Trulicity Drug Information
Generic name: DULAGLUTIDE
GLP-1 Receptor Agonist [EPC]
Uses of Trulicity
- ® is indicated: As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. To reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors. TRULICITY ® is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated : As an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. To reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus who have established cardiovascular disease or multiple cardiovascular risk factors.
- Limitations of Use: Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in these patients. Not for treatment of type 1 diabetes mellitus. Not recommended in patients with severe gastrointestinal disease, including severe gastroparesis.
- Limitations of Use TRULICITY: Has not been studied in patients with a history of pancreatitis . Consider other antidiabetic therapies in patients with a history of pancreatitis. Should not be used in patients with type 1 diabetes mellitus. Has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis and is therefore not recommended in these patients .
Dosage & Administration of Trulicity
Adult Dosage
The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly. Increase the dosage to 1.5 mg once weekly for additional glycemic control. If additional glycemic control is needed, increase the dosage in 1.5 mg increments after at least 4 weeks on the current dosage.
The maximum recommended dosage is 4.5 mg injected subcutaneously once weekly.
Pediatric Dosage
The recommended starting dosage of TRULICITY is 0.75 mg injected subcutaneously once weekly. If additional glycemic control is needed, increase the dosage to the maximum recommended dosage of 1.5 mg once weekly after at least 4 weeks on the 0.75 mg dosage.
Recommendations Regarding Missed Dose
If a dose is missed, instruct patients to administer the dose as soon as possible if there are at least 3 days (72 hours) until the next scheduled dose. If less than 3 days remain before the next scheduled dose, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
The day of weekly administration can be changed, if necessary, as long as the last dose was administered 3 or more days before the new day of administration.
Important
Administration Instructions Prior to initiation, train patients and caregivers on proper injection technique . Administer TRULICITY once weekly, any time of day, with or without food. Inject TRULICITY subcutaneously in the abdomen, thigh, or upper arm. Rotate injection sites with each dose.
Inspect TRULICITY visually before use. It should appear clear and colorless. Do not use TRULICITY if particulate matter or coloration is seen.
When using TRULICITY with insulin, administer as separate injections and never mix. It is acceptable to inject TRULICITY and insulin in the same body region, but the injections should not be adjacent to each other.
Side Effects of Trulicity
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adverse Reactions in the Clinical Trials in Adults with Type 2 Diabetes Mellitus Pool of Adult Placebo-Controlled Trials for TRULICITY 0.75 mg and 1.5 mg Doses The data in Table 1 are derived from a pool of placebo-controlled trials and include 1,670 adult patients with type 2 diabetes mellitus exposed to TRULICITY with a mean duration of exposure of 23.8 weeks . The mean age of patients was 56 years, 1% were 75 years or older and 53% were male. The population was 69% White, 7% Black or African American, 13% Asian; 30% were of Hispanic or Latino ethnicity.
At baseline, the population had diabetes for an average of 8 years, a mean HbA1c of 8.0%, and 2.5% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 96%. Table 1 shows adverse reactions, excluding hypoglycemia, occurring in ≥5% of TRULICITY treated adult patients and more commonly than placebo in a pool of placebo-controlled trials. Table 1: Adverse Reactions in Pool of Placebo-Controlled Trials That Occurred in ≥5% of TRULICITY-Treated Adult Patients with Type 2 Diabetes Mellitus a Includes diarrhea, fecal volume increased, frequent bowel movements. b Includes retching, vomiting, vomiting projectile. c Includes abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, abdominal tenderness, gastrointestinal pain. d Includes fatigue, asthenia, malaise.
Note: Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction. Adverse Reaction Placebo (N=568) % TRULICITY 0.75 mg (N=836) % TRULICITY 1.5 mg (N=834) % Nausea 5.3 12.4
Diarrhea a 6.7 8.9 12.6 Vomiting b 2.3 6.0 12.7 Abdominal Pain
c 4.9 6.5
Decreased Appetite 1.6 4.9 8.6 Dyspepsia 2.3 4.1 5.8 Fatigue d 2.6
4.2
Gastrointestinal Adverse Reactions
In the pool of placebo-controlled trials, gastrointestinal (GI) adverse reactions occurred more frequently among patients who received TRULICITY compared to patients who received placebo (placebo 21%, 0.75 mg 32%, 1.5 mg 41%). A higher percentage of patients who received TRULICITY 0.75 mg (1.3%) and TRULICITY 1.5 mg (3.5%) discontinued treatment due to GI adverse reactions than patients who received placebo (0.2%). Investigators graded the severity of GI adverse reactions that occurred in those treated with 0.75 mg and 1.5 mg of TRULICITY as “mild” in 58% and 48% of cases, respectively, “moderate” in 35% and 42% of cases, respectively, or “severe” in 7% and 11% of cases, respectively. The following GI adverse reactions were reported more frequently in TRULICITY-treated patients than placebo -treated patients (frequencies listed, respectively, as: placebo; 0.75 mg; 1.5 mg): constipation (0.7%, 3.9%, 3.7%), flatulence (1.4%, 1.4%, 3.4%), abdominal distension (0.7%, 2.9%, 2.3%), gastroesophageal reflux disease (0.5%, 1.7%, 2.0%), and eructation (0.2%, 0.6%, 1.6%). Adult Dose Ranging Trial for TRULICITY 3 mg and 4.5 mg Doses Table 2 shows adverse reactions occurring ≥5% in any of the treatment groups through 36 weeks in a clinical trial with 1842 adult patients with type 2 diabetes mellitus treated with TRULICITY 1.5 mg, 3 mg, or 4.5 mg subcutaneously once weekly as an add-on to metformin . The adverse reaction profile is consistent with previous clinical trials in adults. Table 2: Adverse Reactions That Occurred in ≥5% of TRULICITY-treated Adult Patients with Type 2 Diabetes Mellitus in a Clinical Trial through 36 Weeks a a Percentages reflect the number of patients that reported at least 1 treatment-emergent occurrence of the adverse reaction.
