Special Feature Fifth Annual Payers' Guide to New FDA Approvals March 2014 Volume 7 - Payers' Guide
Loretta Fala
Medical Writer
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Diabetes affects an estimated 25.8 million people in the United States—a staggering 8.3% of the population.1 Type 2 diabetes accounts for 90% to 95% of all adult cases of diabetes.1 In addition, an estimated 35% of US adults aged ≥20 years have prediabetes, and the prevalence of prediabetes jumps to 50% in adults aged ≥65 years.1

The number of people with diabetes is projected to rise dramatically over the next few decades, from approximately 1 in 10 adults today to as many as 1 in 3 by 2050.2 This increased prevalence is attributed to the aging population, the increasing number of high-risk groups, and a longer life expectancy for patients with diabetes.2

In addition to being the seventh leading cause of mortality in the United States, diabetes is associated with serious morbidities, including cardiovascular disease, stroke, and nervous system damage.1 It is also the lead­ing cause of kidney failure, nontraumatic lower-limb amputations, and new cases of blindness in adults.1

Economic Burden


In 2012, diabetes accounted for an estimated $245 billion in total costs in the United States, including $176 billion in direct medical costs and $69 billion in indirect costs (ie, disability and lost or reduced productivity).3 Hospital inpatient care accounted for the largest portion (43%) of the total medical expenses. Patients with diagnosed diabetes incurred an average of $13,700 annually in medical expenditures, of which $7900 was attributed directly to diabetes.3

Overall, medical expenditures for patients with diabetes are 2.3 times higher than expenditures for persons without diabetes, with more than 1 in 5 healthcare dollars in the United States attributed to diabetes.3 Healthcare costs are expected to increase as the prevalence of diabetes rises in subsequent years. By the year 2034, the annual costs attributed to diabetes are projected to reach $336 billion (in 2007 US dollars).4

Glycemic Control

Improvements in glycemic control have been shown to benefit patients with diabetes.5 In fact, every 1% reduction in hemoglobin (Hb) A1c is correlated with a 35% decrease in microvascular complications associated with diabetes.5 A 1% reduction in HbA1c is also linked to a 15% relative risk reduction in nonfatal myocardial infarction, although this benefit does not extend to stroke or to all-cause mortality.6

In a 2012 position statement, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) reinforced the importance of a patient-centered approach to managing hyperglycemia in type 2 diabetes.6 The ADA and EASD also emphasize the role of diet, exercise, and education as the hallmarks of type 2 diabetes treatment. Other recommendations include tailoring glycemic targets and glucose therapies to the individual patient and engaging patients in healthcare decisions—an approach that may improve adherence to treatment.6

For initial treatment of patients with type 2 diabetes, the ADA and EASD recommend lifestyle changes (ie, healthy eating, weight control, increased physical activity) and metformin monotherapy.6 If the target A1c goal is not achieved within 3 months, a 2-drug combination therapy with metformin plus one of the following agents is recommended: a sulfonyl­urea, a thiazolidinedione, a dipeptidyl peptidase (DPP)-4 inhibitor, a glucagon-like peptide (GLP)-1 receptor agonist, or insulin (usually basal).6

If an individualized A1c target is not achieved after 3 months, a 3-drug combination is recommended; and if the target A1c is not achieved after 3 to 6 months, a more complex insulin strategy is warranted, usually in combination with 1 or 2 noninsulin agents.6

Three New Agents for Type 2 Diabetes

On January 25, 2013, the US Food and Drug Administration (FDA) approved 3 new oral agents for use with diet and exercise to improve glycemic control in adults with type 2 diabetes—alogliptin (Nesina; Takeda Pharmaceuticals), alogliptin/metformin hydrochloride (Kazano; Takeda Pharmaceuticals), and alogliptin/pioglitazone (Oseni; Takeda Pharmaceuticals).7 (Metformin and pioglitazone have been previously approved by the FDA for the management of type 2 diabetes.) All 3 agents contain the new DPP-4 inhibitor alogliptin, and none of them is indicated for the treatment of patients with type 1 diabetes or with diabetic ketoacidosis.8-11

Nesina is the single alogliptin agent; Kazano is a fixed-dose combination of alogliptin and metformin, a biguanide; and Oseni is a fixed-dose combination of alogliptin and pioglit­azone, a thiazolidinedione.7

According to Mary Parks, MD, Director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, “Controlling blood sugar levels is very important in the overall treatment and care of diabetes. Alogliptin helps stimulate the release of insulin after a meal, which leads to better blood sugar control.”7

