Nesina

Instructions

May take with or without food

Nesina is part of the drug class:

• Dipeptidyl peptidase 4

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop taking alogliptin and call your doctor right away if you have symptoms of pancreatitis: severe pain in your upper stomach spreading to your back, nausea and vomiting, loss of appetite, or fast heartbeats.

Call your doctor at once if you have:

• severe or ongoing pain in your joints;

• heart problems--shortness of breath (even while lying down), rapid weight gain, swelling (especially in your feet, legs, or midsection);

• liver problems--nausea, upper stomach pain, tired feeling, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);

• a severe autoimmune reaction--itching, blisters, breakdown of the outer layer of skin; or

• severe skin reaction--fever, sore throat, swelling in your face or tongue, burning in your eyes, skin pain followed by a red or purple skin rash that spreads (especially in the face or upper body) and causes blistering and peeling.

Common side effects may include:

• headache; or

• cold symptoms such as stuffy nose, sinus pain, sore throat.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.1 13

• Inhibits DPP-4, an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 13

• Increases circulating concentrations of GLP-1 and GIP in a glucose-dependent manner.1

• GLP-1 and GIP stimulate insulin secretion from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are elevated).1

• GLP-1 also decreases glucagon secretion from pancreatic α-cells, leading to reduced hepatic glucose production.1

• Selectively inhibits DPP-4 with no effect on DPP-8 or DPP-9 in vitro at concentrations approximating those from therapeutic exposures.1

• Importance of patient reading medication guide before initiating therapy and each time the drug is dispensed.1 24

• Importance of informing patients of the potential risks and benefits of alogliptin.1 24 Importance of not using alogliptin in patients with type 1 diabetes mellitus or diabetic ketoacidosis.1 24

• Risk of acute pancreatitis; may be severe or fatal.1 24 Importance of patient informing clinicians about a history of pancreatitis, gallstones, alcoholism, or kidney or liver problems.1 24 Importance of patient discontinuing alogliptin and promptly notifying clinician if signs and symptoms of pancreatitis, including persistent severe abdominal pain that may radiate to the back and may or may not be accompanied by vomiting, occur.1 24

• Importance of informing patients of the possibility of severe and disabling joint pain.1 24 41 Advise patients to contact a clinician promptly if severe and persistent joint pain occurs; patients should not discontinue therapy without consulting their clinician.1 24 41

• Importance of informing patients about possibility of heart failure with alogliptin therapy.1 24 42 Importance of patients informing clinicians about a history of heart failure or renal impairment.1 24 42 Importance of informing patients about signs and symptoms of heart failure (e.g., shortness of breath, weight gain, edema); importance of patients immediately contacting a clinician if manifestations of heart failure occur.1 24 42

• Risk of hypoglycemia, particularly if concomitant therapy with a sulfonylurea (i.e., insulin secretagogue) or insulin is used.1 24

• Risk of serious allergic (hypersensitivity) reaction.1 24 If signs or symptoms of such reactions occur (e.g., rash, hives, swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing), importance of discontinuing alogliptin and informing clinician promptly.1 24

• Possibility of liver injury, sometimes fatal.1 24 If signs or symptoms of liver injury (e.g., nausea, vomiting, abdominal pain, unusual/unexplained fatigue, anorexia, dark urine, jaundice) occur, importance of discontinuing alogliptin and informing clinician promptly.1 24

• Importance of taking alogliptin exactly as directed by clinician.1 24 (See Administration under Dosage and Administration.)

• Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.1 24

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1 24

• Importance of informing patients of other important precautionary information. 1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of alogliptin in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of alogliptin in the elderly.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Balofloxacin
• Besifloxacin
• Ciprofloxacin
• Enoxacin
• Fleroxacin
• Flumequine
• Gatifloxacin
• Gemifloxacin
• Lanreotide
• Levofloxacin
• Lomefloxacin
• Moxifloxacin
• Nadifloxacin
• Norfloxacin
• Octreotide
• Ofloxacin
• Pasireotide
• Pazufloxacin
• Pefloxacin
• Prulifloxacin
• Rufloxacin
• Sparfloxacin
• Thioctic Acid
• Tosufloxacin

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acebutolol
• Atenolol
• Betaxolol
• Bisoprolol
• Carteolol
• Carvedilol
• Celiprolol
• Esmolol
• Labetalol
• Levobunolol
• Metipranolol
• Metoprolol
• Nadolol
• Nebivolol
• Oxprenolol
• Penbutolol
• Pindolol
• Practolol
• Propranolol
• Sotalol
• Timolol

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Alcohol, excessive use of or
• Gallbladder stones or
• Pancreas problems, history of—Use with caution. May increase risk for getting pancreatitis (swelling and inflammation of the pancreas).

• Angioedema (swelling of the face, lips, tongue, throat, arms, or legs), history with this dipeptidyl peptidase-4 (DPP-4) inhibitors—Use with caution. May increase the risk of this condition occurring again with this medicine.