Adverse Reaction TRULICITY 1.5 mg (N=612) % TRULICITY 3 mg (N=616) % TRULICITY 4.5 mg (N=614) % Nausea 13.4 15.6
Diarrhea 7.0 11.4 10.7 Vomiting 5.6 8.3 9.3 Dyspepsia 2.8 5.0 2.6
Other Adverse Reactions in Adults Hypoglycemia Table 3 summarizes the incidence of hypoglycemia in the placebo-controlled clinical studies in adult patients with type 2 diabetes mellitus: episodes with a glucose level <54 mg/dL with or without symptoms, and severe hypoglycemia, defined as an episode requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Table 3: Incidence (%) of Hypoglycemia in Adult Patients with Type 2 Diabetes Mellitus in Placebo-Controlled Trials Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Add-on to Metformin (26 weeks) N=177 N=302 N=304 Hypoglycemia with a glucose level <54 mg/dL 0 0.3
Severe hypoglycemia 0 0 0 Add-on to Metformin + Pioglitazone (26 weeks)
N=141 N=280 N=279 Hypoglycemia with a glucose level <54 mg/dL 1.4 2.1 0 Severe hypoglycemia 0 0 0 Add-on to Glimepiride (24 weeks) N=60 - N=239 Hypoglycemia with a glucose level <54 mg/dL 0 -
Severe hypoglycemia 0 - 0
In Combination with Insulin Glargine ± Metformin (28 weeks) N=150 - N=150 Hypoglycemia with a glucose level <54 mg/dL 9.3 -
Severe hypoglycemia 0 - 0.7 Add-on to
SGLT2i ± Metformin (24 weeks) N=140 N=141 N=142 Hypoglycemia with a glucose level <54 mg/dL 0.7 0.7
Severe hypoglycemia 0 0.7 0 Hypoglycemia was more frequent when
TRULICITY was used in combination with a sulfonylurea or insulin than when used with non-secretagogues. In a 78-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 20% and 21% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea. Severe hypoglycemia occurred in 0% and 0.7% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with a sulfonylurea.
In a 52-week adult clinical trial, hypoglycemia (glucose level <54 mg/dL) occurred in 77% and 69% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Severe hypoglycemia occurred in 2.7% and 3.4% of patients when TRULICITY 0.75 mg and 1.5 mg, respectively, were co-administered with prandial insulin. Refer to Table 3 for the incidence of hypoglycemia in patients treated in combination with basal insulin glargine.
In the clinical trial with adult patients on TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, as add-on to metformin, incidences of hypoglycemia (glucose level <54 mg/dL) through 36 weeks were 1.1%, 0.3%, and 1.1%, respectively, and incidences of severe hypoglycemia were 0.2%, 0%, and 0.2%, respectively. Cholelithiasis and Cholecystitis In a cardiovascular outcomes trial in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors with a median follow up of 5.4 years , cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively.
Heart Rate Increase and Tachycardia-Related Adverse Reactions In adult patients, TRULICITY 0.75 mg and 1.5 mg resulted in a mean increase in heart rate (HR) of 2-4 beats per minute (bpm). Adverse reactions of sinus tachycardia were reported more frequently in patients exposed to TRULICITY. Sinus tachycardia was reported in 3.0%, 2.8%, and 5.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Persistence of sinus tachycardia (reported at more than 2 visits) was reported in 0.2%, 0.4% and 1.6% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Episodes of sinus tachycardia, associated with a concomitant increase from baseline in heart rate of ≥15 beats per minute, were reported in 0.7%, 1.3% and 2.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively.
Hypersensitivity Systemic hypersensitivity adverse reactions, sometimes severe (e.g., severe urticaria, systemic rash, facial edema, lip swelling), occurred in 0.5% of adult patients on TRULICITY in clinical studies. Injection-site Reactions In the placebo-controlled studies in adults, injection-site reactions (e.g., injection-site rash, erythema) were reported in 0.5% of TRULICITY-treated patients and in 0.0% of placebo-treated patients. PR Interval Prolongation and Adverse Reactions of First-Degree Atrioventricular (AV) Block A mean increase from baseline in PR interval of 2-3 milliseconds was observed in TRULICITY-treated adult patients in contrast to a mean decrease of 0.9 milliseconds in placebo-treated patients.
The adverse reaction of first-degree AV block occurred more frequently in patients treated with TRULICITY than placebo (0.9%, 1.7% and 2.3% for placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively). On electrocardiograms, a PR interval increase to at least 220 milliseconds was observed in 0.7%, 2.5% and 3.2% of patients treated with placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg, respectively. Amylase and Lipase Increase Adult patients exposed to TRULICITY had mean increases from baseline in lipase and/or pancreatic amylase of 14% to 20%, while placebo-treated patients had mean increases of up to 3%. Adverse Reactions in the Clinical Trial of Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus TRULICITY was administered to 150 pediatric patients 10 years of age and older with type 2 diabetes mellitus for a mean duration of 41.3 weeks. The mean age was 14.5 years and 71% of patients were female.
Overall, 55% were White, 15% were Black or African American, 12% were Asian, 10% were American Indian or Alaska Native, 5% were other races, and 3% had unknown race. Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity. At baseline, the mean duration of type 2 diabetes mellitus was 2 years, mean HbA1c was 8.1%, mean weight was 90.5 kg and mean BMI was 34.1 kg/m 2. The safety profile in pediatric patients treated with TRULICITY 0.75 mg and 1.5 mg subcutaneously once-weekly was consistent with that described above for adult patients with type 2 diabetes mellitus with the exception of injection site reactions.
In pediatric patients, the incidence of injection site reactions was 3.9% (2 patients) in the TRULICITY 0.75 mg group, 3.8% (2 patients) in the TRULICITY 1.5 mg group, and 2.0% (1 patient) in the placebo group.
Postmarketing Experience
The following additional adverse reactions have been reported during post-approval use of TRULICITY. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: ileus Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy, cholestasis, elevation of liver enzymes, hepatitis Hypersensitivity: anaphylactic reactions, angioedema Renal: acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis
Warnings & Cautions for Trulicity
Risk of Thyroid C-cell Tumors
In male and female rats, dulaglutide causes a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and carcinomas) after lifetime exposure . Glucagon-like peptide-1 (GLP-1) receptor agonists have induced thyroid C-cell adenomas and carcinomas in mice and rats at clinically relevant exposures. It is unknown whether TRULICITY will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of dulaglutide-induced rodent thyroid C-cell tumors has not been determined. One case of MTC was reported in a patient treated with TRULICITY in a clinical trial.
This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. TRULICITY is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of TRULICITY and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TRULICITY. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated.
Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
Pancreatitis
In a pooled analysis from the original registration studies, 12 (3.4 cases per 1000 patient years) pancreatitis-related adverse reactions were reported in patients exposed to TRULICITY versus 3 in non-incretin comparators (2.7 cases per 1000 patient years). An analysis of adjudicated events revealed 5 cases of confirmed pancreatitis in patients exposed to TRULICITY (1.4 cases per 1000 patient years) versus 1 case in non-incretin comparators (0.88 cases per 1000 patient years). Based on an analysis of adjudicated events in a clinical trial evaluating Trulicity 1.5 mg, 3 mg, or 4.5 mg once weekly, pancreatitis occurred in 1 patient exposed to TRULICITY 1.5 mg (0.2%), in 2 patients exposed to TRULICITY 3 mg (0.3%), and 3 patients exposed to TRULICITY 4.5 mg (0.5%). After initiation of TRULICITY, observe patients carefully for signs and symptoms of pancreatitis, including persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, promptly discontinue TRULICITY and initiate appropriate management. If pancreatitis is confirmed, TRULICITY should not be restarted.