Nesina (alogliptin)

Dosing
Alogliptin (Nesina) is an oral tablet available in 3 strengths—25 mg, 12.5 mg, and 6.25 mg. The recommended dose for patients with normal renal function or with mild renal impairment is 25 mg once daily. Alogliptin can be taken with or without food. If the patient has moderate or severe renal impairment, the dose should be adjusted.9

Mechanism of Action
Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin hormones GLP-1 and glucose-dependent insulinotropic polypeptide, thereby increasing their bloodstream concentrations in a glucose-dependent manner in patients with type 2 dia­betes. Alogliptin selectively binds to and inhibits DPP-4 (but not DPP-8 or DPP-9) activity in vitro at concentrations approximating therapeutic exposures.9

Clinical Studies
The FDA approval of alogliptin as monotherapy (Nesina) was based on safety and efficacy data from 14 clini­cal studies with approximately 8500 patients with type 2 diabetes.7 With its approval, the FDA required 5 postmarketing studies for alogliptin—1 a cardiovascular outcomes trial; 2 enhanced pharmacovigilance programs to monitor liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions; and 2 pediatric safety and efficacy studies under the Pediatric Research Equity Act.7

The safety and efficacy of alogliptin as monotherapy were evaluated in a 26-week, double-blind, placebo-controlled study in patients with type 2 diabetes inadequately controlled with diet and exercise. Treatment with alogliptin 25 mg demonstrated statistically significant improvements from baseline in A1c and fasting plasma glucose compared with placebo at week 26 (Table 1).9



Adverse Events
The most common adverse reactions reported in ≥4% of patients receiving alogliptin 25 mg that were also more frequent than in the placebo arm were nasopharyngitis, headache, and upper respiratory tract infection (Table 2).9



In clinical trials that compared alogliptin and placebo, adverse events included acute pancreatitis (0.2% vs <0.1%, respectively), hypersensitivity (0.6% vs 0.8%, respectively), and hypoglycemia (1.5% vs 1.6%, respectively).

Table 3 outlines the warnings and precautions associated with the use of alogliptin based on clinical trials, as well as postmarketing studies.





Contraindications
Alogliptin is contraindicated in patients with a history of a serious hypersensitivity reaction to alogliptin-­containing products, including ana­phylaxis, angioedema, or severe cutaneous adverse reactions. Alogliptin is not associated with a boxed warning.

Kazano (alogliptin/metformin)

Dosing
Alogliptin/metformin (Kazano) is an oral tablet available in 2 strengths—alogliptin 12.5 mg/metformin 500 mg, and alogliptin 12.5 mg/metformin 1000 mg.

The starting dose of alogliptin/metformin is individualized based on the patient’s current regimen. Alo­gliptin/metformin is taken twice daily with food. Dosing may be adjusted based on effectiveness and tolerability, without exceeding the maximum recommended daily dose of alogliptin 25 mg/metformin 2000 mg.8

Mechanism of Action
The combination of alogliptin and metformin hydrochloride—2 antihyperglycemic agents with complementary and distinct mechanisms of action—improves glycemic control in patients with type 2 diabetes.8

The alogliptin mechanism of action was discussed earlier in this article.

Metformin is a biguanide that improves glucose tolerance in patients with type 2 diabetes, lowering basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Metformin does not produce hypoglycemia in patients with type 2 diabetes or in healthy persons, except in special circumstances, and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged and fasting insulin levels and day-long plasma insulin response may actually decrease.8

Clinical Studies
The FDA approval of alogliptin/metformin was based on 4 clinical studies in more than 2500 patients with type 2 diabetes.7 The FDA required that 2 postmarketing studies be conducted with alogliptin/metformin to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions through an enhanced pharmacovigilance program. A pediatric safety and efficacy study under the Pediatric Research Equity Act was also required by the FDA.7

A 26-week, double-blind, placebo-controlled study assessed the safety and efficacy of alogliptin/metformin coadministration in patients whose type 2 diabetes was inadequately controlled with diet and exercise alone. A total of 784 patients (mean baseline A1c, 8.4%) were randomized to 1 of 7 treatment groups.

Significant improvements in A1c levels were demonstrated in the 2 combination treatment arms—alogliptin 12.5 mg/metformin 500 mg, and alogliptin 12.5 mg/metformin 1000 mg compared with the respective individual component regimens of alogliptin alone and metformin alone (Table 4).



