Nesina Drug Information
Generic name: ALOGLIPTIN
Uses of Nesina
® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. NESINA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: Should not be used in patients with type 1 diabetes mellitus.
Limitations of Use NESINA is not recommended for use in patients with type 1 diabetes mellitus.
Dosage & Administration of Nesina
| Moderate | ≥30 to <60 |
|---|---|
| Severe/ESRD | <30 |
Side Effects of Nesina
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 14,778 patients with type 2 diabetes mellitus participated in 14 randomized, double-blind, controlled clinical trials of whom 9,052 subjects were treated with NESINA, 3,469 subjects were treated with placebo and 2,257 were treated with an active comparator. The racial distribution of patients exposed to trial medication was 71% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups.
The ethnic distribution was 30% Hispanic or Latino and 70% was not Hispanic or Latino. The mean duration of diabetes mellitus was seven years, the mean body mass index (BMI) was 31 kg/m 2 (49% of patients had a BMI ≥30 kg/m 2 ), and the mean age was 58 years (26% of patients ≥65 years of age). The mean exposure to NESINA was 49 weeks with 3,348 subjects treated for more than one year. In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse reactions was 73% in patients treated with NESINA 25 mg compared to 75% with placebo and 70% with active comparator.
Overall discontinuation of therapy due to adverse reactions was 6.8% with NESINA 25 mg compared to 8.4% with placebo or 6.2% with active comparator. Adverse reactions reported in ≥4% of adult patients treated with NESINA 25 mg and more frequently than in patients who received placebo are summarized in Table 1. Table 1. Adverse Reactions Reported in ≥4% of Adult Patients with Type 2 Diabetes Mellitus Treated with NESINA 25 mg and More Frequently Than in Patients Given Placebo in Pooled Trials Number of Patients (%) NESINA 25 mg Placebo Active Comparator N=6447 N=3469 N=2257 Nasopharyngitis 309 152 113 Upper Respiratory Tract Infection 287 121 113 Headache 278 101 121 Hypoglycemia Hypoglycemic events were documented based upon a blood glucose value and/or clinical signs and symptoms of hypoglycemia. In the monotherapy trial, the incidence of hypoglycemia was 1.5% in patients treated with NESINA compared to 1.6% with placebo.
The use of NESINA as add-on therapy to glyburide or insulin did not increase the incidence of hypoglycemia compared to placebo. In a monotherapy trial comparing NESINA to a sulfonylurea in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared to 26% with glipizide (Table 2). Table 2. Incidence and Rate of Hypoglycemia Adverse reactions of hypoglycemia were based on all reports of symptomatic and asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to-treat population in Placebo and Active-Controlled Trials in Adults with Type 2 Diabetes Mellitus when NESINA Was Used as Add-On Therapy to Glyburide, Insulin, Metformin, Pioglitazone or Compared to Glipizide or Metformin Add-On to Glyburide (26 Weeks) NESINA 25 mg Placebo N=198 N=99 Overall (%) 19 11 Severe (%) Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level or loss of consciousness or seizure 0 1 Add-On to Insulin (± Metformin) (26 Weeks) NESINA 25 mg Placebo N=129 N=129 Overall (%) 35 31 Severe (%) 1 2 Add-On to Metformin (26 Weeks) NESINA 25 mg Placebo N=207 N=104 Overall (%) 0 3 Severe (%) 0 0 Add-On to Pioglitazone (± Metformin or Sulfonylurea) (26 Weeks) NESINA 25 mg Placebo N=199 N=97 Overall (%) 14 5 Severe (%) 0 1 Compared to Glipizide (52 Weeks) NESINA 25 mg Glipizide N=222 N=219 Overall (%) 12 57 Severe (%) 0 3 Compared to Metformin (26 Weeks) NESINA 25 mg Metformin 500 mg twice daily N=112 N=109 Overall (%) 2 2 Severe (%) 0 0 Add-On to Metformin Compared to Glipizide (52 Weeks) NESINA 25 mg Glipizide N=877 N=869 Overall (%) 12 207 Severe (%) 0 4 In the EXAMINE trial, the incidence of investigator reported hypoglycemia was 6.7% in patients receiving NESINA and 6.5% in patients receiving placebo. Serious adverse reactions of hypoglycemia were reported in 0.8% of patients treated with NESINA and in 0.6% of patients treated with placebo.
