Tresiba Drug Information
Generic name: INSULIN DEGLUDEC
Insulin Analog [EPC]
Uses of Tresiba
- TRESIBA is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. Limitations of Use
- Not recommended for the treatment of diabetic ketoacidosis. TRESIBA is a long-acting human insulin analog indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. Limitations of Use:
- Not recommended for the treatment of diabetic ketoacidosis.
Dosage & Administration of Tresiba
Important Administration Instructions •
Always check insulin labels before administration. • Inspect visually for particulate matter and discoloration. Only use TRESIBA if the solution appears clear and colorless. • Inject TRESIBA subcutaneously into the thigh, upper arm, or abdomen. • Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis. • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring. • For pediatric patients requiring less than 5 units of TRESIBA each day, use the TRESIBA U-100 vial. • DO NOT administer TRESIBA intravenously or in an insulin infusion pump. • DO NOT dilute or mix TRESIBA with any other insulin or solution. • DO NOT transfer TRESIBA from the TRESIBA FlexTouch pen into a syringe for administration. • Use TRESIBA FlexTouch pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
General Dosing Instructions • TRESIBA is available in 2 concentrations (U-100 and U-200): o TRESIBA U-100 is available, as a single-patient use FlexTouch pen and multiple-dose vial. ▪ The FlexTouch pen delivers doses in 1 unit increments and can deliver up to 80 units in a single injection. o TRESIBA U-200 is available as a single-patient-use FlexTouch pen. ▪ The FlexTouch pen delivers doses in 2 unit increments and can deliver up to 160 units in a single injection. • DO NOT perform dose conversion when using the TRESIBA U-100 or U-200 FlexTouch pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. • In adults, inject TRESIBA subcutaneously once-daily at any time of day. • In pediatric patients inject TRESIBA subcutaneously once-daily at the same time every day. • Individualize and titrate the dose of TRESIBA based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal. • The recommended days between dose increases are 3 to 4 days. • Dose adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia. • For adult patients, instruct patients who miss a dose of TRESIBA to inject their daily dose during waking hours upon discovering the missed dose. Instruct patients to ensure that at least 8 hours have elapsed between consecutive TRESIBA injections. • For pediatric patients, instruct patients who miss a dose of TRESIBA to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled TRESIBA dose. • In patients with type 1 diabetes, TRESIBA must be used concomitantly with short-acting insulin.
Starting Dose in Insulin Naïve Patients Recommended Starting Dosage in Patients with Type 1 Diabetes Mellitus: The recommended starting dose of TRESIBA in insulin naïve patients with type 1 diabetes is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be administered as a short-acting insulin and divided between each daily meal. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naïve patients with type 1 diabetes.
Recommended Starting Dosage in Patients with Type 2 Diabetes Mellitus: The recommended starting dose of TRESIBA in insulin naïve patients with type 2 diabetes mellitus is 10 units once daily.
Switching to TRESIBA from Other Insulin Therapies
Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to Insulin Degludec from another insulin therapy. Adults with Type 1 or Type 2 Diabetes Mellitus: Start TRESIBA at the same unit dose as the total daily long or intermediate-acting insulin unit dose. Pediatric Patients 1 Year of Age and Older with Type 1 or Type 2 Diabetes Mellitus: Start TRESIBA at 80% of the total daily long or intermediate-acting insulin unit dose to minimize the risk of hypoglycemia.
Side Effects of Tresiba
Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of TRESIBA in subjects with type 1 diabetes or type 2 diabetes was evaluated in nine trials of 6-12 month duration in adults and in one trial of 12-month duration in pediatric patients 1 year of age and older with type 1 diabetes. The cardiovascular safety of TRESIBA was evaluated in one double-blinded, event-driven trial of 2-year median duration in patients with type 2 diabetes at high risk of cardiovascular events.
The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 34 weeks in three open-label trials; Study A, B and C. The mean age was 43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were White, 2% were Black or African American and 4% were Hispanic.
The mean body mass index (BMI) was 26 kg/m 2. The mean duration of diabetes was 18 years and the mean HbA 1c at baseline was 7.8%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in respectively.
