Diabetes and Sodium-Glucose Cotransporter-2 Inhibitors

Diabetes is a disease that affects a person’s life each day by having a negative effect on quality of life and creating a financial burden for patients and families.¹ Diabetes occurs when the pancreas is incapable of producing the required amount of insulin or when the body does not use the insulin produced effectively (insulin resistance).²

Most patients with diabetes are considered to be in one of the following categories³:

• Type 1 diabetes: characterized by lack of insulin production
• Type 2 diabetes: characterized by ineffective use of insulin by the body and lack of insulin secretion; combination therapy (oral and injectable medications) is often needed to achieve glycemic control and treat type 2 diabetes

In the United States, the number of Americans with diabetes is continuing to increase. This rise can be partly attributed to advances in health care that have increased the average life expectancy of patients.⁴

Epidemiology

The number of US adults with a diabetes diagnosis has quadrupled since 1980.⁵ If this trend continues, 1 in 3 Americans will have diabetes by 2050.⁴ In 2013, diabetes was the seventh leading cause of death in the United States, affecting more than 29.1 million Americans.⁴ Among these individuals, it is estimated that 8.1 million have not been given a diagnosis.⁵

Diabetes is a chronic disease that can lead to macrovascular complications (eg, peripheral artery disease, stroke, myocardial infarction) and microvascular complications (eg, retinopathy, nephropathy, neuropathy) if left untreated. In 2012, the economic impact of diabetes in the United States was $245 billion.⁵ This economic impact will steadily increase as the number of Americans with diabetes continues to increase.

Pathophysiology

Diabetes is a metabolic disorder characterized by hyperglycemia resulting from lack of insulin secretion or action, or both.⁶ The kidneys are essential for helping maintain glucose balance. On average, the glomeruli filter 180 g of glucose every day through the glucose transporter proteins.^7,8 The kidneys normally function to retrieve as much glucose as possible, which leaves urine almost completely free of glucose.⁸ Within the kidneys, the sodium-glucose cotransporter-2 (SGLT2) proteins help control glucose levels by actively transporting glucose against a concentration gradient. The SGLT2 proteins found in the proximal renal tubules reabsorb 90% of the glucose being filtered.⁸ Inhibition of these cotransporters allows lowering of insulin-independent glucose.⁹

Table 1 lists the currently available SGLT2 inhibitors. On March 29, 2013, the FDA approved Invokana (canagliflozin) for the treatment of diabetes in adults. Canagliflozin was the first in a new class of medications called SGLT2 inhibitors, which inhibit renal proximal tubular glucose reabsorption. With this insulin-independent mechanism of action, SGLT2 inhibitors have a very low risk of causing hypoglycemia and are effective at lowering glycated hemoglobin. In addition, they have been shown to have several other favorable effects, including reduction of body weight and blood pressure.¹⁰ SGLT2 inhibition results in diuresis of 400 mL of fluid and 75 g of glucose per day, as well as a subsequent weight loss of 2.5 to 3.2 kg over 4 weeks, mainly because of reduced fat mass.¹⁰

General Clinical Dosing

SGLT2 inhibitors are available as once-daily tablets, with their bioavailability ranging from 60% with empagliflozin to 78% with dapagliflozin. These drugs should be taken 30 minutes before the first meal of the day to maximize absorption. SGLT2 inhibitor dosing is optimized at a once-daily dose because these agents have a half-life of 10 to 13 hours.^11-13

Precautions

The most common adverse effect (AE) of concern with SGLT2 inhibitor therapy is fungal infection of the genitourinary tract, which affects approximately 5% to 11% of patients; canagliflozin is most often associated with this AE.^11-13 SGLT2 inhibitors have also been documented to cause serious urinary tract infections, including urosepsis and pyelonephritis.¹⁴

The FDA has warned that the use of SGLT2 inhibitors can result in ketoacidosis, a serious condition in which the body produces high levels of blood acids called ketones. Patients should stop taking their SGLT2 inhibitor and seek medical attention immediately if they have symptoms of ketoacidosis, which include nausea, vomiting, abdominal pain, tiredness, and trouble breathing.¹⁴ The FDA is also currently investigating whether the risk of leg and foot amputations is increased while taking canagliflozin. Patients are advised to notify their physician if they notice any new pain, tenderness, sores, ulcers, or infections in their lower extremities.¹⁵ SGLT2 inhibitors can also decrease blood pressure due to their volume-depleting diuretic effects, leading to AEs in some patients.¹⁶