Renal Impairment In glycemic control trials in patients with type 2 diabetes mellitus, 3.4% of patients treated with NESINA and 1.3% of patients treated with placebo had renal function adverse reactions. The most commonly reported adverse reactions were renal impairment (0.5% for NESINA and 0.1% for active comparators or placebo), decreased creatinine clearance (1.6% for NESINA and 0.5% for active comparators or placebo) and increased blood creatinine (0.5% for NESINA and 0.3% for active comparators or placebo) . In the EXAMINE trial of high CV risk type 2 diabetes mellitus patients, 23% of patients treated with NESINA and 21% of patients treated with placebo had an investigator reported renal impairment adverse reaction. The most commonly reported adverse reactions were renal impairment (7.7% for NESINA and 6.7% for placebo), decreased glomerular filtration rate (4.9% for NESINA and 4.3% for placebo) and decreased renal clearance (2.2% for NESINA and 1.8% for placebo). Laboratory measures of renal function were also assessed.
Estimated glomerular filtration rate decreased by 25% or more in 21.1% of patients treated with NESINA and 18.7% of patients treated with placebo. Worsening of chronic kidney disease stage was seen in 16.8% of patients treated with NESINA and in 15.5% of patients treated with placebo.
Postmarketing Experience
The following adverse reactions have been identified during the postmarketing use of NESINA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: acute pancreatitis, diarrhea, constipation, nausea, ileus Hepatobiliary Disorders: fulminant hepatic failure Immune System Disorders: hypersensitivity reactions including anaphylaxis Investigations: hepatic enzyme elevations Musculoskeletal and Connective Tissue Disorders: severe and disabling arthralgia, rhabdomyolysis Renal and Urinary Disorders: tubulointerstitial nephritis Skin and Subcutaneous Tissue Disorders: angioedema, rash, urticaria and severe cutaneous adverse reactions including Stevens-Johnson syndrome, bullous pemphigoid
Warnings & Cautions for Nesina
Pancreatitis Acute pancreatitis has been reported in the postmarketing setting and in
randomized clinical trials. In glycemic control trials in patients with type 2 diabetes mellitus, acute pancreatitis was reported in 6 (0.2%) patients treated with NESINA 25 mg and 2 (<0.1%) patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), acute pancreatitis was reported in 10 (0.4%) of patients treated with NESINA and in 7 (0.3%) of patients treated with placebo.
It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using NESINA. After initiation of NESINA, patients should be observed for signs and symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be discontinued and appropriate management should be initiated.
Heart Failure
In the EXAMINE trial which enrolled patients with type 2 diabetes mellitus and recent acute coronary syndrome, 106 (3.9%) of patients treated with NESINA and 89 (3.3%) of patients treated with placebo were hospitalized for congestive heart failure. Consider the risks and benefits of NESINA prior to initiating treatment in patients at risk for heart failure, such as those with a prior history of heart failure and a history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Patients should be advised of the characteristic symptoms of heart failure and should be instructed to immediately report such symptoms.
If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of NESINA.
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions in patients treated with NESINA . These reactions include anaphylaxis, angioedema and severe cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, discontinue NESINA, assess for other potential causes for the event and institute alternative treatment for diabetes mellitus. Use caution in patients with a history of angioedema with another dipeptidyl peptidase-4 (DPP-4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with NESINA.
Hepatic Effects
There have been postmarketing reports of fatal and nonfatal hepatic failure in patients taking NESINA, although some of the reports contain insufficient information necessary to establish the probable cause . In glycemic control trials in patients with type 2 diabetes mellitus, serum alanine aminotransferase (ALT) elevations greater than three times the upper limit of normal (ULN) were reported in 1.3% of patients treated with NESINA 25 mg and 1.7% of patients treated with active comparators or placebo. In the EXAMINE trial (a cardiovascular outcomes trial of patients with type 2 diabetes mellitus and high cardiovascular (CV) risk), increases in serum alanine aminotransferase three times the upper limit of the reference range occurred in 2.4% of patients treated with NESINA and in 1.8% of patients treated with placebo. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
In this clinical context, if the patient is found to have clinically significant liver enzyme elevations and if abnormal liver tests persist or worsen, NESINA should be interrupted and investigation done to establish the probable cause. NESINA should not be restarted in these patients without another explanation for the liver test abnormalities.
Hypoglycemia with
Concomitant Use with Insulin or Insulin Secretagogues Insulin and insulin secretagogues, such as sulfonylureas, are known to cause hypoglycemia. Therefore, a lower dosage of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with NESINA.
Severe and Disabling Arthralgia
There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication.
A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
Bullous Pemphigoid Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported
with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving NESINA. If bullous pemphigoid is suspected, NESINA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Drug Interactions with Nesina
Insulin Secretagogues and Insulin Insulin and insulin secretagogues are known to cause
hypoglycemia. Coadministration of NESINA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower dosages of the insulin secretagogue and insulin to reduce the risk of hypoglycemia .