The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA with a mean exposure duration to TRESIBA of 36 weeks in six open-label trials; Study D, E, F, G, H and I. The mean age was 58 years and 3% were older than 75 years. Fifty-eight percent were male, 71% were White, 7% were Black or African American and 13% were Hispanic.
The mean BMI was 30 kg/m 2. The mean duration of diabetes was 11 years and the mean HbA 1c at baseline was 8.3%. Common adverse reactions (excluding hypoglycemia) occurring in TRESIBA treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and adults with type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively.
Common adverse reactions were defined as reactions occurring in ≥5% of the population studied. Hypoglycemia is not shown in these tables but discussed in a dedicated subsection below. 174 pediatric patients 1 year of age and older with type 1 diabetes were exposed to TRESIBA with a mean exposure to TRESIBA of 48 weeks. Common adverse reactions in TRESIBA treated pediatric patients with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1.
Table 1: Adverse Reactions Occurring in ≥5% of TRESIBA-Treated Adult Patients with Type 1 Diabetes Mellitus s Occurring in ≥5% of TRESIBA-Treated Adult Patients with Type 2 Diabetes Mellitus Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with TRESIBA. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.
In the open-label adult clinical trials of patients with type 1 and type 2 diabetes, and in the open-label pediatric clinical trial of patients with type 1 diabetes, percentages of adult and pediatric patients with type 1 diabetes randomized to TRESIBA who experienced at least one episode of hypoglycemia in clinical trials and adults with type 2 diabetes are shown in Tables 3 and 4, respectively. Severe hypoglycemia in the open-label trials with adult patients was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe hypoglycemia in the pediatric trial was defined as an altered mental status where the child could not assist in his own care, was semiconscious or unconscious, or in a coma ± convulsions and may require parenteral therapy (glucagon or intravenous glucose).
A hypoglycemia episode was defined as a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms). Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including TRESIBA and may be life threatening. Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients treated with TRESIBA.
Lipodystrophy Long-term use of insulin, including TRESIBA, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption. In the clinical program, lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated with TRESIBA.
Injection Site Reactions Patients taking TRESIBA may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical program, injection site reactions occurred in 3.8% of patients treated with TRESIBA. Weight Gain Weight gain can occur with insulin therapy, including TRESIBA, and has been attributed to the anabolic effects of insulin.
Peripheral Edema TRESIBA, may cause sodium retention and edema. In the clinical program, peripheral edema occurred in 0.9% of patients with type 1 diabetes mellitus and 3.0% of patients with type 2 diabetes mellitus treated with TRESIBA.
Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to TRESIBA with the incidence of antibodies in other studies or to other products may be misleading.
In a 52-week trial of adult insulin-experienced type 1 diabetes patients, 68.9% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 12.3% of the patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of pediatric insulin-experienced type 1 diabetes patients, 84.1% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 5.8% of patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received TRESIBA were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients developed anti-insulin degludec antibodies at least once during the trial.
In these trials, between 96.7% and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive for anti-human insulin antibodies.
Postmarketing Experience
The following additional adverse reactions have been identified during post-approval use of TRESIBA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Localized cutaneous amyloidosis at the injection site has occurred.
Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.