TRULICITY has not been evaluated in patients with a prior history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis.
Hypoglycemia with
Concomitant Use of Insulin Secretagogues or Insulin Patients receiving TRULICITY in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogue) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.
Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions including anaphylactic reactions and angioedema in patients treated with TRULICITY . If a hypersensitivity reaction occurs, discontinue TRULICITY; treat promptly per standard of care, and monitor until signs and symptoms resolve. TRULICITY is contraindicated in patients with a previous serious hypersensitivity reaction to dulaglutide or to any of the components of TRULICITY. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema or anaphylaxis with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to anaphylaxis with TRULICITY.
Acute Kidney Injury
In patients treated with GLP-1 receptor agonists, including TRULICITY, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration.
Because these reactions may worsen renal function, use caution when initiating or escalating doses of TRULICITY in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions .
Severe Gastrointestinal Disease Use of
TRULICITY may be associated with gastrointestinal adverse reactions, sometimes severe . TRULICITY has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.
Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy
In a cardiovascular outcomes trial with a median follow up of 5.4 years involving patients with type 2 diabetes with established cardiovascular disease or multiple cardiovascular risk factors, diabetic retinopathy complications occurred in patients treated with TRULICITY 1.5 mg (1.9%) and placebo (1.5%). These events were prospectively ascertained as a secondary composite endpoint. The proportion of patients with diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (TRULICITY 8.5%, placebo 6.2%) than among patients without a known history of diabetic retinopathy (TRULICITY 1%, placebo 1%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.
Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or
cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a cardiovascular outcomes trial with a median follow up of 5.4 years, cholelithiasis occurred at a rate of 0.62/100 patient-years in TRULICITY-treated patients and 0.56/100 patient-years in placebo-treated patients after adjusting for prior cholecystectomy. Serious events of acute cholecystitis were reported in 0.5% and 0.3% of patients on TRULICITY and placebo respectively.
If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
Drug Interactions with Trulicity
Oral Medications
TRULICITY delays gastric emptying and thus has the potential to reduce the rate of absorption of concomitantly administered oral medications. The delay in gastric emptying is dose-dependent but is attenuated with the recommended dose escalation to higher doses of TRULICITY . The delay is largest after the first dose and diminishes with subsequent doses. In clinical pharmacology studies, TRULICITY 1.5 mg did not affect the absorption of the tested orally administered medications to a clinically relevant degree . There is limited experience with the use of concomitant medications in clinical trials with TRULICITY doses of 3 mg and 4.5 mg.
Monitor drug levels of oral medications with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with TRULICITY.
Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
When initiating TRULICITY, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia.
Pregnancy Safety for Trulicity
Pregnancy Risk Summary Limited data with TRULICITY in pregnant women are not sufficient to determine a drug-associated risk for major birth defects and miscarriage. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy. Based on animal reproduction studies, there may be risks to the fetus from exposure to dulaglutide during pregnancy.
TRULICITY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In pregnant rats administered dulaglutide during organogenesis, early embryonic deaths, fetal growth reductions, and fetal abnormalities occurred at systemic exposures at least 6-times human exposure at the maximum recommended human dose (MRHD) of 4.5 mg/week. In pregnant rabbits administered dulaglutide during organogenesis, major fetal abnormalities occurred at 5-times human exposure at the MRHD. Adverse embryo/fetal effects in animals occurred in association with decreased maternal weight and food consumption attributed to the pharmacology of dulaglutide . The estimated background risk of major birth defects is 6–10% in women with pre-gestational diabetes with an HbA1c >7% and has been reported to be as high as 20–25% in women with an 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 in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.
Data Animal Data Pregnant rats given subcutaneous doses of 0.49, 1.63, or 4.89 mg/kg dulaglutide every 3 days during organogenesis had systemic exposures 2-, 6-, and 18-times human exposure at the maximum recommended human dose (MRHD) of 4.5 mg/week, respectively, based on plasma area under the time-concentration curve (AUC) comparison. Reduced fetal weights associated with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide were observed at ≥1.63 mg/kg. Irregular skeletal ossifications and increases in post-implantation loss also were observed at 4.89 mg/kg.
In pregnant rabbits given subcutaneous doses of 0.04, 0.12, or 0.41 mg/kg dulaglutide every 3 days during organogenesis, systemic exposures in pregnant rabbits were 0.5-, 2-, and 5-times human exposure at the MRHD, based on plasma AUC comparison. Fetal visceral malformation of lung lobular agenesis and skeletal malformations of the vertebrae and/or ribs were observed in conjunction with decreased maternal food intake and decreased weight gain attributed to the pharmacology of dulaglutide at 0.41 mg/kg. In a prenatal-postnatal study in F 0 maternal rats given subcutaneous doses of 0.2, 0.49, or 1.63 mg/kg every third day from implantation through lactation, systemic exposures in pregnant rats were 1-, 2-, and 7-times human exposure at the MRHD, based on plasma AUC comparison.
F 1 pups from F 0 maternal rats given 1.63 mg/kg dulaglutide had statistically significantly lower mean body weight from birth through postnatal day 63 for males and postnatal day 84 for females. F 1 offspring from F 0 maternal rats receiving 1.63 mg/kg dulaglutide had decreased forelimb and hindlimb grip strength and males had delayed balano-preputial separation. Females had decreased startle response.
These physical findings may relate to the decreased size of the offspring relative to controls as they appeared at early postnatal assessments but were not observed at a later assessment. F 1 female offspring of the F 0 maternal rats given 1.63 mg/kg of dulaglutide had a longer mean escape time and a higher mean number of errors relative to concurrent control during 1 of 2 trials in the memory evaluation portion of the Biel water maze. These findings occurred in conjunction with decreased F 0 maternal food intake and decreased weight gain attributed to the pharmacologic activity at 1.63 mg/kg.
The human relevance of these memory deficits in the F 1 female rats is not known.
Pediatric Use of Trulicity
Pediatric Use The safety and effectiveness of TRULICITY as an adjunct to diet and exercise to improve glycemic control in pediatric patients 10 years of age and older with type 2 diabetes mellitus have been established. Use of TRULICITY for this indication is supported by a 26-week, multicenter, randomized, double-blind, parallel arm, placebo-controlled trial in 154 pediatric patients 10 years of age and older with type 2 diabetes mellitus . TRULICITY-treated pediatric patients reported a higher incidence of injection site-related reactions compared to TRULICITY-treated adults . The safety and effectiveness of TRULICITY have not been established in pediatric patients less than 10 years of age.