Pregnancy Safety for Nesina
Pregnancy Risk Summary Limited data with NESINA in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy . No adverse developmental effects were observed when alogliptin was administered to pregnant rats and rabbits during organogenesis at exposures 180- and 149-times the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes mellitus with a HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations Disease-associated Maternal and/or Embryo/Fetal Risk Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Animal Data Alogliptin administered to pregnant rabbits and rats during the period of organogenesis did not cause adverse developmental effects at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180 times, the 25 mg clinical dose, respectively, based on plasma drug exposure (AUC). Placental transfer of alogliptin into the fetus was observed following oral dosing to pregnant rats.
No adverse developmental outcomes were observed in offspring when alogliptin was administered to pregnant rats during gestation and lactation at doses up to 250 mg/kg (~95 times the 25 mg clinical dose, based on AUC).
Pediatric Use of Nesina
Pediatric Use The safety and effectiveness of NESINA have not been established in pediatric patients. Effectiveness of NESINA was not demonstrated in a 52 week, randomized, double-blind, placebo-controlled trial (NCT02856113) in 151 pediatric patients aged 10 to 17 years with inadequately controlled type 2 diabetes mellitus.
Contraindications for Nesina
is contraindicated in patients with a history of serious hypersensitivity to alogliptin or any of the excipients in NESINA. Reactions such as anaphylaxis, angioedema and severe cutaneous adverse reactions have been reported . History of serious hypersensitivity to alogliptin or any of the excipients in NESINA.
Overdosage Information for Nesina
In the event of an overdose, it is reasonable to institute the necessary clinical monitoring and supportive therapy as dictated by the patient's clinical status. Per clinical judgment, it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal tract. Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately 7% of the drug was removed.
Therefore, hemodialysis is unlikely to be beneficial in an overdose situation. It is not known if NESINA is dialyzable by peritoneal dialysis. In the event of an overdose, contact the Poison Help Line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.
Clinical Studies of Nesina
Overview of Clinical Trials in Adults with Type 2 Diabetes Mellitus
NESINA has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione (either alone or in combination with metformin or a sulfonylurea) and insulin (either alone or in combination with metformin). A total of 14,053 patients with type 2 diabetes mellitus were randomized in 11 double-blind, placebo- or active-controlled clinical safety and efficacy trials conducted to evaluate the effects of NESINA on glycemic control. The racial distribution of patients exposed to trial medication was 70% White, 17% Asian, 6% Black or African American, 2% American Indian or Alaska Native, 0% Native Hawaiian/Other Pacific Islander and 5% Multiracial or other racial groups. The ethnic distribution was 30% Hispanic or Latino.
Patients had an overall mean age of 57 years (range 21 to 91 years). In patients with type 2 diabetes mellitus, treatment with NESINA produced clinically meaningful and statistically significant improvements in hemoglobin A1c (A1C) compared to placebo. As is typical for trials of agents to treat type 2 diabetes mellitus, the mean reduction in A1C with NESINA appears to be related to the degree of A1C elevation at baseline. NESINA had similar changes from baseline in serum lipids compared to placebo.
Patients with Inadequate Glycemic Control on Diet and Exercise
A total of 1,768 patients with type 2 diabetes mellitus participated in three double-blind trials to evaluate the efficacy and safety of NESINA in patients with inadequate glycemic control on diet and exercise. All three trials had a four week, single-blind, placebo run-in period followed by a 26 week randomized treatment period. Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment periods received glycemic rescue therapy.
In a 26 week, double-blind, placebo-controlled trial, a total of 329 patients (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo once daily. Treatment with NESINA 25 mg resulted in statistically significant improvements from baseline in A1C and fasting plasma glucose (FPG) compared to placebo at Week 26 (Table 3). A total of 8% of patients receiving NESINA 25 mg and 30% of those receiving placebo required glycemic rescue therapy. Improvements in A1C were not affected by gender, age or baseline body mass index (BMI). The mean change in body weight with NESINA was similar to placebo.