| Adverse Reaction | TRESIBA (N=1,102) |
|---|---|
| Nasopharyngitis | 23.9 % |
| Upper respiratory tract infection | 11.9 % |
| Headache | 11.8 % |
| Sinusitis | 5.1 % |
| Gastroenteritis | 5.1 % |
| Adverse Reaction | TRESIBA (N=2,713) |
|---|---|
| Nasopharyngitis | 12.9 % |
| Headache | 8.8 % |
| Upper respiratory tract infection | 8.4 % |
| Diarrhea | 6.3 % |
| Study A Adults + insulin aspart 52 weeks | Study B Adults + insulin aspart 26 weeks | Study C Adults + insulin aspart 26 weeks | Study J Pediatrics + insulin aspart 52 weeks | ||
|---|---|---|---|---|---|
| TRESIBA (N=472) | TRESIBA (N=301) | TRESIBA at the same time each day (N=165) | TRESIBA at alternating times (N=164) | TRESIBA (N=174) | |
| Severe hypoglycemia* | |||||
| Percent of patients | 12.3% | 10.6% | 12.7% | 10.4% | 17.8% |
| Hypoglycemia § | |||||
| Percent of patients | 95.6% | 93.0% | 99.4% | 93.9% | 98.3% |
| Study D + 1-2 OADs* insulin naïve 52 weeks | Study E + 1-2 OADs* insulin naïve 26 weeks | Study F ± 1-3 OADs* insulin naïve 26 weeks | Study G T2DM ± 0-3 OADs* 26 weeks | Study H T2DM ± 0-2 OADs* + insulin aspart 52 weeks | Study I T2DM ± 1-2 OADs* insulin naïve 26 weeks | ||
|---|---|---|---|---|---|---|---|
| TRESIBA (N=766) | TRESIBA (N=228) | TRESIBA (N=284) | TRESIBA (N=226) | TRESIBA (alternating time) (N=230) | TRESIBA (N=753) | TRESIBA (N=226) | |
| Severe Hypoglycemia | |||||||
| Percent of patients | 0.3% | 0 | 0 | 0.9% | 0.4% | 4.5% | 0.4% |
| Hypoglycemia § | |||||||
| Percent of patients | 46.5% | 28.5% | 50% | 43.8% | 50.9% | 80.9% | 42.5% |
Warnings & Cautions for Tresiba
Never Share a TRESIBA FlexTouch Pen, Needle, or Insulin Syringe Between Patients TRESIBA FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Patients using TRESIBA vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring.
Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic treatment may be needed.
Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin, including TRESIBA. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).
TRESIBA, or any insulin, should not be used during episodes of hypoglycemia. Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers), or who experience recurrent hypoglycemia.
The long-acting effect of TRESIBA may delay recovery from hypoglycemia compared to shorter-acting insulins. Risk Factors for Hypoglycemia The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal.
As with all insulins the glucose lowering effect time course of TRESIBA may vary among different patients or at different times in the same patients and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.
Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.
Hypoglycemia Due to Medication Errors
Accidental mix-ups between insulin products, have been reported. To avoid medication errors between TRESIBA and other insulins, instruct patients to always check the insulin label before each injection. To avoid dosing errors and potential overdose, never use a syringe to remove TRESIBA from the TRESIBA FlexTouch disposable insulin prefilled pen.
Hypersensitivity Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including TRESIBA. If hypersensitivity reactions occur, discontinue TRESIBA; treat per standard of care and monitor until symptoms and signs resolve. TRESIBA is contraindicated in patients who have had hypersensitivity reactions to insulin degludec or any of the excipients.
Hypokalemia
All insulins, including TRESIBA, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).
Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists can cause dose related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated with insulin, including TRESIBA and a PPAR-gamma agonist should be observed for signs and symptoms of congestive heart failure.
If congestive heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.
Drug Interactions with Tresiba
- Table 5 includes clinically significant drug interactions with TRESIBA. Table 5: Clinically Significant Drug Interactions with TRESIBA
- Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage mey be needed.
- Antiandrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent.
| Drugs That May Increase the Risk of Hypoglycemia | |
| Drugs: | Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors. |
| Intervention: | Dosage reductions and increased frequency of glucose monitoring may be required when TRESIBA is co-administered with these drugs. |
| Drugs That May Decrease the Blood Glucose Lowering Effect of TRESIBA | |
| Drugs: | Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. |
| Intervention: | Dosage increases and increased frequency of glucose monitoring may be required when TRESIBA is co-administered with these drugs. |
| Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of TRESIBA | |
| Drugs: | Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. |
| Intervention: | Dosage adjustment and increased frequency of glucose monitoring may be required when TRESIBA is co-administered with these drugs. |
| Drugs That May Blunt Signs and Symptoms of Hypoglycemia | |
| Drugs: | Beta-blockers, clonidine, guanethidine, and reserpine |
| Intervention: | Increased frequency of glucose monitoring may be required when TRESIBA is co-administered with these drugs. |
Pregnancy Safety for Tresiba
Pregnancy Risk Summary Available data from one unpublished trial and the published literature with TRESIBA use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label actively controlled clinical trial that included 91 pregnant women with type 1 diabetes who were administered TRESIBA once daily and insulin aspart, beginning in gestational weeks 8 to 13 or prior to conception, no clear evidence of maternal or fetal risk associated with TRESIBA use was observed ( see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy ( see Clinical Considerations ).
Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis. Pre-and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. These effects were similar to those observed in rats administered human insulin (NPH) (see Data).
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo/fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes.
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, still birth, and macrosomia related morbidity. Data Human Data In an open-label clinical trial, 185 pregnant females with type 1 diabetes were treated with either TRESIBA (once daily) or insulin detemir (once or twice daily); both groups received insulin aspart 2 to 4 times daily with meals.
There were no significant drug-associated differences in pregnancy outcomes or the health of the fetus and newborn between the two groups. In this study, the proportion of subjects with severe hypoglycemia and hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and hypoglycemia. Poor glucose control during pregnancy in both groups and small sample size were limitations of the study.
In about two thirds of infants, insulin degludec was detected in the infant cord blood at levels above the lower level of quantification of the assay. Animal Data Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development in rats and during the period of embryo-fetal development in rabbits. Human insulin (NPH insulin) was included as comparator.
Overall, the effects of insulin degludec were similar to those observed with human insulin, which were probably secondary to maternal hypoglycemia.
Pediatric Use of Tresiba
Pediatric Use The safety and effectiveness of TRESIBA to improve glycemic control in pediatric patients 1 year of age and older with diabetes mellitus have been established. The use of TRESIBA for this indication is supported by evidence from an adequate and well-controlled trial and a pharmacokinetic study (trials included pediatric patients 1 year of age and older with type 1 diabetes mellitus). The use of TRESIBA in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also supported by evidence from adequate and well-controlled trials in adults with type 2 diabetes mellitus.
In pediatric patients 1 year of age and older already on insulin therapy, start TRESIBA at a reduced dose to minimize the risk of hypoglycemia. The safety and effectiveness of TRESIBA have not been established in pediatric patients less than 1-year-old.
Contraindications for Tresiba
- TRESIBA is contraindicated:
- During episodes of hypoglycemia.
- In patients with hypersensitivity to insulin degludec or any of the excipients in TRESIBA.
- During episodes of hypoglycemia.
Overdosage Information for Tresiba
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Lowering the insulin dosage, and adjustment in meal patterns or exercise may be needed.
More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with a glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid reoccurrence of hypoglycemia. Hypokalemia must be corrected appropriately.
Clinical Studies of Tresiba
Type 1 Diabetes – Adult TRESIBA Administered at the Same Time Each Day in Combination with a Rapid-Acting Insulin Analog at Mealtimes in Adult Patients Study A The efficacy of TRESIBA was evaluated in a 52-week randomized, open-label, multicenter trial in 629 patients with type 1 diabetes mellitus (Study A). Patients were randomized to TRESIBA once-daily with the evening meal or insulin glargine U-100 once-daily according to the approved labeling. Insulin aspart was administered before each meal in both treatment arms.
The mean BMI was approximately 26.3 kg/m 2. See Table 6, Study A. Study B The efficacy of TRESIBA was evaluated in a 26-week randomized, open-label, multicenter trial in 455 patients with type 1 diabetes mellitus (Study B).
Patients were randomized to TRESIBA or insulin detemir once-daily in the evening. After 8 weeks, insulin detemir could be dosed twice-daily. 67% used insulin detemir once daily at end of trial. 33% used insulin detemir twice daily at end of trial. The mean BMI was approximately 23.9 kg/m 2.
See Table 6, Study B. Table 6: Results at Week 52 in a Trial Comparing TRESIBA to Insulin Glargine U-100 (Study A) and Week 26 in a Trial Comparing TRESIBA to Insulin Detemir (Study B) in Adult Patients with Type 1 Diabetes Mellitus Receiving Insulin Aspart at Mealtimes 1 At Week 52 2 At Week 26 The change from baseline to end of treatment visit in HbA 1c was analyzed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA 1c as covariates. In Study A, there were 14.8% of subjects in the TRESIBA and 11.5% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement.