Contraindications for Trulicity
is contraindicated in patients with: Personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) . Serious hypersensitivity reaction to dulaglutide or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with TRULICITY . Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. Patients with a serious hypersensitivity reaction to dulaglutide or any of the product components.
Overdosage Information for Trulicity
Overdoses have been reported in clinical studies. Effects associated with these overdoses were primarily mild or moderate gastrointestinal events (e.g., nausea, vomiting) and non-severe hypoglycemia. In the event of overdose, appropriate supportive care (including frequent plasma glucose monitoring) should be initiated according to the patient's clinical signs and symptoms.
Clinical Studies of Trulicity
Overview of Clinical Trials
TRULICITY has been studied in adults as monotherapy and in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and thiazolidinedione, sodium-glucose co-transporter-2 inhibitors (SGLT2i) with or without metformin, basal insulin with or without metformin, and prandial insulin with or without metformin. TRULICITY has also been studied in patients with type 2 diabetes mellitus and moderate to severe renal impairment. Dose escalation was performed in one trial in adults with TRULICITY doses up to 4.5 mg added to metformin.
All other clinical studies in adults evaluated TRULICITY 0.75 mg and 1.5 mg without dose escalation; patients were initiated and maintained on either 0.75 mg or 1.5 mg for the duration of the trials . TRULICITY 0.75 mg and 1.5 mg was studied in pediatric patients 10 years of age and older with type 2 diabetes in combination with or without metformin and/or basal insulin treatment . In patients with type 2 diabetes mellitus, TRULICITY produced reductions from baseline in HbA1c compared to placebo. No overall differences in glycemic effectiveness were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes). A cardiovascular outcomes trial was conducted in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors. Patients were randomized to TRULICITY 1.5 mg or placebo both added to standard of care.
TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke .
Glycemic Control Monotherapy Trials in Adults with Type 2 Diabetes Mellitus
In a double-blind trial with primary endpoint at 26 weeks, 807 adult patients inadequately treated with diet and exercise, or with diet and exercise and one antidiabetic agent used at submaximal dose, were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or metformin 1500 to 2000 mg/day following a two-week washout. Seventy-five percent (75%) of the randomized population were treated with one antidiabetic agent at the screening visit. Most patients previously treated with an antidiabetic agent were receiving metformin (~90%) at a median dose of 1000 mg daily and approximately 10% were receiving a sulfonylurea.
Patients had a mean age of 56 years and a mean duration of type 2 diabetes of 3 years. Forty-four percent were male. The White, Black and Asian race accounted for 74%, 7% and 8% of the population, respectively.
Twenty-nine percent of the trial population were from the US. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in reduction in HbA1c from baseline at 26-weeks ( Table 4 ). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and metformin excluded the pre-specified non-inferiority margin of 0.4%. Table 4: Results at Week 26 in a Trial of TRULICITY as Monotherapy in Adult Patients with Type 2 Diabetes Mellitus a Abbreviation: HbA1c = hemoglobin A1c. a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing.
At Week 26, primary efficacy was missing for 10%, 12% and 14% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and metformin, respectively. b Least-squares mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 265 individuals in each of the treatment arms. 26-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Metformin 1500-2000 mg Intent-to-Treat (ITT) Population (N) ‡ 270 269 268 HbA1c (%) (Mean) Baseline 7.6 7.6
Change from baseline b -0.7 -0.8 -0.6 Fasting Serum Glucose (mg/dL) (Mean)
Baseline 161 164 161 Change from baseline b -26 -29 -24 Body Weight (kg) (Mean) Baseline 91.8 92.7
Change from baseline b -1.4 -2.3 -2.2 14.3 Glycemic Control Combination Therapy
Trials in Adults with Type 2 Diabetes Mellitus Sitagliptin-Controlled Trial (Add-on to Metformin) In this placebo-controlled, double-blind trial with primary endpoint at 52 weeks, 972 adult patients were randomized to placebo, TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or sitagliptin 100 mg/day (after 26 weeks, patients in the placebo treatment group received blinded sitagliptin 100 mg/day for the remainder of the trial), all as add-on to metformin. Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemic stabilization period. Patients had a mean age of 54 years; mean duration of type 2 diabetes of 7 years; 48% were male; race: White, Black and Asian were 53%, 4% and 27%, respectively; and 24% of the trial population were in the US. At the 26-week placebo-controlled time point, the HbA1c change was 0.1%, -1.0%, -1.2%, and -0.6% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively.
The percentage of patients who achieved HbA1c <7.0% was 22%, 56%, 62% and 39% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL, and 18 mg/dL for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively.
Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 26 and 52 weeks), all in combination with metformin ( Table 5 and Figure 3 ). Table 5: Results at Week 52 of TRULICITY Compared to Sitagliptin used as Add-On to Metformin in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a All ITT patients randomized after the dose-finding portion of the trial. Last observation carried forward (LOCF) was used to impute missing data. At Week 52 primary efficacy was missing for 15%, 19%, and 20% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment.
The primary analysis included 276, 277, and 270 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively. †† Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to sitagliptin, assessed only for HbA1c. ## p<0.001 TRULICITY compared to sitagliptin, assessed only for HbA1c <7.0%. 52-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Sitagliptin 100 mg Intent-to-Treat (ITT) Population (N) ‡ 281 279 273 HbA1c (%) (Mean) Baseline 8.2 8.1
Change from baseline b -0.9 -1.1 -0.4 Difference from sitagliptin b (95%
CI) -0.5 (-0.7, -0.3) †† -0.7 (-0.9, -0.5) †† - Percentage of patients HbA1c <7.0% 49 ## 59 ## 33 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 174 173 171 Change from baseline b -30 -41 -14 Difference from sitagliptin b (95% CI) -15 (-22, -9) -27 (-33, -20) - Body Weight (kg) (Mean) Baseline 85.5 86.5
Change from baseline b -2.7 -3.1 -1.5 Difference from sitagliptin b (95%
CI) -1.2 (-1.8, -0.6) -1.5 (-2.1, -0.9) - Mean HbA1c adjusted for baseline HbA1c and country. Number of patients with observed data Placebo 139 108 TRULICITY 0.75 mg 281 258 238 TRULICITY 1.5 mg 279 249 225 Sitagliptin 273 241 219 Figure 3: Adjusted Mean HbA1c at each Time Point (ITT, MMRM) and at Week 52 (ITT, LOCF) in Adult Patients with Type 2 Diabetes Mellitus Figure 3 Dosage Ranging Trial of TRULICITY 1.5, 3 mg, and 4.5 mg (Add-on to Metformin) In this parallel-arm, double-blind trial with primary endpoint at 36 weeks, a total of 1842 adult patients were randomized 1:1:1 to TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, all as add-on to metformin (NCT03495102). Following randomization, all patients received TRULICITY 0.75 mg once weekly. The dose was increased every 4 weeks to the next higher dose until the patients reached their assigned dose (1.5 mg, 3 mg, or 4.5 mg). Patients were to remain on the assigned study dose for the duration of the trial.