• Diabetic ketoacidosis (high ketones and acid in the blood) or
• Type 1 diabetes—Should not be used in patients with these conditions.

• Heart failure, history of or
• Kidney disease, history of—Use with caution. May increase the risk of serious side effects.

• Kidney disease, moderate or severe—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

• Liver disease—Use with caution. May make this condition worse.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Do not drive if your blood sugar has been low. There is a greater chance of you having a crash.
• Check your blood sugar as you have been told by your doctor.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Follow the diet and workout plan that your doctor told you about.
• Talk with your doctor before you drink alcohol.
• It may be harder to control your blood sugar during times of stress like when you have a fever, an infection, an injury, or surgery. A change in level of physical activity or exercise and a change in diet may also affect your blood sugar. Talk with your doctor.
• Heart failure has happened in people taking Nesina. Tell your doctor if you have ever had heart failure or kidney problems. Call your doctor right away if you feel very tired or you have shortness of breath, a big weight gain, or swelling in the arms or legs.
• A skin reaction called bullous pemphigoid has happened with drugs like this one. Sometimes, people have had to go to the hospital. Call your doctor right away if you have blisters or if your skin starts to break down.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Recommended Dosing

The recommended dose of Nesina is 25 mg once daily. Nesina may be taken with or without food.

Patients with Renal Impairment

No dose adjustment of Nesina is necessary for patients with mild renal impairment (creatinine clearance [CrCl] ≥60 mL/min).

The dose of Nesina is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min).

The dose of Nesina is 6.25 mg once daily for patients with severe renal impairment (CrCl ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or requiring hemodialysis). Nesina may be administered without regard to the timing of dialysis. Nesina has not been studied in patients undergoing peritoneal dialysis [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Because there is a need for dose adjustment based upon renal function, assessment of renal function is recommended prior to initiation of Nesina therapy and periodically thereafter.

History of a serious hypersensitivity reaction to alogliptin-containing products, such as anaphylaxis, angioedema or severe cutaneous adverse reactions.

Nesina is primarily renally excreted. Cytochrome (CYP) P450-related metabolism is negligible. No significant drug-drug interactions were observed with the CYP-substrates or inhibitors tested or with renally excreted drugs [see Clinical Pharmacology (12.3)].

Nesina tablets contain the active ingredient alogliptin, which is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4).

Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile monobenzoate. It has a molecular formula of C18H21N5O2∙C7H6O2 and a molecular weight of 461.51 daltons. The structural formula is:

Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and isopropyl acetate.

Each Nesina tablet contains 34 mg, 17 mg or 8.5 mg alogliptin benzoate, which is equivalent to 25 mg, 12.5 mg or 6.25 mg, respectively, of alogliptin and the following inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, ferric oxide (red or yellow) and polyethylene glycol, and is marked with printing ink (Gray F1).

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 were randomized in 11 double-blind, placebo- or active-controlled clinical safety and efficacy studies conducted to evaluate the effects of Nesina on glycemic control. The racial distribution of patients exposed to study medication was 70% Caucasian, 17% Asian, 6% Black and 7% other racial groups. The ethnic distribution was 30% Hispanic. Patients had an overall mean age of 57 years (range 21 to 91 years).

In patients with type 2 diabetes, 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, 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 1768 patients with type 2 diabetes participated in three double-blind studies to evaluate the efficacy and safety of Nesina in patients with inadequate glycemic control on diet and exercise. All three studies 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 study, 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.

In a 26-week, double-blind, active-controlled study, 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.

In a 26 week, double-blind, placebo-controlled study, 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.

Combination Therapy

Add-On Therapy to Metformin

A total of 2081 patients with type 2 diabetes participated in two 26 week, double-blind, placebo-controlled studies to evaluate the efficacy and safety of Nesina as add-on therapy to metformin. In both studies, 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 study, 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.

In the second 26 week, double-blind, placebo-controlled study, a total of 1554 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.

Add-On Therapy to a Thiazolidinedione

In a 26 week, placebo-controlled study, 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.

Add-on Combination Therapy with Pioglitazone and Metformin

In a 52 week, active-comparator study, 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.

Add-On Therapy to a Sulfonylurea

In a 26 week, placebo-controlled study, 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.

Add-On Therapy to Insulin

In a 26 week, placebo-controlled study, 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.

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 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 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 [see Dosage and Administration (2.2)]. 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%), Caucasian (73%), and were recruited from outside of the United States (86%). Asian and Black 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 m2) were prevalent co-morbid conditions. Use of medications to treat diabetes (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 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 study was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE. The median exposure to study drug was 526 days and 95% of the patients were followed to study completion or death.

Table 12 shows the study 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.

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 study. The observed incidence of MACE was highest within the first 60 days after randomization in both treatment arms (14.8 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).

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.

Nesina (alogliptin) is an oral diabetes medicine that helps control blood sugar levels. It works by regulating the levels of insulin your body produces after eating.

Nesina is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus. This medicine is not for treating type 1 diabetes.

Nesina is sometimes used in combination with other diabetes medications.