Table 3. Glycemic Parameters at Week 26 in a Placebo-Controlled Monotherapy Trial of NESINA Intent-to-treat population using last observation in the trial NESINA 25 mg Placebo A1C (%) N=128 N=63 Baseline (mean) 7.9
Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline
value, geographic region and duration of diabetes mellitus ) -0.6 0 Difference from placebo (adjusted mean with 95% confidence interval) -0.6 p<0.01 compared to placebo (-0.8, -0.3) ˗ % of patients (n/N) achieving A1C ≤7% 44% (58/131) 23% (15/64) FPG (mg/dL) N=129 N=64 Baseline (mean) 172 173 Change from baseline (adjusted mean ) -16 11 Difference from placebo (adjusted mean with 95% confidence interval) -28 (-40, -15) ˗ In a 26 week, double-blind, active-controlled trial, a total of 655 patients (mean baseline A1C = 8.8%) were randomized to receive NESINA 25 mg alone, pioglitazone 30 mg alone, NESINA 12.5 mg with pioglitazone 30 mg or NESINA 25 mg with pioglitazone 30 mg once daily. Coadministration of NESINA 25 mg with pioglitazone 30 mg resulted in statistically significant improvements from baseline in A1C and FPG compared to NESINA 25 mg alone and to pioglitazone 30 mg alone (Table 4). A total of 3% of patients receiving NESINA 25 mg coadministered with pioglitazone 30 mg, 11% of those receiving NESINA 25 mg alone and 6% of those receiving pioglitazone 30 mg alone required glycemic rescue. Improvements in A1C were not affected by gender, age or baseline BMI. The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone.
Table 4. Glycemic Parameters at Week 26 in an Active-Controlled Trial of NESINA, Pioglitazone, and NESINA in Combination with Pioglitazone Intent-to-treat population using last observation carried forward NESINA 25 mg Pioglitazone 30 mg NESINA 25 mg + Pioglitazone 30 mg A1C (%) N=160 N=153 N=158 Baseline (mean) 8.8 8.8
Change from baseline (adjusted mean Least squares means adjusted for treatment, geographic
region and baseline value ) -1.0 -1.2 -
Difference from
NESINA 25 mg (adjusted mean with 95% confidence interval) ˗ ˗ -0.8 p<0.01 compared to NESINA 25 mg or pioglitazone 30 mg (-1.0, -0.5) Difference from pioglitazone 30 mg (adjusted mean with 95% confidence interval) ˗ ˗ -0.6 (-0.8, -0.3) % of patients (n/N) achieving A1C ≤7% 24% (40/164) 34% (55/163) 63% (103/164) FPG (mg/dL) N=162 N=157 N=162 Baseline (mean) 189 189 185 Change from baseline (adjusted mean ) -26 -37 -50 Difference from NESINA 25 mg (adjusted mean with 95% confidence interval) ˗ ˗ -24 (-34, -15) Difference from pioglitazone 30 mg (adjusted mean with 95% confidence interval) ˗ ˗ -13 (-22, -4) In a 26 week, double-blind, placebo-controlled trial, a total of 784 patients inadequately controlled on diet and exercise alone (mean baseline A1C = 8.4%) were randomized to one of seven treatment groups: placebo; metformin HCl 500 mg or metformin HCl 1000 mg twice daily; NESINA 12.5 mg twice daily; NESINA 25 mg daily; or NESINA 12.5 mg in combination with metformin HCl 500 mg or metformin HCl 1000 mg twice daily. Both coadministration treatment arms (NESINA 12.5 mg + metformin HCl 500 mg and NESINA 12.5 mg + metformin HCl 1000 mg) resulted in statistically significant improvements in A1C and FPG when compared with their respective individual alogliptin and metformin component regimens (Table 5). Coadministration treatment arms demonstrated improvements in two hour postprandial glucose (PPG) compared to NESINA alone or metformin alone (Table 5). A total of 12.3% of patients receiving NESINA 12.5 mg + metformin HCl 500 mg, 2.6% of patients receiving NESINA 12.5 mg + metformin HCl 1000 mg, 17.3% of patients receiving NESINA 12.5 mg, 22.9% of patients receiving metformin HCl 500 mg, 10.8% of patients receiving metformin HCl 1000 mg and 38.7% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean decrease in body weight was similar between metformin alone and NESINA when coadministered with metformin.