Patients had a mean age of 57.1 years; a mean duration of type 2 diabetes of 7.6 years; 51.2% were male; race: White, Black, and Asian were 85.8%, 4.5%, and 2.4%, respectively; and 27.6% of the trial population was in the US. At 36 weeks, treatment with TRULICITY 4.5 mg resulted in a statistically significant reduction in HbA1c and in body weight compared to TRULICITY 1.5 mg ( Table 6 and Figure 4 ). Table 6. Results at Week 36 of TRULICITY 1.5 mg Compared to 3 mg and 4.5 mg as Add-On to Metformin in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c a Intent-to-treat population. At Week 36, primary efficacy was missing for 7%, 7%, and 6% of individuals treated with TRULICITY 1.5 mg, TRULICITY 3 mg, and TRULICITY 4.5 mg, respectively. b Least-squares mean adjusted for baseline value and other stratification factors. Missing data were imputed using multiple imputation. c Patients with missing HbA1c data at Week 36 were considered as not achieving HbA1c target. ^ p=0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled. ^^ p<0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled. 36-Week Primary Time Point TRULICITY 1.5 mg TRULICITY 3 mg TRULICITY 4.5 mg Intent-to-Treat (ITT) Population (N) 612 616 614 HbA1c (%) (Mean) Baseline 8.6 8.6
Change from baseline b -1.5 -1.6 -1.8 Difference from 1.5 mg b
(95% CI) -0.1 (-0.2, 0.0) -0.2 (-0.4, -0.1) ^ Percentage of patients HbA1c <7.0% c 50 56 62 Fasting Serum Glucose (mg/dL) (Mean) Baseline 185 184 183 Change from baseline b -45 -46 -51 Difference from 1.5 mg b (95% CI) - 2 (-7, 3) -6 (-11, -2) Body Weight (kg) (Mean) Baseline 95.5 96.3
Change from baseline b -3.0 -3.8 -4.6 Difference from 1.5 mg b
(95% CI) -0.9 (-1.4, -0.4) -1.6 (-2.2, -1.1) ^^ Observed mean HbA1c at scheduled visits and retrieved dropout multiple imputation (MI) based estimate at week 36. Number of patients with observed data TRULICITY 1.5 mg 612 567 TRULICITY 3 mg 616 572 TRULICITY 4.5 mg 614 575 Figure 4: Mean HbA1c at each Time Point (ITT) and at Week 36 (ITT, MI) Figure 4 Placebo-Controlled Trial (Add-on to Sulfonylurea) In this 24-week placebo-controlled, double-blind trial, 299 adult patients were randomized to and received placebo or once weekly TRULICITY 1.5 mg, both as add-on to glimepiride. Patients had a mean age of 58 years; mean duration of type 2 diabetes of 8 years; 44% were male; race: White, Black, and Asian were 83%, 4%, and 2%, respectively; and 24% of the trial population were in the US. At 24 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo ( Table 7 ). Table 7: Results at Week 24 of TRULICITY Compared to Placebo as Add-On to Glimepiride in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a Intent-to-treat population. Data post-onset of rescue therapy are treated as missing.
At Week 24 primary efficacy was missing for 10% and 12% of individuals randomized to TRULICITY 1.5 mg and placebo, respectively. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to the baseline values, was used to model a wash-out of the treatment effect for patients having missing Week 24 data. c Patients with missing HbA1c data at Week 24 were considered as non-responders. †† p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled. 24-Week Primary Time Point Placebo TRULICITY 1.5 mg Intent-to-Treat (ITT) Population (N) 60 239 HbA1c (%) (Mean) Baseline 8.4
Change from baseline b -0.3 -1.3 Difference from placebo b (95% CI)
-1.1 (-1.4, -0.7) †† Percentage of patients HbA1c <7.0% c 17 50 †† Fasting Serum Glucose (mg/dL) (Mean) Baseline 175 178 Change from baseline b 2 -28 Difference from placebo b (95% CI) -30 (-44, -15) †† Body Weight (kg) (Mean) Baseline 89.5
Change from baseline b -0.2 -0.5 Difference from placebo b (95% CI)
-0.4 (-1.2, 0.5) Placebo- and Exenatide-Controlled Trial (Add-on to Metformin and Thiazolidinedione) In this placebo-controlled trial with primary endpoint at 26 weeks, 976 adult patients were randomized to and received placebo, TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of metformin (≥1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignment was open-label while the treatment assignments to placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg were blinded. After 26 weeks, patients in the placebo treatment group were randomized to either TRULICITY 0.75 mg once weekly or TRULICITY 1.5 mg once weekly to maintain blinding. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and pioglitazone; this was followed by an 8-week glycemic stabilization period prior to randomization.
Patients randomized to exenatide started at a dose of 5 mcg BID for 4 weeks and then were escalated to 10 mcg BID. Patients had a mean age of 56 years; mean duration of type 2 diabetes of 9 years; 58% were male; race: White, Black and Asian were 74%, 8% and 3%, respectively; and 81% of the trial population were in the US. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to exenatide at 26 weeks ( Table 8 and Figure 5 ). Over the 52-week trial period, the percentage of patients who required glycemic rescue was 8.9% in the TRULICITY 0.75 mg once weekly + metformin and pioglitazone treatment group, 3.2% in the TRULICITY 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in the exenatide BID + metformin and pioglitazone treatment group. Table 8: Results at Week 26 of TRULICITY Compared to Placebo and Exenatide, All as Add-On to Metformin and Thiazolidinedione in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: BID = twice daily; HbA1c = hemoglobin A1c. a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data.
Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 23%, 10%, 7% and 12% of individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 119, 269, 271 and 266 individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively. ‡‡ Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to placebo, assessed only for HbA1c. †† Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to exenatide, assessed only for HbA1c. ** p<0.001 TRULICITY compared to placebo, assessed only for HbA1c <7.0%. ## p<0.001 TRULICITY compared to exenatide, assessed only for HbA1c <7.0%. 26-Week Primary Time Point Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Exenatide 10 mcg BID Intent-to-Treat (ITT) Population (N) ‡ 141 280 279 276 HbA1c (%) (Mean) Baseline 8.1 8.1 8.1
Change from baseline b -0.5 -1.3 -1.5 -1.0 Difference from placebo b
(95% CI) - -0.8 (-1.0, -0.7) ‡‡ -1.1 (-1.2, -0.9) ‡‡ - Difference from exenatide b (95% CI) - -0.3 (-0.4, -0.2) †† -0.5 (-0.7, -0.4) †† - Percentage of patients HbA1c <7.0% 43 66**, ## 78**, ## 52 Fasting Serum Glucose (mg/dL) (Mean) Baseline 166 159 162 164 Change from baseline b -5 -34 -42 -24 Difference from placebo b (95% CI) - -30 (-36, -23) -38 (-45, -31) - Difference from exenatide b (95% CI) - -10 (-15, -5) -18 (-24, -13) - Body Weight (kg) (Mean) Baseline 94.1 95.5 96.2
Change from baseline b 1.2 0.2 -1.3 -1.1 Difference from placebo b
(95% CI) - -1.0 (-1.8, -0.3) -2.5 (-3.3, -1.8) - Difference from exenatide b (95% CI) - 1.3 -0.2 (-0.9, 0.4) - Mean HbA1c adjusted for baseline HbA1c and country. Number of patients with observed data Placebo 141 108 TRULICITY 0.75 mg 280 251 TRULICITY 1.5 mg 279 259 Exenatide 276 242 Figure 5: Adjusted Mean HbA1c at Each Time Point (ITT, MMRM) and at Week 26 (ITT, LOCF) Figure 5 Placebo-Controlled Trial (Add-on to SGLT2i, with or without Metformin) In this 24-week placebo-controlled, double-blind trial, 423 adult patients were randomized to and received TRULICITY 0.75 mg, TRULICITY 1.5 mg, or placebo, as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4% without metformin). Trulicity was administered once weekly, and SGLT2i was administered according to the local country label. Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9.4 years; 50% were male; race: White, Black, and Asian were 89%, 3%, and 0.2%, respectively; and 21% of the trial population was in the US. At 24 weeks, treatment with once weekly TRULICITY 0.75 mg and 1.5 mg resulted in a statistically significant reduction from baseline in HbA1c compared to placebo ( Table 9 ). The mean baseline body weight was 90.5, 91.1, and 92.9 kg in the placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg groups, respectively.
The mean changes from baseline in body weight at Week 24 were -2.0, -2.5, and -2.9 kg for placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. The difference from placebo (95% CI) was -0.9 kg (-1.7, -0.1) for TRULICITY 1.5 mg. Table 9: Results at Week 24 of TRULICITY as Add-on to SGLT2i in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c; SGLT2i = sodium-glucose co-transporter-2 inhibitors. a Intent-to-treat population.
At Week 24, primary efficacy was missing for 3%, 4%, and 6% of individuals treated with placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. b Least-squares mean adjusted for baseline value and other stratification factors. Placebo multiple imputation, using baseline and 24-week values from the placebo arm, was applied to model a washout of the treatment effect for patients missing 24-week values (HbA1c, fasting serum glucose, and body weight). c Patients with missing HbA1c data at Week 24 were considered as non-responders. †† p<0.001 for superiority of TRULICITY compared to placebo, overall type I error controlled. 24-Week Primary Time Point Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg Intent-to-Treat (ITT) Population (N) 140 141 142 HbA1c (%) (Mean) Baseline 8.1 8.1
Change from baseline b -0.6 -1.2 -1.3 Difference from placebo b (95%
CI) - -0.7 (-0.8, -0.5) †† -0.8 (-0.9, -0.6) †† Percentage of patients HbA1c <7.0% c 31 59 †† 67 †† Fasting Serum Glucose (mg/dL) (Mean) Baseline 153 162 161 Change from baseline b -6 -25 -30 Difference from placebo b (95% CI) - -19 (-25, -13) -24 (-30, -18) †† Insulin Glargine Controlled Trial (Add-on to Metformin and Sulfonylurea) In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 52 weeks, 807 adult patients were randomized to and received TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred after a 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and glimepiride. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization.
Patients randomized to insulin glargine were started on a dose of 10 units once daily. Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weekly titration through Week 8 of treatment, utilizing an algorithm that targeted a fasting plasma glucose of <100 mg/dL. Only 24% of patients were titrated to goal at the 52-week primary endpoint. The dose of glimepiride could be reduced or discontinued after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia.
The dose of glimepiride was reduced or discontinued in 28%, 32%, and 29% of patients randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine. Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9 years; 51% were male; race: White, Black and Asian were 71%, 1% and 17%, respectively; and 0% of the trial population were in the US. Treatment with TRULICITY once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea ( Table 10 ). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%. Table 10: Results at Week 52 of TRULICITY Compared to Insulin Glargine, Both as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a Intent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data.
Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy was missing for 17%, 13% and 12% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 267, 263 and 259 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively. 52-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine Intent-to-Treat (ITT) Population (N) ‡ 272 273 262 HbA1c (%) (Mean) Baseline 8.1 8.2
Change from baseline b -0.8 -1.1 -0.6 Fasting Serum Glucose (mg/dL) (Mean)
Baseline 161 165 163 Change from baseline b -16 -27 -32 Difference from insulin glargine b (95% CI) 16 5 (-2, 12) - Body Weight (kg) (Mean) Baseline 86.4 85.2
Change from baseline b -1.3 -1.9 1.4 Difference from insulin b (95%
CI) -2.8 (-3.4, -2.2) -3.3 (-3.9, -2.7) - Placebo-Controlled Trial (Add-on to Basal Insulin, with or without Metformin) In this 28-week placebo-controlled, double-blind trial, 300 adult patients were randomized to placebo or once weekly TRULICITY 1.5 mg, as add-on to titrated basal insulin glargine (with or without metformin). Patients had a mean age of 60 years; mean duration of type 2 diabetes of 13 years; 58% were male; race: White, Black, and Asian were 94%, 4%, and 0.3%, respectively; and 20% of the trial population was in the US. The mean starting dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receiving TRULICITY 1.5 mg. At randomization, the initial insulin glargine dose in patients with HbA1c <8.0% was reduced by 20%. At 28 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo ( Table 11 ). Table 11: Results at Week 28 of TRULICITY Compared to Placebo as Add-On to Basal Insulin in Adult Patients with Type 2 Diabetes Mellitus a Abbreviations: HbA1c = hemoglobin A1c. a Intent-to-treat population. At Week 28, primary efficacy was missing for 12% and 8% of individuals randomized to placebo and TRULICITY 1.5 mg, respectively. b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.