In Study B, there were 6.3% of subjects in the TRESIBA and 9.8% Insulin detemir arms for whom data was missing at the time of the HbA 1c measurement. The any time each day TRESIBA arm was designed to simulate a worst-case scenario injection schedule of alternating short and long, once daily, dosing intervals (i.e., alternating intervals of 8 to 40 hours between doses). TRESIBA in this arm was dosed in the morning on Monday, Wednesday, and Friday and in the evening on Tuesday, Thursday, Saturday, and Sunday.
At week 26, the difference in HbA 1c reduction from baseline between TRESIBA administered at alternating times and insulin glargine U-100 was 0.17% with a 95% confidence interval of and met the pre-specified non-inferiority margin (0.4%). See Table 7. Table 7: Results at Week 26 in a Trial Comparing TRESIBA Dosed Once Daily at the Same and at Alternating Times Each Day to Insulin Glargine U-100 in Adult Patients with Type 1 Diabetes Mellitus Receiving Insulin Aspart at Mealtimes The change from baseline to end of treatment visit in HbA 1c was analyzed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA 1c as covariates.
In Study C, there were 15.8% and 15.9% of subjects in the TRESIBA (same time and alternating times respectively) and 7.9% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement.
Subjects on a twice-daily insulin detemir regimen were dosed at breakfast and in the evening either with the main evening meal or at bedtime. At end of trial, 36% used insulin detemir once daily and 64% used insulin detemir twice daily. The mean z-score for body weight was 0.31.
See Table 8. Table 8: Results at Week 26 in a Trial Comparing TRESIBA to Insulin Detemir in Pediatric Patients 1 Year of Age and Older with Type 1 Diabetes Mellitus Receiving Insulin Aspart at Mealtimes ± The change from baseline to end of treatment visit in HbA 1c was analyzed using ANOVA with missing data imputed by multiple imputation carrying forward the baseline value and adding the error term, with treatment, region, sex, and age group as fixed factors, and baseline HbA 1c as covariate. In Study J, there were 2.9% of subjects in TRESIBA and 6.3% Insulin detemir arms for whom data was missing at the 26-week HbA 1c measurement.
- Type 2 Diabetes - Adult Study D: TRESIBA Administered at the Same Time Each Day as an Add-on to Metformin with or without a DPP-4 Inhibitor in Insulin Naïve Adult Patients The efficacy of TRESIBA was evaluated in a 52-week randomized, open-label, multicenter trial that enrolled 1030 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs). Metformin alone (83%) or in combination with a DPP-4 inhibitor (18%) was used as background therapy in both treatment arms. The mean BMI was approximately 31.1 kg/m 2.
- Table 9: Results at Week 52 in a Trial Comparing TRESIBA to Insulin Glargine U-100 in Adult Patients with Type 2 Diabetes Mellitus on OAD(s) OAD: oral antidiabetic agent The change from baseline to end of treatment visit in HbA 1c was analyzed using ANOVA with treatment, region, sex, and anti-diabetic treatment at screening as fixed effects, and age and baseline HbA 1c as covariates. In Study D, there were 20.6% of subjects in the TRESIBA and 22.2% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement. Both treatment arms were receiving metformin alone (84%) or in combination with a DPP-4 inhibitor (16%) as background therapy. The mean BMI was approximately 32.4 kg/m 2. See Table 10. In Study E, there were 12.3% of subjects in the TRESIBA and 12.7% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement.
- Study F: TRESIBA Administered at the Same Time Each Day in Insulin Naïve Adult Patients as an Add-on to One or More of the Following Oral Agents: Metformin, Sulfonylurea, Glinides or Alpha-Glucosidase Inhibitors The efficacy of TRESIBA was evaluated in a 26-week randomized, open-label, multicenter trial in Asia in 435 insulin naïve patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agents (OADs) at baseline. Pre-trial oral antidiabetes agents were continued as background therapy except for DPP-4 inhibitors or thiazolidinediones in both treatment arms. The mean age of the trial population was 59 years and mean duration of diabetes was 12 years. 54% were male. All patients were Asian. 11% of patients had eGFR<60 mL/min/1.73m 2. The mean BMI was approximately 25.0 kg/m 2. See Table 11. In Study F, there were 10% of subjects in the TRESIBA and 6.8% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement.