Table 5. Glycemic Parameters at Week 26 for NESINA and Metformin Alone and in Combination in Adult Patients with Type 2 Diabetes Mellitus Placebo NESINA 12.5 mg Twice Daily Metformin HCl 500 mg Twice Daily Metformin HCl 1000 mg Twice Daily NESINA 12.5 mg + Metformin HCl 500 mg Twice Daily NESINA 12.5 mg + Metformin HCl 1000 mg Twice Daily A1C (%) Intent-to-treat population using last observation on trial prior to discontinuation of double-blind trial medication or sulfonylurea rescue therapy for patients needing rescue N=102 N=104 N=103 N=108 N=102 N=111 Baseline (mean) 8.5 8.4 8.5 8.4 8.5
Change from baseline (adjusted mean Least squares means adjusted for treatment, geographic
region and baseline value ) 0.1 -0.6 -0.7 -1.1 -1.2 -
Difference from metformin (adjusted mean with 95% confidence interval) - - -
- -0.6 p<0.05 when compared to metformin and NESINA alone (-0.9, -0.3) -0.4 (-0.7, -0.2) Difference from NESINA (adjusted mean with 95% confidence interval) - - - - -0.7 (-1.0, -0.4) -1.0 (-1.3, -0.7) % of patients (n/N) achieving A1C <7% Compared using logistic regression 4% (4/102) 20% (21/104) 27% (28/103) 34% (37/108) 47% (48/102) 59% (66/111) FPG (mg/dL) N=105 N=106 N=106 N=110 N=106 N=112 Baseline (mean) 187 177 180 181 176 185 Change from baseline (adjusted mean ) 12 -10 -12 -32 -32 -46 Difference from metformin (adjusted mean with 95% confidence interval) - - - - -20 (-33, -8) -14 (-26, -2) Difference from NESINA (adjusted mean with 95% confidence interval) - - - - -22 (-35, -10) -36 (-49, -24) 2-Hour PPG (mg/dL) Intent-to-treat population using data available at Week 26 N=26 N=34 N=28 N=37 N=31 N=37 Baseline (mean) 263 272 247 266 261 268 Change from baseline (adjusted mean ) -21 -43 -49 -54 -68 -86 Difference from metformin (adjusted mean with 95% confidence interval) - - - - -19 (-49, 11) -32 (-58, -5) Difference from NESINA (adjusted mean with 95% confidence interval) - - - - -25 (-53, -3) -43 (-70, -16)
Combination Therapy Add-On Therapy to Metformin
A total of 2081 patients with type 2 diabetes mellitus participated in two 26 week, double-blind, placebo-controlled trials to evaluate the efficacy and safety of NESINA as add-on therapy to metformin. In both trials, patients were inadequately controlled on metformin at a dose of at least 1500 mg per day or at the maximum tolerated dose. All patients entered a four week, single-blind placebo run-in period prior to randomization.
Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment periods received glycemic rescue therapy. In the first 26 week, placebo-controlled trial, a total of 527 patients already on metformin (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period.
NESINA 25 mg in combination with metformin resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 6). A total of 8% of patients receiving NESINA 25 mg and 24% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, baseline BMI or baseline metformin dose. The mean decrease in body weight was similar between NESINA and placebo when given in combination with metformin.
Table 6. Glycemic Parameters at Week 26 in a Placebo-Controlled Trial of NESINA as Add-On Therapy to Metformin in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on trial NESINA 25 mg + Metformin Placebo + Metformin A1C (%) N=203 N=103 Baseline (mean) 7.9
Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline
value, geographic region and baseline metformin dose ) -0.6 -
Difference from placebo (adjusted mean with 95% confidence interval) -0.5 p<0.001 compared
to placebo (-0.7, -0.3) ˗ % of patients (n/N) achieving A1C ≤7% 44% (92/207) 18% (19/104) FPG (mg/dL) N=204 N=104 Baseline (mean) 172 180 Change from baseline (adjusted mean ) -17 0 Difference from placebo (adjusted mean with 95% confidence interval) -17 (-26, -9) ˗ In the second 26 week, double-blind, placebo-controlled trial, a total of 1,554 patients already on metformin (mean baseline A1C = 8.5%) were randomized to one of 12 double-blind treatment groups: placebo; 12.5 mg or 25 mg of NESINA alone; 15 mg, 30 mg or 45 mg of pioglitazone alone; or 12.5 mg or 25 mg of NESINA in combination with 15 mg, 30 mg or 45 mg of pioglitazone. Patients were maintained on a stable dose of metformin (median dose = 1700 mg) during the treatment period. Coadministration of NESINA and pioglitazone provided statistically significant improvements in A1C and FPG compared to placebo, to NESINA alone or to pioglitazone alone when added to background metformin therapy (Table 7, Figure 3). In addition, improvements from baseline A1C were comparable between NESINA alone and pioglitazone alone (15 mg, 30 mg and 45 mg) at Week 26. A total of 4%, 5% or 2% of patients receiving NESINA 25 mg with 15 mg, 30 mg or 45 mg pioglitazone, 33% of patients receiving placebo, 13% of patients receiving NESINA 25 mg and 10%, 15% or 9% of patients receiving pioglitazone 15 mg, 30 mg or 45 mg alone required glycemic rescue.