Placebo multiple imputation, with respect to baseline values, was used to model a wash-out of the treatment effect for patients having missing Week 28 data. c Patients with missing HbA1c data at Week 28 were considered as non-responders. †† p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled. † p≤0.005 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled. 28-Week Primary Time Point Placebo TRULICITY 1.5 mg Intent-to-Treat (ITT) Population (N) 150 150 HbA1c (%) (Mean) Baseline 8.3
Change from baseline b -0.7 -1.4 Difference from placebo b (95% CI)
-0.7 (-0.9, -0.5) †† Percentage of patients HbA1c <7.0% c 33 67 †† Fasting Serum Glucose (mg/dL) (Mean) Baseline 156 157 Change from baseline b -30 -44 Difference from placebo b (95% CI) -14 (-23, -4) † Body Weight (kg) (Mean) Baseline 92.6
Change from baseline b 0.8 -1.3 Difference from placebo b (95% CI)
-2.1 (-2.9, -1.4) †† Insulin Glargine-Controlled Trial (Combination with Prandial Insulin, with or without Metformin) In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, 884 adult patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; during the initial 2 weeks of the lead-in period, patients continued their pre-trial insulin regimen but could be initiated and/or up-titrated on metformin, based on investigator discretion; this was followed by a 7-week glycemic stabilization period prior to randomization. At randomization, patients discontinued their pre-trial insulin regimen and were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, with or without metformin.
Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine was titrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fasting glucose goal at the 26-week primary timepoint. Patients had a mean age of 59 years; mean duration of type 2 diabetes of 13 years; 54% were male; race: White, Black and Asian were 79%, 10% and 4%, respectively; and 33% of the trial population were in the US. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4% ( Table 12 ). Table 12: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro in Adult Patients with Type 2 Diabetes Mellitus a Abbreviation: HbA1c = hemoglobin A1c a Intent-to-treat population.
Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 14%, 15%, and 14% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively. b Least-squares (LS) mean adjusted for baseline value and other stratification factors. ‡ Patients included in the analysis are a subset of the ITT population that had at least one post-baseline assessment.
The primary analysis included 275, 273 and 276 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively. 26-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine Intent-to-Treat (ITT) Population (N) ‡ 293 295 296 HbA1c (%) (Mean) Baseline 8.4 8.5
Change from baseline b -1.6 -1.6 -1.4 Fasting Serum Glucose (mg/dL) (Mean)
Baseline 150 157 154 Change from baseline b 4 -5 -28 Difference from insulin glargine b (95% CI) 32 24 - Body Weight (kg) (Mean) Baseline 91.7 91.0
Change from baseline b 0.2 -0.9 2.3 Difference from insulin glargine b
(95% CI) -2.2 (-2.8, -1.5) -3.2 (-3.8, -2.6) -
Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus and Moderate
to Severe Chronic Kidney Disease In this open-label comparator trial (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, a total of 576 adult patients with type 2 diabetes were randomized and treated to compare TRULICITY 0.75 mg and 1.5 mg with insulin glargine (NCT01621178). Patients on insulin and other antidiabetic therapy (e.g., oral antidiabetic drugs, pramlintide) had non-insulin therapies discontinued and had their insulin dose adjusted for 12 weeks prior to randomization. Patients on insulin therapy alone maintained a stable insulin dose for 3 weeks prior to randomization. At randomization, patients discontinued their pre-trial insulin regimen and patients were randomized to TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro.
For patients randomized to insulin glargine, the initial insulin glargine dose was based on the basal insulin dose prior to randomization. Insulin glargine was allowed to be titrated with a fasting plasma glucose goal of ≤150 mg/dL. Insulin lispro was allowed to be titrated with a preprandial and bedtime glucose goal of ≤180 mg/dL. Patients had a mean age of 65 years; a mean duration of type 2 diabetes of 18 years; 52% were male; race: White, Black, and Asian were 69%, 16%, and 3%, respectively; and 32% of the trial population were in the US. At baseline, overall mean eGFR was 38 mL/min/1.73 m 2, 30% of patients had eGFR <30 mL/min/1.73 m 2, and 45% of patients had macroalbuminuria. Patients on over 70 units/day of basal insulin were excluded from the trial.
Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c at 26-weeks from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%. Mean fasting plasma glucose increased in the TRULICITY arms ( Table 13 ). Mean baseline body weight was 90.9 kg, 88.1 kg, and 88.2 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively. The mean changes from baseline at Week 26 were -1.1, -2, and 1.9 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively.
Table 13: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lispro, in Patients with Moderate to Severe Chronic Kidney Disease in Adult Patients with Type 2 Diabetes Mellitus a Abbreviation: HbA1c = hemoglobin A1c a Intent-to-treat population (all randomized and treated patients) was used in the analysis regardless of discontinuation of study drug or initiation of rescue therapy. At Week 26, primary efficacy was missing for 12%, 15%, and 9% of individuals randomized to and treated with TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine, respectively. Missing data were imputed using multiple imputation within treatment group. b Least-squares (LS) mean from ANCOVA pattern mixture model adjusted for baseline value and other stratification factors. 26-Week Primary Time Point TRULICITY 0.75 mg TRULICITY 1.5 mg Insulin Glargine Intent-to-Treat Population (N) 190 192 194 HbA1c (%) (Mean) Baseline 8.6 8.6
Change from baseline b -0.9 -1.0 -1.0 Difference from insulin glargine b
(95% CI) 0.0 (-0.2, 0.3) -0.1 (-0.3, 0.2) Percentage of patients HbA1c <8.0% 73 75 74 Fasting Serum Glucose (mg/dL) (Mean) Baseline 167 161 170 Change from baseline b 6 14 -23 Difference from insulin glargine b (95% CI) 30 37
Cardiovascular Outcomes Trial in Adults with Type 2 Diabetes Mellitus and Cardiovascular
Disease or Multiple Cardiovascular Risk Factors The REWIND trial (NCT01394952) was a multi-national, multi-center, randomized, placebo-controlled, double-blind trial. In this trial, 9901 adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors were randomized to TRULICITY 1.5 mg or placebo both added to standard of care. The median follow-up duration was 5.4 years.
The primary endpoint was the time to the first occurrence of a composite 3-component Major Adverse Cardiovascular Events (MACE) outcome, which included CV death, non-fatal myocardial infarction (MI), and non-fatal stroke. Patients eligible to enter the trial were 50 years of age or older who had type 2 diabetes mellitus, had an HbA1c value ≤9.5% with no lower limit at screening, and had either established CV disease, or did not have established CV disease but had multiple CV risk factors. Patients who were confirmed to have established CV disease (31.5% of randomized patients) had a history of at least one of the following: MI (16.2%); myocardial ischemia by a stress test or with cardiac imaging (9.3%); ischemic stroke (5.3%); coronary, carotid, or peripheral artery revascularization (18.0%); unstable angina (5.9%); or hospitalization for unstable angina with at least one of the following: ECG changes, myocardial ischemia on imaging, or a need for percutaneous coronary intervention (12.0%). Patients confirmed to be without established CV disease, but with multiple CV risk factors, comprised 62.8% of the randomized trial population.