- Study G: TRESIBA Administered at the Same Time Each Day or Any Time Each Day as an Add-on to One and up to Three of the Following Oral Agents: Metformin, Sulfonylurea or Glinides or Pioglitazone in Adult Patients The efficacy of TRESIBA was evaluated in a 26-week randomized, open-label, multicenter trial in 687 patients with type 2 diabetes mellitus inadequately controlled on basal insulin alone, oral antidiabetic agents (OADs) alone or both basal insulin and OAD. Up to three of the following oral antidiabetes agents (metformin, sulfonylureas, glinides or thiazolidinediones) were administered as background therapy in both treatment arms. The mean BMI was approximately 29.6 kg/m 2. This comparison met the pre-specified non-inferiority margin (0.4%). See Table 12. In Study G, there were 11.4% subjects for TRESIBA (both same time and alternating times) and 11.7% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement. Up to two of the following oral antidiabetes agents (metformin or pioglitazone) were used as background therapy in both treatment arms. See Table 13. In Study H, there were 16.1% of subjects in the TRESIBA and 14.5% Insulin glargine arms for whom data was missing at the time of the HbA 1c measurement.
- Study I: TRESIBA Administered at Any Time Each Day as an Add-on to One or Two of the Following Oral Agents: Metformin, Sulfonylurea, or Pioglitazone in Adult Patients The efficacy of TRESIBA was evaluated in a 26-week randomized, open-label, multicenter trial in 447 patients with type 2 diabetes mellitus inadequately controlled on one or more oral antidiabetic agent (OADs) at baseline. Patients were randomized to TRESIBA once-daily at any time of day or sitagliptin once-daily according to the approved labeling. One or two of the following oral antidiabetes agents (metformin, sulfonylurea or pioglitazone) were also administered in both treatment arms. At the end of 26 weeks, TRESIBA provided greater reduction in mean HbA 1c compared to sitagliptin (p < 0.001). See Table 14. In Study I, there were 20.9% of subjects in the TRESIBA and 22.5% Sitagliptin arms for whom data was missing at the time of the HbA 1c measurement. 1 p <0.001; 1-sided p-value evaluated at 2.5% level for superiority
Safety Outcomes Trial DEVOTE (NCT01959529) Cardiovascular Outcomes Trial of TRESIBA Administered Once-Daily Between Dinner and Bedtime in Combination with Standard of Care in Subjects with Type 2 Diabetes and Atherosclerotic Cardiovascular Disease DEVOTE was a multi-center, multi-national, randomized, double-blinded, active-controlled, treat-to-target, event-driven trial. 7,637 patients with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease were randomized to either TRESIBA or insulin glargine U-100. Each was administered once-daily between dinner and bedtime in addition to standard of care for diabetes and cardiovascular disease for a median duration of 2 years. Patients eligible to enter the trial were; 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure (85% of the enrolled population) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (15% of the enrolled population).
At baseline, demographic and disease characteristics were balanced between treatment groups. The mean age of the trial population was 65 years and the mean duration of diabetes was 16 years. The mean HbA 1c was 8.4% and the mean BMI was 33.6 kg/m 2.
Previous history of severe hypoglycemia was not captured in the trial. At baseline, patients treated their diabetes with oral antidiabetic drugs (72%) and with an insulin regimen (84%). The most common background oral antidiabetic drugs used at baseline were metformin (60%), sulfonylureas (29%) and DPP-4 inhibitors (12%).
During the trial, investigators could modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets for lipids and blood pressure. Cardiovascular Outcomes - Patients with T2DM and Atherosclerotic CVD The incidence of major cardiovascular events with TRESIBA was evaluated in DEVOTE. Subjects treated with TRESIBA had a similar incidence of major adverse cardiovascular events (MACE) when compared to those treated with insulin glargine U-100.
