August/September 2014, Vol 2, No 4 - Drug Update
Loretta Fala

Improvements in glycemic control have been shown to reduce the morbidity and mortality associated with type 2 diabetes by decreasing chronic complications.

An estimated 25.8 million people—more than 8% of the US population—are affected by diabetes.1 Moreover, approximately 35% of US adults aged ≥20 years have prediabetes; the rate of prediabetes increases to 50% for adults aged ≥65 years.1 More concerning is the projection that the prevalence of diabetes will increase dramatically, from 1 in 10 adults today to 1 in 3 adults by 2050—a trend that coincides with the aging of the US population over the next few decades.2

Diabetes is a chronic illness associated with multiple comorbidities and health complications.1 Aside from being a major cause of heart disease and stroke, diabetes is the leading cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness in US adults. In fact, diabetes is the seventh leading cause of mortality in the United States.1

In 2012, US healthcare costs attributable to diabetes totaled $245 billion, including $176 billion in direct medical costs, and $69 billion in indirect costs (ie, increased absenteeism, reduced productivity, lost productivity because of early mortality, and inability to work resulting from disability).3 Overall, medical expenses for patients with diabetes are approximately 2.3 times higher than expenses for people without diabetes.3

Type 2 diabetes accounts for 90% to 95% of all cases of diabetes, whereas type 1 diabetes accounts for approximately 5% of all cases.1 Type 2 diabetes requires ongoing management and support to prevent acute long-term complications.4 According to the American Diabetes Association (ADA), diabetes management is complex and generally requires multiple risk-reduction strategies, including glycemic control.4

Improvements in glycemic control have been shown to reduce the morbidity and mortality associated with type 2 diabetes by decreasing chronic complications.5 In fact, a 1% reduction in glycated hemoglobin (HbA1c) is associated with a 35% reduction in diabetes-related microvascular complications, including dia­betic neuropathy, nephropathy, and retinopathy.5

In a 2013 position statement, the ADA recommended a general target HbA1c level of <7% for adults with diabetes; however, the stringency of this goal may need to be adapted, based on the patient’s duration of diabetes, comorbidities, age, known cardiovascular or advanced microvascular complications, and other relevant patient factors.4

The American Association of Clinical Endocrinologists recommends an HbA1c target level of <6.5% in the majority of patients with type 2 diabetes, with the caveat that this goal may be too aggressive for some patients and not aggressive enough for others (ie, younger patients for whom a lower target may prevent later complications).6 According to the American Association of Clinical Endocrinologists 2013 consensus statement, the goals of lifestyle modification and antihyperglycemic pharmacotherapy are “(1) to achieve clinical and biochemical glucose targets; (2) to avoid hypoglycemia; (3) to avoid weight gain in persons who are obese and to assist with weight loss; and (4) to reduce or avoid increasing CVD [cardiovascular disease] risk.”6

Despite strides made in the number of people in the United States who achieve the target HbA1c level of <7%, there is still a substantial need for strategies to improve the achievement of glycemic-control targets and outcomes for individuals with diabetes and prediabetes.7

Over the past 2 decades, accumulating evidence has shown that the kidney plays an important role in regulating glucose.8 In patients with type 2 diabetes, there is an increased reabsorption and release of renal glucose.9 In hyperglycemia, excess glucose is reabsorbed by the kidney. This reabsorption process increases the renal glucose threshold and perpetuates a cycle of hyperglycemia, along with its associated microvascular complications.9

The sodium-glucose cotransporter (SGLT)-2, a cotransporter expressed in the proximal renal tubules, is responsible for reabsorbing 90% of the glucose filtered at the glomerulus.9,10 By reducing the reabsorption of filtered glucose and lowering the renal threshold for glucose, the SGLT-2 inhibitors increase urinary glucose excretion and lower blood glucose levels.11

Dapagliflozin: A New Oral SGLT-2 Option
On January 8, 2014, dapagliflozin (Farxiga; Bristol-Myers Squibb/AstraZeneca), an oral SGLT-2 inhibitor, was approved by the US Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.12 Dapagliflozin is not indicated for the treatment of type 1 diabetes mellitus or for diabetic ketoacidosis.13

According to the FDA, the safety and efficacy of dapagliflozin were evaluated in 16 clinical trials that involved more than 9400 patients with type 2 diabetes.12 Curtis Rosebraugh, MD, MPH, Director of the Office of Drug Evaluation II at the FDA Center for Drug Evaluation and Research, commented, “Controlling blood sugar levels is very important in the overall treatment and care of diabetes, and Farxiga provides an additional treatment option for millions of Americans with type 2 diabetes.”12