Improvements in A1C were not affected by gender, age or baseline BMI. The mean increase in body weight was similar between pioglitazone alone and NESINA when coadministered with pioglitazone. Table 7. Glycemic Parameters in a 26 Week Trial of NESINA, Pioglitazone and NESINA in Combination with Pioglitazone when Added to Metformin in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation in the trial Placebo NESINA 25 mg Pioglitazone 15 mg Pioglitazone 30 mg Pioglitazone 45 mg NESINA 25 mg + Pioglitazone 15 mg NESINA 25 mg + Pioglitazone 30 mg NESINA 25 mg + Pioglitazone 45 mg A1C (%) N=126 N=123 N=127 N=123 N=126 N=127 N=124 N=126 Baseline (mean) 8.5 8.6 8.5 8.5 8.5 8.5 8.5
Change from baseline (adjusted mean Least squares means adjusted for treatment, geographic
region, metformin dose and baseline value ) -0.1 -0.9 -0.8 -0.9 -1.0 -1.3 p≤0.01 when compared to corresponding doses of pioglitazone and NESINA alone -1.4 -
Difference from pioglitazone (adjusted mean with 95% confidence interval) - - -
- -0.5 (-0.7, -0.3) -0.5 (-0.7, -0.3) -0.6 (-0.8, -0.4) Difference from NESINA (adjusted mean with 95% confidence interval) - - - - - -0.4 (-0.6, -0.1) -0.5 (-0.7, -0.3) -0.7 (-0.9, -0.5) Patients (%) achieving A1C ≤7% 6% (8/129) 27% (35/129) 26% (33/129) 30% (38/129) 36% (47/129) 55% (71/130) 53% (69/130) 60% (78/130) FPG (mg/dL) N=129 N=126 N=127 N=125 N=129 N=130 N=126 N=127 Baseline (mean) 177 184 177 175 181 179 179 178 Change from baseline (adjusted mean ) 7 -19 -24 -29 -32 -38 -42 -53 Difference from pioglitazone (adjusted mean with 95% confidence interval) - - - - - -14 (-24, -5) -13 (-23, -3) -20 (-30, -11) Difference from NESINA (adjusted mean with 95% confidence interval) - - - - - -19 (-29, -10) -23 (-33, -13) -34 (-44, -24) Figure 3. Change from Baseline in A1C at Week 26 with NESINA and Pioglitazone Alone and NESINA in Combination with Pioglitazone When Added to Metformin in Adults with Type 2 Diabetes Mellitus Figure 3 Add-On Therapy to a Thiazolidinedione In a 26 week, placebo-controlled trial, a total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10 mg) (mean baseline A1C = 8%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of pioglitazone (median dose = 30 mg) during the treatment period; those who were also previously treated on metformin (median dose = 2000 mg) or sulfonylurea (median dose = 10 mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a four week, single-blind placebo run-in period prior to randomization.
Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment period received glycemic rescue therapy. The addition of NESINA 25 mg once daily to pioglitazone therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, compared to placebo (Table 8). A total of 9% of patients who were receiving NESINA 25 mg and 12% of patients receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, baseline BMI or baseline pioglitazone dose.
Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin or sulfonylurea (-0.2% placebo versus -0.9% NESINA) therapy or pioglitazone alone (0% placebo versus -0.52% NESINA). The mean increase in body weight was similar between NESINA and placebo when given in combination with pioglitazone. Table 8. Glycemic Parameters in a 26 Week, Placebo-Controlled Trial of NESINA as Add-On Therapy to Pioglitazone in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on trial NESINA 25 mg + Pioglitazone ± Metformin ± Sulfonylurea Placebo + Pioglitazone ± Metformin ± Sulfonylurea A1C (%) N=195 N=95 Baseline (mean) 8 8 Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline value, geographic region, baseline treatment regimen (pioglitazone, pioglitazone + metformin or pioglitazone + sulfonylurea) and baseline pioglitazone dose ) -0.8 -
Difference from placebo (adjusted mean with 95% confidence interval) -0.6 p<0.01 compared
to placebo (-0.8, -0.4) ˗ % of patients (n/N) achieving A1C ≤7% 49% (98/199) 34% (33/97) FPG (mg/dL) N=197 N=97 Baseline (mean) 170 172 Change from baseline (adjusted mean ) -20 -6 Difference from placebo (adjusted mean with 95% confidence interval) -14 (-23, -5) ˗ Add-on Combination Therapy with Pioglitazone and Metformin In a 52 week, active-comparator trial, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin at least 1500 mg per day or at the maximum tolerated dose were randomized to either receive the addition of NESINA 25 mg or the titration of pioglitazone 30 mg to 45 mg following a four week, single-blind placebo run-in period. Patients were maintained on a stable dose of metformin (median dose = 1700 mg). Patients who failed to meet prespecified hyperglycemic goals during the 52 week treatment period received glycemic rescue therapy. In combination with pioglitazone and metformin, NESINA 25 mg was shown to be statistically superior in lowering A1C and FPG compared with the titration of pioglitazone from 30 mg to 45 mg at Week 26 and at Week 52 (Table 9; results shown only for Week 52). A total of 11% of patients in the NESINA 25 mg treatment group and 22% of patients in the pioglitazone up-titration group required glycemic rescue.