At baseline, demographic and disease characteristics were balanced between treatment groups. Patients had a mean age of 66 years; 46% were female; race: White, Black, and Asian were 76%, 7%, and 4%, respectively. The median baseline HbA1c was 7.2%. The mean duration of type 2 diabetes was 10.5 years and the mean BMI was 32.3 kg/m 2. At baseline, 50.5% of patients had mild renal impairment (eGFR ≥60 but <90 mL/min/1.73m 2 ), 21.6% had moderate renal impairment (eGFR ≥30 but <60 mL/min/1.73m 2 ), and 1.1% of patients had severe renal impairment (eGFR <30 mL/min/1.73m 2 ) out of 9713 patients whose eGFR were available.
At baseline, 94.7% of patients were taking antidiabetic medication, with 10.5% of patients taking three or more antidiabetic drugs. The most common background antidiabetic drugs used at baseline were metformin (81.2%), sulfonylurea (46.0%), and insulin (23.9%). At baseline, CV disease and risk factors were managed with ACE inhibitors or angiotensin receptor blockers (81.5%), beta blockers (45.6%), calcium channel blockers (34.4%), diuretics (46.5%), statin therapy (66.1%), antithrombotic agents (58.7%), and aspirin (51.7%). During the trial, investigators were to modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipids, and blood pressure, and manage patients recovering from an acute coronary syndrome or stroke event per local treatment guidelines. For the primary analysis, a Cox proportional hazards model was used to test for superiority.
Type I error was controlled across multiple tests. TRULICITY significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke (HR: 0.88, 95% CI 0.79, 0.99). Refer to Figure 6 and Table 14. Vital status was available for 99.7% of patients in the trial. A total of 1128 deaths were recorded during the REWIND trial.
A majority of the deaths in the trial were adjudicated as CV deaths, and non-CV deaths were comparable between the treatment groups (4.4% in patients treated with TRULICITY and 5.0% in patients treated with placebo). There were 536 all-cause deaths (10.8%) in the dulaglutide group compared to 592 deaths (12.0%) in the placebo group. Number of patients at risk Placebo 4952 4791 4625 4437 4275 3575 742 Dulaglutide 4949 4815 4670 4521 4369 3686 741 Figure 6. KAPLAN MEIER CURVE: Time to First Occurrence of MACE in the REWIND Trial Table 14: Treatment Effect for MACE and the Individual Components in the REWIND Trial, Median Trial Observation Time of 5.4 years in Adult Patients with Type 2 Diabetes Mellitus a a All randomized patients. b Cox-proportional hazards model with treatment as a factor. Type I error was controlled for the primary and secondary endpoints. c p=0.026 for superiority (2-sided). d Number and percentage of patients with events. e Results for components of MACE, fatal and non-fatal stroke, and fatal and non-fatal MI are listed descriptively for supportive purposes.
No statistical significance should be inferred since these CIs are not adjusted for multiplicity. Time to First Occurrence of: TRULICITY N=4949 Placebo N=4952 Hazard Ratio (95% CI) b Composite of non-fatal myocardial infarction, non-fatal stroke, cardiovascular death (MACE) d 594 (12.0%) 663 (13.4%) 0.88 c Cardiovascular death d,e 317 (6.4%) 346 (7.0%) 0.91 Non-fatal myocardial infarction d,e 205 (4.1%) 212 (4.3%) 0.96 Non-fatal stroke d,e 135 (2.7%) 175 (3.5%) 0.76 Fatal or non-fatal myocardial infarction d,e 223 (4.5%) 231 (4.7%) 0.96 Fatal or non-fatal stroke d,e 158 (3.2%) 205 (4.1%) 0.76 Figure 6
Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older
with Type 2 Diabetes Mellitus In this 26-week randomized, double-blind, placebo-controlled, parallel-arm, multicenter trial with an open-label extension for an additional 26 weeks,154 pediatric patients 10 years of age and older with type 2 diabetes mellitus, who had inadequate glycemic control despite diet and exercise, were randomized to subcutaneous TRULICITY once weekly (0.75 mg and 1.5 mg) or subcutaneous placebo once weekly in combination with or without metformin and/or basal insulin treatment (NCT02963766). Overall, in this trial demographic and baseline disease characteristics were comparable across the treatment groups. At baseline, 71% of patients were female, and the mean age was 14.5 years (ranging from 10 to 17 years). Overall, 55% were White, 15% were Black or African American, 12% were Asian, 10% were American Indian or Alaska Native, 5% were other races, and 3% had unknown race. Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity.
At baseline, the mean duration of type 2 diabetes mellitus was 2 years, mean HbA1c was 8.1%, mean weight was 90.5 kg and mean BMI was 34.1 kg/m 2. In this trial, once weekly TRULICITY (0.75 mg and 1.5 mg, pooled) (with or without metformin and/or basal insulin) was superior to placebo (p<0.001) in the change from baseline at Week 26 in HbA1c in pediatric patients 10 years of age and older with type 2 diabetes mellitus (see Table 15 ). Table 15: Glycemic Results at Week 26 in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus with Inadequate Glycemic Control Despite Diet and Exercise (With or Without Metformin and/or Basal Insulin) Abbreviations: HbA1c = hemoglobin A1c. a Combined results for TRULICITY 0.75 mg and 1.5 mg. The comparison of the two dosages together and individually with placebo was prespecified with overall type I error controlled. b The change from baseline and difference from placebo were analyzed using analysis of covariance with effects for treatment, the baseline value as a covariate, and stratification factors which were HbA1c at screening (< 8% vs >= 8%), insulin use at baseline (yes/no), metformin use at baseline (yes/no). c For HbA1c and Fasting Blood Glucose, multiple imputation was performed for missing data guided by washout method. At Week 26 primary efficacy (HbA1c) was missing for 8%, 6%, and 10% of patients on placebo, TRULICITY 0.75 mg and TRULICITY 1.5 mg respectively. d For percentage of patients HbA1c < 7%, missing data was imputed as not achieving the target.
Placebo TRULICITY 0.75 mg once weekly TRULICITY 1.5 mg once weekly TRULICITY once weekly Pooled a Intent-to-Treat Population (N) 51 51 52 103 HbA1c (%) (Mean) c Baseline Change from baseline at Week 26 b Difference from placebo (95% CI) b 8.1 0.6 - 7.9 -0.6 -1.2 (-1.8, -0.6) 8.2 -0.9 -1.5 (-2.1, -0.9) 8.0 -0.8 -1.4 (-1.9, -0.8) Percentage of Patients with HbA1c <7.0% at Week 26 d 14% 55% 48% 52% Fasting Blood Glucose (mg/dL) (Mean) c Baseline Change from baseline at Week 26 b Difference from placebo (95% CI) b 159 17.1 - 149 -12.8 -29.9 (-50.7, -9.1) 163 -24.9 -42.0 (-63.0, -20.9) 156 -18.9 -35.9 (-54.2, -17.6)
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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