The FDA is requiring the manufacturer to conduct 6 postmarketing studies for dapagliflozin, including a cardiovascular outcomes trial in patients with a high baseline risk for cardiovascular disease; a double-blind, randomized, controlled evaluation of bladder cancer risk in patients enrolled in the cardiovascular outcomes study; an animal study to assess dapagliflozin-induced urinary flow, rate, and composition changes on bladder tumor promotion; 2 clinical studies on the pharmacokinetics, efficacy, and safety of dapagliflozin in pediatric patients; and an enhanced pharmacovigilance program to monitor any reports of liver abnormalities and pregnancy outcomes.12

Mechanism of Action
Dapagliflozin is an inhibitor of SGLT-2, a protein expressed in the proximal renal tubules that is responsible for the majority of the reabsorption of filtered glucose from the tubular lumen. By inhibiting SGLT-2, dapagliflozin reduces the reabsorption of filtered glucose and lowers the renal threshold for glucose, and thereby increases urinary glucose excretion.13

Dosing and Administration
Dapagliflozin is available as a 5-mg and a 10-mg tablet for oral use. The recommended starting dose is 5 mg once daily, taken in the morning. The dose can be increased to 10 mg once daily in patients who can tolerate dapagliflozin and who require additional glycemic control. Dap­agliflozin can be administered with or without food.13

Before initiating treatment with dapagliflozin, renal function should be assessed. Treatment with dapagliflozin should not be initiated if the patient’s estimated glomerular filtration rate (eGFR) is <60 mL/min/1.73 m2. If the eGFR falls persistently below 60 mL/min/1.73 m2, dapagliflozin should be discontinued.13

Clinical Trials
Dapagliflozin was studied as monotherapy and in combination with metformin, pioglitazone, glimepiride, sitagliptin (with or without metformin), or insulin (with or without other oral antidiabetes therapy). The efficacy of dapagliflozin was compared with a sulfonyl­urea (glipizide) added on to metformin. Dapagliflozin was also studied in patients with type 2 diabetes and moderate renal impairment.13

Treatment with dap­agliflozin as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin produced significant improvements in the mean change of HbA1c levels from baseline at week 24 compared with the control HbA1c levels. These reductions in HbA1c levels were seen across a number of subgroups, including gender, age, race, duration of disease, and the baseline body mass index.14,15

Monotherapy Studies
Two placebo-controlled clinical trials evaluated the safety and efficacy of dapagliflozin monotherapy in 840 treatment-naïve patients with inadequately controlled type 2 diabetes.13,14

One of the monotherapy trials was a 24-week study that included 558 treatment-naïve patients with inadequately controlled diabetes.14 Following a 2-week diet and exercise placebo lead-in period, 485 patients with HbA1c levels of ≥7% and ≤10% were randomized to dapagliflozin 5 mg or 10 mg once daily in the morning (main cohort) or in the evening, or to placebo. At week 24, patients receiving dapagliflozin 10 mg once daily in the morning showed significant improvements in HbA1c and fasting plasma glucose (FPG) levels compared with patients receiving placebo (Table 1).13,14

Combination Therapy
Studies with Metformin

Two active-controlled, 24-week studies evaluated the safety and efficacy of initial therapy with dapagliflozin 5 mg or 10 mg in combination with metformin extended-release (XR) formulation.

A total of 1241 treatment-naïve patients with inadequately controlled type 2 diabetes (HbA1c ≥7.5% and ≤12%) participated in these 2 studies.15

Study 1. Dapagliflozin 10 mg plus metformin XR. A total of 638 patients were randomized to 1 of 3 treatment arms after a 1-week lead-in period: dapagliflozin 10 mg plus metformin XR (up to 2000 mg daily), dapagliflozin 10 mg plus placebo, or metformin XR (up to 2000 mg daily) plus placebo. The metformin XR dose was uptitrated weekly in 500-mg increments, as tolerated, with a median dose of 2000 mg.15

The combination treat­ment of dapagliflozin 10 mg plus metformin XR demonstrated significant improvements in HbA1c and FPG levels compared with either of the monotherapy treatments, as well as a significant reduction in body weight compared with metformin XR alone (Table 2). Moreover, dapagliflozin 10-mg monotherapy provided significant improvements in FPG levels and a significant reduction in body weight versus metformin alone; in addition, it was noninferior to metformin XR monotherapy in lowering HbA1c levels.15

Study 2. Dapagliflozin 5 mg plus metformin XR. In this study of 603 patients, the combination treatment of dapagliflozin 5 mg plus metformin XR showed significant improvements in HbA1c and FPG levels compared with either of the monotherapy treatments; in addition, there was a significant reduction in body weight compared with metformin XR alone.15

Safety
The safety data for dap­agliflozin were derived from 12 placebo-controlled clinical trials that ranged from 12 to 24 weeks, in which 2338 patients were exposed to dap­agliflozin for a mean duration of 21 weeks. In these studies, the most common (≥5% incidence) adverse reactions associated with dapagliflozin were female genital mycotic infections, nasopharyngitis, and urinary tract infections (Table 3).13