Significant improvements in fasting plasma glucose were also demonstrated in the 2 treatment arms of alogliptin/metformin versus the respective individual component regimens of each drug alone (Table 4).8

In a 26-week, double-blind, placebo-controlled study, 527 patients already receiving metformin (mean baseline A1c, 8%) were randomized to receive alogliptin 12.5 mg, alogliptin 25 mg, or placebo once daily. During the treatment period, patients continued to use a stable dose of metformin (median daily dose, 1700 mg).

Alogliptin 25 mg in combination with metformin showed statistically significant improvements from baseline in A1c and fasting plasma glucose levels at week 26 compared with placebo (Table 5).8



A 52-week study with 803 patients showed that alogliptin 25 mg, in combination with pioglitazone and metformin, was statistically superior in lowering A1c and fasting plasma glucose levels compared with the titration of pioglitazone from 30 mg to 45 mg at week 26 and at week 52 in patients whose disease was inadequately controlled with pioglitazone 30 mg and metformin.8

Adverse Events
The most common adverse reactions reported in clinical trials in ≥4% of patients using alogliptin/metformin were upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, back pain, and urinary tract infection.8 Table 3 lists the warnings and precautions associated with alogliptin/metformin, based on clinical studies, as well as in postmarketing studies.

Boxed Warning
Alogliptin/metformin was approved with a boxed warning about lactic acidosis, a rare but serious complication that can occur from metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure. If acidosis is suspected, alogliptin/metformin should be discontinued and the patient should be hospitalized immediately.

Contraindications
Alogliptin/metformin is contraindicated in patients with renal impairment; normal renal function should be verified before initiating treatment with this medication, and at least annually thereafter.

The use of alogliptin/metformin is also contraindicated in patients with metabolic acidosis, including diabetic ketoacidosis.

In addition, alogliptin/metformin is contraindicated in patients with a history of a serious hypersensitivity reaction to alogliptin or to metformin (the components of alogliptin/metformin), such as anaphylaxis, angioedema, or severe cutaneous adverse reactions.

Oseni (alogliptin/pioglitazone)

Dosing
Alogliptin/pioglitazone (Oseni) is an oral tablet available in several strengths: alogliptin 25 mg/pioglitazone 15 mg, alogliptin 25 mg/pioglit­azone 30 mg, alogliptin 25 mg/pio­glitazone 45 mg, alogliptin 12.5 mg/pioglitazone 15 mg, alogliptin 12.5 mg/pioglitazone 30 mg, and alogliptin 12.5 mg/pioglitazone 45 mg.

The starting dose of alogliptin/pioglitazone should be individualized based on the patient’s current regimen and concurrent medical condition but should not exceed a daily dose of alogliptin 25 mg and pioglitazone 45 mg. Alogliptin/pioglitazone can be taken with or without food.

In patients with New York Heart Association (NYHA) class I or II heart failure, the initial dose of pio­glitazone should be limited to 15 mg once daily.

In patients with moderate renal impairment, the dose of alogliptin/pioglitazone should be adjusted. Alogliptin/pioglitazone is not recommended for patients with severe renal impairment or with end-stage renal disease that requires dialysis. In patients taking strong cytochrome (CY)P2C8 inhibitors (eg, gemfibrozil), the maximum recommended dose of pioglitazone is 15 mg once daily.10

Mechanism of Action
The combination of 2 antihyperglycemic agents—alogliptin and pioglitazone—with 2 complementary and distinct mechanisms of action improves glycemic control in patients with type 2 diabetes.10 The alogliptin mechanism of action was discussed earlier.

Pioglitazone, a thiazolidinedione, is an agonist for peroxisome proliferator-activated receptor gamma; activation of these nuclear receptors modulates the transcription of a number of insulin-responsive genes involved in the control of glucose and lipid metabolism.10

Clinical Studies
The FDA approval of alogliptin/pioglitazone (Oseni) was based on 4 clinical studies in more than 1500 patients with type 2 diabetes.7 The FDA required an enhanced pharmacovigilance program for alogliptin/pioglit­azone to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions.7

Based on a 26-week, double-blind, active-controlled study of 655 patients whose disease was inadequately controlled with diet and exercise alone, the coadministration of alogliptin 25 mg with pioglitazone 30 mg showed a significant improvement from baseline in A1c and fasting plasma glucose compared with alogliptin 25 mg alone or with pioglitazone 30 mg alone (Table 6).10



In a 26-week, double-blind, placebo-controlled study, 1554 patients already receiving metformin (mean baseline A1c, 8.5%) were randomized to 1 of 12 groups—placebo; alogliptin alone (12.5 mg or 25 mg); pioglitazone alone (15 mg, 30 mg, or 45 mg); or alogliptin (12.5 mg or 25 mg) in combination with 15 mg, 30 mg, or 45 mg of pio­glitazone. During the treatment period, patients continued to take a stable dose of metformin (median daily dose, 1700 mg).

