A New Weapon in the Fight Against Diabetes: SGLT2 Inhibitors

Diabetes is a disease state that is both psychologically and economically draining on the patient and on the economy as a whole. According to the American Diabetes Association (ADA), there are 25.8 million people in the United States living with diabetes, with an even greater prevalence in minority populations.¹ An additional 79 million people are classified as having prediabetes.¹

Long-term effects of the disease include cardiovascular disease, hypertension, kidney disease, blindness, neuropathy, and amputation.¹ In addition to the physical burden that diabetes can bring, there is also a large financial burden that accompanies this disease. In 2012, the total cost of diabetes was $245 billion, which includes direct medical costs and reduced productivity.¹ The medical expenditures of patients with diabetes are more than twice as much as those without the disease.¹

A New Treatment Option

The treatment options for diabetes are plentiful. However, despite the plethora of treatment options available, adequate glycemic control is still difficult to achieve. According to the ADA and the American Association of Clinical Endocrinologists, treatment starts with lifestyle changes. After that, medication therapy is initiated, mostly with metformin and then other agents added on when appropriate. Some patients may need to use multiple medications to help combat the disease.² The common drug classes include biguanides, dipeptidyl peptidase (DPP)-4 inhibitors, sulfonylureas, and thiazolidinediones. Recently, a novel drug class was introduced to the US market, when the US Food and Drug Administration (FDA) approved canagliflozin (Invokana) in March 2013.³

Canagliflozin is the first FDA-approved drug in its class, known as sodium-glucose cotransporter 2 (SGLT2) inhibitors. It is dosed at 100 mg before the first meal of the day and may be titrated up to 300 mg daily. This medication class works in the proximal tubule of the kidneys and promotes the renal excretion of glucose, thereby lowering the blood glucose levels of the patient.⁴ In terms of ability to lower hemoglobin A_1c levels, studies have shown that SGLT2 inhibitors decrease A_1c levels by 0.5% to 0.7%, which is comparable to the DPP-4 inhibitors. In addition to lowering blood glucose, the benefits of SGLT2 inhibitors include reduced blood pressure, weight loss, increased high-density lipoproteins, and decreased triglycerides.⁵

Conversely, prescribers and pharmacists should be aware of some significant side effects that are associated with SGLT2 inhibitors. Hyperkalemia has been seen, especially in patients using potassium-sparing diuretics and medications that inhibit the renin-angiotensin-
aldosterone system (ie, angiotensin-converting enzyme [ACE] inhibitors and angiotensin receptor blockers [ARBs]). This may be common because both ACE inhibitors and ARBs are common medication classes prescribed to patients with diabetes.

In addition to hyperkalemia, there is an increased incidence in vaginal candidiasis, genital infections, and urinary tract infections. This is because of the glycosuria that is precipitated by these medications. These infections should be monitored and treated appropriately.

Increased low-density lipoprotein levels have also been observed with this medication. Because canagli­fl­ozin works in the kidneys, it is contraindicated in patients with severe renal impairment, end-stage renal disease, or those on dialysis.⁴

Emerging SGLT2 Inhibitors

Several other agents in the SGLT2 inhibitor class are seeking FDA approval in the United States. In 2011, the FDA chose not to approve dapagliflozin, citing reports of associated cases of breast and bladder cancer and liver injury. Since its initial denial by the FDA, dapagliflozin has been approved in Europe and is currently awaiting FDA approval after resubmitting a New Drug Application (NDA) in July 2013.6 Boehringer Ingelheim and Eli Lilly have also submitted an NDA for empagliflozin in March 2013.⁶

It is still unknown exactly where this new drug class will fit in, in terms of treating patients with diabetes. Because of the associated side effects and the mechanism of action, prescribers should be careful when selecting patients for this class of medication. As more data become available on this drug class, long-term effects will be determined that may increase its use. Currently, there are other treatment options with more evidence behind them, and prescribers may be more comfortable with other options that have equal efficacy. For now, it does not seem that this class is a game-changer, but it is simply another potential option to choose for patients with diabetes. Time will tell exactly where this medication will fall in the treatment of diabetes.

References

1. American Diabetes Association. Economic costs of diabetes in the United States in 2012. Diabetes Care. 2013;36:1033-1046.
   
2. Garber AJ, Abrahamson MJ, Barzilay JI. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19(2):327-335.
   
3. US Food and Drug Administration. FDA approves Invokana to treat type 2 diabetes. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. Accessed September 12, 2013.
   
4. Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2013.
   
5. Musso G, Gambino R, Cassader M, et al. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and meta-analysis of randomized trials. Ann Med. 2012;44:375-393.
   
6. Eli Lilly. Boehringer Ingelheim and Eli Lilly and Company submit new drug application to FDA for empagliflozin, an investigational type 2 diabetes treatment [press release]. March 25, 2013.