiovascular risk reduction data from EMPA-REG, and the agency accepted their application.

How Important Are CV Outcomes When Choosing Diabetes Treatments?

As mentioned earlier, factors other than elevated glucose may be responsible for predisposing type 2 diabetic patients to heart attacks and strokes. In addition, we have many evidence-based therapies that reduce cardiovascular risk, such as statins, antihypertensive drugs, and aspirin. Thus, while the findings of the empagliflozin trial may be of interest, they may not substantially affect prescribing patterns because physicians are used to treating cardiovascular risk factors with these other agents and do not consider cardiovascular outcomes a priority when choosing a glucose-lowering agent.

On the other hand, while the SGLT2 inhibitors lower glucose similarly compared with other antidiabetic agents, the additive effects of blood pressure lowering and weight reduction may factor into treatment decisions, regardless of the cardiovascular findings of this study.

Cost and Coverage

The single most important factor that will affect the use of SGLT2 inhibitors is the high cost of these medications, along with insurance coverage, which is related to cost. In other countries, where drug prices and drug coverage are regulated by governments, these medications may simply be too expensive for most patients to obtain.

Here in the United States, insurers may cover these medications, but in many cases, they are requiring proof of failure from multiple generic antidiabetic medications before approving their use. Even with coverage, co-pays for these medications may be cost prohibitive to patients, although all three drugmakers offer coupons.

Other Barriers

In medical training, I learned that sugar in the urine was a sign of poor diabetes control. Thus, it may take some getting used to before physicians are willing to prescribe a medication that purposely leads to glucosuria.

In addition, the FDA has warned of instances of diabetic ketoacidosis occurring in patients with type 2 diabetes taking SGLT2 inhibitors. While these occurrences have thus far been rare, and the mechanism of ketoacidosis is unclear, providers may be reluctant to use these newer products until more time has passed.


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