Improvements in A1C were not affected by gender, age, race or baseline BMI. The mean increase in body weight was similar in both treatment arms. Table 9. Glycemic Parameters in a 52 Week, Active-Controlled Trial of NESINA as Add-On Combination Therapy to Metformin and Pioglitazone in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation in the trial NESINA 25 mg + Pioglitazone 30 mg + Metformin Pioglitazone 45 mg + Metformin A1C (%) N=397 N=394 Baseline (mean) 8.2
Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline
value, geographic region and baseline metformin dose ) -0.7 -
Difference from pioglitazone 45 mg + metformin (adjusted mean with 95% confidence
interval) -
Noninferior and statistically superior to metformin + pioglitazone at the 0.025 one-sided
significance level (-0.5, -0.3) ˗ % of patients (n/N) achieving A1C≤7% 33% (134/404) p<0.001 compared to pioglitazone 45 mg + metformin 21% (85/399) Fasting Plasma Glucose (mg/dL) N=399 N=396 Baseline (mean) 162 162 Change from baseline (adjusted mean ) -15 -4 Difference from pioglitazone 45 mg + metformin (adjusted mean with 95% confidence interval) -11 (-16, -6) ˗ Add-On Therapy to a Sulfonylurea In a 26 week, placebo-controlled trial, a total of 500 patients inadequately controlled on a sulfonylurea (mean baseline A1C = 8.1%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on a stable dose of glyburide (median dose = 10 mg) during the treatment period. All patients entered into a four week, single-blind, placebo run-in period prior to randomization.
Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment period received glycemic rescue therapy. The addition of NESINA 25 mg to glyburide therapy resulted in statistically significant improvements from baseline in A1C at Week 26 when compared to placebo (Table 10). Improvements in FPG observed with NESINA 25 mg were not statistically significant compared with placebo. A total of 16% of patients receiving NESINA 25 mg and 28% of those receiving placebo required glycemic rescue.
Improvements in A1C were not affected by gender, age, baseline BMI or baseline glyburide dose. The mean change in body weight was similar between NESINA and placebo when given in combination with glyburide. Table 10. Glycemic Parameters in a 26 Week, Placebo-Controlled Trial of NESINA as Add-On Therapy to Glyburide in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation on trial NESINA 25 mg + Glyburide Placebo + Glyburide A1C (%) N=197 N=97 Baseline (mean) 8.1
Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline
value, geographic region and baseline glyburide dose ) -0.5 0 Difference from placebo (adjusted mean with 95% confidence interval) -0.5 p<0.01 compared to placebo (-0.7, -0.3) ˗ % of patients (n/N) achieving A1C ≤7% 35% (69/198) 18% (18/99) FPG (mg/dL) N=198 N=99 Baseline (mean) 174 177 Change from baseline (adjusted mean ) -8 2 Difference from placebo (adjusted mean with 95% confidence interval) -11 (-22, 1) ˗ Add-On Therapy to Insulin In a 26 week, placebo-controlled trial, a total of 390 patients inadequately controlled on insulin alone (42%) or in combination with metformin (58%) (mean baseline A1C = 9.3%) were randomized to receive NESINA 12.5 mg, NESINA 25 mg or placebo. Patients were maintained on their insulin regimen (median dose = 55 IU) upon randomization and those previously treated with insulin in combination with metformin (median dose = 1700 mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the trial on short-, intermediate- or long-acting (basal) insulin or premixed insulin.
Patients who failed to meet prespecified hyperglycemic goals during the 26 week treatment period received glycemic rescue therapy. The addition of NESINA 25 mg once daily to insulin therapy resulted in statistically significant improvements from baseline in A1C and FPG at Week 26, when compared to placebo (Table 11). A total of 20% of patients receiving NESINA 25 mg and 40% of those receiving placebo required glycemic rescue. Improvements in A1C were not affected by gender, age, baseline BMI or baseline insulin dose.