Baseline kidney function and serum potassium level should be determined at initiation of any SGLT2 inhibitor and monitored periodically thereafter for adverse changes. Patients with renal impairment may require a dose reduction, or SGLT2 inhibitors may be contraindicated in these patients (Table 2).¹⁷

Conclusion

SGLT2 inhibitors have been quickly adopted into practice, and pharmacists are responsible for ensuring that these medications are used safely and effectively in patients. Since 2013, when the FDA approved canagliflozin as a first-in-class medication for treating diabetes, 5 new medications and combination treatments in this class have gained FDA approval. Each SGLT2 inhibitor is slightly different than the others, which should be considered in making the best choice for patients. As the market presence of these medications increases, pharmacists should be mindful of the long-term risks and benefits to patients in order to optimize treatment of diabetes.

Jerry Barbee, Jr, PharmD, BCPS, CPh, is a clinical pharmacist at HCA West Florida Hospital. Glenn Schulman, PharmD, MS, BCPS, BCACP, CGP,

is a clinical pharmacist at HCA West Florida Hospital. Curtis Brashear is a 2016 PharmD candidate at Auburn University. Max Greenlee is a 2016 PharmD candidate at the University of Florida.

References

• McCulloch DK. Overview of medical care in adults with diabetes mellitus. UpToDate.com website. uptodate.com/contents/overview-of-medical-care-in-adults-with-diabetes-mellitus?source=search_result&search=%22Overview+of+medical+care+in+adults+with+diabetes+mellitus%22&selectedTitle=1~1. Updated Mar 9, 2016. Accessed December 15, 2015.
• 2015 diabetes fact sheet. World Health Organization website. who.int/topics/diabetes_mellitus/en/. Accessed December 10, 2015.
• Kishore P. Diabetes mellitus (DM). Merck Manual website. merckmanuals.com/professional/endocrine-and-metabolic-disorders/diabetes-mellitus-and-disorders-of-carbohydrate-metabolism/diabetes-mellitus-dm. Accessed April 29, 2016.
• Diabetes report card 2014. CDC website. cdc.gov/diabetes/pdfs/library/diabetesreportcard2014.pdf. Published 2015. Accessed April 29, 2016.
• American Diabetes Association. 2014 National Diabetes Statistics Report. ADA website. diabetes.org/diabetes-basics/statistics/. Accessed Dec. 5, 2015
• Triplitt CL, Repas T, Alvarez CA. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 9th ed. New York, NY: McGraw-Hill Medical; 2014:1143-1190.
• Pérez López G, González Albarrán O, Cano Megías M. Type 2 sodium-glucose cotransporter (SGLT2) inhibitors: from familial renal glucosuria to the treatment of type 2 diabetes mellitus. Nefrologia. 2010;30(6):618-625. doi: 10.3265/Nefrologia.pre2010.Sep.10494.
• Triplitt CL. Understanding the kidneys’ role in blood glucose regulation. Am J Manag Care. 2012;18(suppl 1):S11-S16.
• American Diabetes Association. Approaches to glycemic treatment. Diabetes Care. 2015;38(suppl 38):S41-S48. doi: 10.2337/dc15-S010.
• Rajeev SP, Cuthbertson DJ, Wilding JP. Energy balance and metabolic changes with SGLT2 inhibition. Diabetes, Obesity and Metabolism. John Wiley & Sons Ltd; 2015.
• Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals; 2013.
• Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2014.
• Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.
• FDA drug safety communication: labels to include warnings about too much acid in the blood and serious urinary tract infections. FDA website. www.fda.gov/Drugs/DrugSafety/ucm475463.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery. Published December 4, 2015. Accessed December 4, 2015.
• FDA Drug Safety Communication: interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet). FDA website. www.fda.gov/Drugs/DrugSafety/ucm500965.htm. Published May 18, 2016. Accessed June 25, 2016.
• FDA approves Invokana to treat type 2 diabetes [news release]. Silver Spring, MD: FDA; March 29, 2013. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm. Accessed April 29, 2016.
• Sarnoski-Brocavich S, Hilas O. Canagliflozin (Invokana), a novel oral agent for type-2 diabetes. P T. 2013;38(11):656-666.