Warnings and Precautions
Contraindications.
Dapa­gliflozin is contraindicated in patients with a history of serious hypersensitivity reaction to dap­agliflozin and in patients with severe renal impairment or end-stage renal disease, or those on dialysis.13

Hypotension. Dapagliflozin may cause osmotic diuresis, which may lead to reductions in intravascular volume. Adverse reactions related to volume depletion include reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension. Before initiating dapagliflo­zin therapy, volume status should be assessed and hypovolemia should be corrected in elderly patients, in patients with renal impairment or low systolic blood pressure, and in patients taking diuretics. Patients should also be monitored for signs and symptoms of volume depletion during therapy.13

Impairment in renal function. Because dapagliflozin increases serum creatinine levels and decreases the eGFR, renal function should be monitored before and after therapy with dapagliflozin.13

Hypoglycemia. To reduce the risk for hypoglycemia, a lower dose of insulin or insulin sec­re­tagogue should be considered in patients taking dapagliflozin with insulin or with an insulin secre­tagogue.13

Genital mycotic infections. Dapagliflozin is associated with an increased risk for genital mycotic infections. Patients with a history of genital mycotic infections were more likely to develop these infections. Patients should be monitored and managed appropriately.13

Increased low-density lipoprotein cholesterol (LDL-C). Increases in LDL-C levels often occur with dap­agliflozin. Elevated LDL-C levels should be treated according to standard of care after dapagliflozin therapy.13

Bladder cancer. In clinical trials, dapagliflo­zin was associated with an increased risk for bladder cancers compared with placebo or the comparator drug. Dapagliflozin should not be used in patients with active bladder cancer and should be used with caution in patients with a history of bladder cancer.13

Macrovascular outcomes. Clinical studies have not established conclusive evidence of macrovascular risk reduction with dapagliflozin or with any other antidiabetic drug.13

Drug Interactions
In in vitro studies, dap­agliflozin and dapagliflozin 3-0-glucuronide neither inhibited cytochrome (CY)P1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4, nor induced CYP1A2, CYP2B6, or CYP3A4. Overall, dap­agliflozin is unlikely to affect the pharmacokinetics of concurrently administered medications that are P-glycoproteins, OCT2, OAT1, or OAT3 substrates.13

Use in Specific Populations
Pregnancy. There are no adequate and well-controlled studies of dapagliflozin in pregnant women. Dapagliflozin should only be used in pregnant women if the potential benefit justifies the potential risk.13

Nursing mothers. Because many drugs are excreted in human milk, a decision should be made whether to discontinue nursing or to discontinue dapagliflozin.13

Geriatric use. More patients aged ≥65 years receiving dapagliflozin had adverse reactions related to volume depletion and renal impairment or failure compared with patients receiving placebo.13

Renal impairment. Dapagliflozin is associated with an increased incidence of adverse reactions related to reduced intravascular volume and renal function.13

Conclusion
The FDA approval of dapagliflozin marked the availability of a new oral SGLT-2 option for patients with type 2 diabetes, as an adjunct to diet and exercise. Dapagliflo­zin blocks renal glucose reabsorption, increases urinary glucose excretion, and lowers blood glucose levels. In 16 clinical trials with more than 9400 patients with type 2 diabetes, dapagliflozin significantly improved HbA1c levels. This approval provides the millions of patients with diabetes an additional option in controlling their blood glucose levels. The most common adverse reactions associated with dap­agliflozin were female genital mycotic infections, nasopharyngitis, and urinary tract infections.

References

  1. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. 2011. www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Accessed March 7, 2014.
  2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US adult population: dynamic modeling of incidence, mortality, and prediabetes prevalence. Popul Health Metr. 2010;8:29.
  3. American Diabetes Association. Economic costs of diabetes in the U.S. in 2012. Diabetes Care. 2013;36:1033-1046.
  4. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36 (suppl 1):S11-S66.
  5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
  6. Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(suppl 2):1-48.
  7. Cheung BM, Ong KL, Cherny SS, et al. Diabetes prevalence and therapeutic target achievement in the United States, 1999 to 2006. Am J Med. 2009;122:443-453.
  8. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27:136-142.
  9. Triplitt CL. Understanding the kidneys’ role in blood glucose regulation. Am J Manag Care. 2012;18(1 suppl): S11-S16.
  10. Marsenic O. Glucose control by the kidney: an emerging target in diabetes. Am J Kidney Dis. 2009;53:875-883.
  11. List JF, Whaley JM. Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int Suppl. 2011; 79(suppl 120):S20-S27.
  12. US Food and Drug Administration. FDA approves Farxiga to treat type 2 diabetes. Press release. January 8, 2014. Updated January 9, 2014. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm380829.htm. Accessed February 26, 2014.
  13. Farxiga (dapagliflozin) tablets [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company, and Wilmington, DE: AstraZeneca Pharmaceuticals LP; January 2014.
  14. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33:2217-2224.
  15. Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012;66:446-456.
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