Clinically meaningful reductions in A1C were observed with NESINA compared to placebo regardless of whether subjects were receiving concomitant metformin and insulin (-0.2% placebo versus -0.8% NESINA) therapy or insulin alone (0.1% placebo versus -0.7% NESINA). The mean increase in body weight was similar between NESINA and placebo when given in combination with insulin. Table 11. Glycemic Parameters in a 26 Week, Placebo-Controlled Trial of NESINA as Add-On Therapy to Insulin in Adults with Type 2 Diabetes Mellitus Intent-to-treat population using last observation in the trial NESINA 25 mg + Insulin ± Metformin Placebo + Insulin ± Metformin A1C (%) N=126 N=126 Baseline (mean) 9.3
Change from baseline (adjusted mean Least squares means adjusted for treatment, baseline
value, geographic region, baseline treatment regimen (insulin or insulin + metformin) and baseline daily insulin dose ) -0.7 -
Difference from placebo (adjusted mean with 95% confidence interval) -0.6 p<0.05 compared
to placebo (-0.8, -0.4) ˗ % of patients (n/N) achieving A1C ≤7% 8% (10/129) 1% (1/129) FPG (mg/dL) N=128 N=127 Baseline (mean) 186 196 Change from baseline (adjusted mean ) -12 6 Difference from placebo (adjusted mean with 95% confidence interval) -18 (-33, -2) ˗
Cardiovascular Safety Trial
A randomized, double-blind, placebo-controlled cardiovascular outcomes trial (EXAMINE) was conducted to evaluate the cardiovascular risk of NESINA. The trial compared the risk of major adverse cardiovascular events (MACE) between NESINA (N=2701) and placebo (N=2679) when added to standard of care therapies for diabetes mellitus and atherosclerotic vascular disease (ASCVD). The trial was event driven and patients were followed until a sufficient number of primary outcome events accrued. Eligible patients were adults with type 2 diabetes mellitus who had inadequate glycemic control at baseline (e.g., HbA1c >6.5%) and had been hospitalized for an acute coronary syndrome event (e.g., acute myocardial infarction or unstable angina requiring hospitalization) 15 to 90 days prior to randomization. The dose of NESINA was based on estimated renal function at baseline per dosage and administration recommendations . The average time between an acute coronary syndrome event and randomization was approximately 48 days.
The mean age of the population was 61 years. Most patients were male (68%), White (73%), and were recruited from outside of the United States (86%). Asian and Black or African American patients contributed 20% and 4% of the total population, respectively. At the time of randomization patients had a diagnosis of type 2 diabetes mellitus for approximately 9 years, 87% had a prior myocardial infarction and 14% were current smokers.
Hypertension (83%) and renal impairment (27% with an eGFR ≤60 mL/min/1.73 m 2 ) were prevalent co-morbid conditions. Use of medications to treat diabetes mellitus (e.g., metformin 73%, sulfonylurea 54%, insulin 41%), and ASCVD (e.g., statin 94%, aspirin 93%, renin-angiotensin system blocker 88%, beta-blocker 87%) was similar between patients randomized to NESINA and placebo at baseline. During the trial, medications to treat diabetes mellitus and ASCVD could be adjusted to ensure care for these conditions adhered to standard of care recommendations set by local practice guidelines.
The primary endpoint in EXAMINE was the time to first occurrence of a MACE defined as the composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. The trial was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The median exposure to trial drug was 526 days and 95% of the patients were followed to trial completion or death. Table 12 shows the trial results for the primary MACE composite endpoint and the contribution of each component to the primary MACE endpoint.
The upper bound of the confidence interval was 1.16 and excluded a risk margin larger than 1.3. Table 12. Patients with MACE and Type 2 Diabetes Mellitus in EXAMINE Composite of first event of CV death, nonfatal MI or nonfatal stroke (MACE) NESINA Placebo Hazard Ratio Number of Patients (%) Rate per 100 PY Patient Years (PY) Number of Patients (%) Rate per 100 PY (98% CI) N=2701 N=2679 305 7.6 316 7.9 0.96 CV Death 89 2.2 111
Non-fatal MI 187 4.6 173 4.3 Non-fatal stroke 29 0.7 32 0.8
The Kaplan-Meier based cumulative event probability is presented in Figure 4 for the time to first occurrence of the primary MACE composite endpoint by treatment arm. The curves for placebo and NESINA overlap throughout the duration of the trial. The observed incidence of MACE was highest within the first 60 days after randomization in both treatment arms (
MACE per 100 PY), decreased from day 60 to the end of
the first year (8.4 per 100 PY) and was lowest after one year of follow-up (5.2 per 100 PY). Figure 4. Observed Cumulative Rate of MACE in EXAMINE The rate of all cause death was similar between treatment arms with 153 (3.6 per 100 PY) recorded among patients randomized to NESINA and 173 (4.1 per 100 PY) among patients randomized to placebo. A total of 112 deaths (2.9 per 100 PY) among patients on NESINA and 130 among patients on placebo (3.5 per 100 PY) were adjudicated as cardiovascular deaths. Figure 4
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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