When added to metformin, the coadministration of alogliptin and pio­glitazone showed significant improvements from baseline in A1c and fasting plasma glucose levels at week 26 compared with placebo, with alogliptin alone, or with pioglitazone alone.10

In a 52-week study of 803 patients, adding alogliptin 25 mg to pioglitazone used in combination with metformin was statistically superior in lowering A1c and fasting plasma glucose levels compared with the titration of pioglitazone from 30 mg to 45 mg at weeks 26 and 52 in patients whose disease was inadequately controlled with pioglitazone 30 mg plus metformin.10

Adverse Events
The most common adverse reactions reported in ≥4% of patients receiving coadministration of alo­gliptin 25 mg and pioglitazone 15 mg, 30 mg, or 45 mg in clinical trials were nasopharyngitis, back pain, and up­per respiratory tract infection.10 Table 3 provides additional safety information, including the warnings and precautions associated with the use of alogliptin/pioglitazone, based on clinical trials, and in postmarketing studies.

Boxed Warning
Alogliptin/pioglitazone was approved with a boxed warning, stating that thiazolidinediones, including pio­glitazone, cause or exacerbate congestive heart failure in some patients. In addition, alogliptin/pioglitazone should be used with caution in patients with liver disease.

Contraindications
Alogliptin/pioglitazone is contraindicated in patients with a serious hypersensitivity reaction to alogliptin or pioglitazone, such as anaphylaxis, angioedema, or severe cutaneous adverse reactions. Alogliptin/pioglitazone is also contraindicated in patients with established NYHA class III or IV heart failure.

Conclusion

Three new oral treatment options for type 2 diabetes became available in 2013 with the FDA approval of alogliptin alone, alogliptin in combination with metformin, and alogliptin in combination with pio­glitazone. These 3 independent agents are indicated as adjuncts to diet and exercise to improve glycemic control in patients with type 2 diabetes. They are not indicated for use in patients with type 1 diabetes or with diabetic ketoacidosis. Each of these 3 medications has unique benefits and potential adverse events and contraindications, based on the individual components of the specific medication.

All 3 agents contain alogliptin, a novel DPP-4 inhibitor, with a positive safety profile. Of these new agents, the novel fixed-dose combination of alogliptin plus pioglit­azone is the first treatment option in the United States to include a DPP-4 inhibitor and a thiazolidinedione in a single tablet,11 providing patients with type 2 diabetes a new approach to glycemic control.

In clinical studies that evaluated the efficacy of alogliptin alone, alogliptin/metformin combination, and alogliptin/pioglitazone combination plus other type 2 diabetes treatments, all 3 agents demonstrated clinically meaningful and significant improvements in patients’ HbA1c levels versus comparators in patients with type 2 diabetes.

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 April 15, 2013.
  2. Boyle JP, Thompson TJ, Gregg EW, et al. Projection of the year 2050 burden of diabetes in the US 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 US in 2012. Diabetes Care. 2013;36:1033-1046.
  4. Huang ES, Basu A, O’Grady M, Capretta JC. Projecting the future diabetes population size and related costs for the US. Diabetes Care. 2009;32:2225-2229.
  5. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 1998;21:2180-2184.
  6. Inzucchi SE, Bergenstal RM, Buse JB, et al; American Diabetes Association (ADA), European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-1379. Erratum in Diabetes Care. 2013;36:490.
  7. US Food and Drug Administration. FDA approves three new drug treatments for type 2 diabetes. News release; January 25, 2013. Updated January 28, 2013. www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm336942.htm. Accessed April 16, 2013.
  8. Kazano (alogliptin and metformin HCl) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013.
  9. Nesina (alogliptin) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013.
  10. Oseni (alogliptin and pioglitazone) tablets [prescribing information]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; 2013.
  11. Nordqvist J. Three type 2 diabetes pills from Takeda approved by FDA. Medical News Today. January 27, 2013. www.medicalnewstoday.com/articles/255487.php. Accessed April 15, 2013.
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