The primary endpoint in DEVOTE was time from randomization to the first occurrence of a 3-component major adverse cardiovascular event (MACE): cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. The trial was designed to exclude a pre-specified risk margin of 1.3 for the hazard ratio of MACE comparing TRESIBA to insulin glargine U-100. The primary outcome at end of trial was available for 98.2% of participants in each treatment group.
The time to first occurrence of MACE with TRESIBA as compared to insulin glargine U-100 was non-inferior (HR: 0.91; 95% CI; see Figure 3). The results of the primary composite MACE endpoint and a summary of its individual components are shown in Table 15. Table 15: Analysis of the Composite 3-point MACE and Individual Cardiovascular Endpoints in DEVOTE PYO = patient-years of observation until first MACE, death, or trial discontinuation Figure 3: Cumulative Event Probability for Time to First MACE in DEVOTE Hypoglycemia Outcomes - Patients with T2DM and Atherosclerotic CVD The pre-specified secondary endpoints of event and incidence rates of severe hypoglycemia were sequentially tested.
Severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions and during which plasma glucose concentration may not have been available, but where neurological recovery following the return of plasma glucose to normal was considered sufficient evidence that the event was induced by a low plasma glucose concentration. The incidence of severe hypoglycemia was lower in the TRESIBA group as compared to the insulin glargine U-100 group (Table 16). Glycemic control between the two groups was similar at baseline and throughout the trial.
| Study A | Study B | |||
|---|---|---|---|---|
| TRESIBA + Insulin aspart | Insulin glargine U-100 + Insulin aspart | TRESIBA + Insulin aspart | Insulin detemir + Insulin aspart | |
| N | 472 | 157 | 302 | 153 |
| HbA 1c (%) | ||||
| Baseline | 7.7 | 7.7 | 8.0 | 8.0 |
| End of trial | 7.3 | 7.3 | 7.3 | 7.3 |
| Adjusted mean change from baseline | -0.36 | -0.34 | -0.71 | -0.61 |
| Estimated treatment difference [95%CI] TRESIBA - basal insulin U-100 | -0.01 [-0.14;0.11] | -0.09 [-0.23;0.05] | ||
| Proportion Achieving HbA 1c < 7% at Trial End | 39.8% | 42.7% | 41.1% | 37.3% |
| FPG (mg/dL) | ||||
| Baseline | 165 | 174 | 178 | 171 |
| End of trial | 141 | 149 | 131 | 161 |
| Adjusted mean change from baseline | -27.6 | -21.6 | -43.3 | -13.5 |
| Daily basal insulin dose | ||||
| Baseline mean | 28 U | 26 U | 22 U | 22 U |
| Mean dose at end of study | 29 U 1 | 31 U 1 | 25 U 2 | 29 U 2 |
| Daily bolus insulin dose | ||||
| Baseline mean | 29 U | 29 U | 28 U | 31 U |
| Mean dose at end of study | 32 U 1 | 35 U 1 | 36 U 2 | 41 U 2 |
| TRESIBA at the same time each day + Insulin aspart | TRESIBA at alternating times + Insulin aspart | Insulin glargine U-100 + Insulin aspart | |
|---|---|---|---|
| N | 165 | 164 | 164 |
| HbA 1c (%) | |||
| Baseline | 7.7 | 7.7 | 7.7 |
| End of trial | 7.3 | 7.3 | 7.1 |
| Adjusted mean change from baseline | -0.41 | -0.40 | -0.57 |
| Estimated treatment difference [95%CI] TRESIBA alternating - Insulin glargine U-100 | 0.17 [0.04;0.30] | ||
| Proportion Achieving HbA 1c < 7% at Trial End | 37.0% | 37.2% | 40.9% |
| FPG (mg/dL) | |||
| Baseline | 179 | 173 | 175 |
| End of trial | 133 | 149 | 151 |
| Adjusted mean change from baseline | -41.8 | -24.7 | -23.9 |
| Daily basal insulin dose | |||
| Baseline mean | 28 U | 29 U | 29 U |
| Mean dose at end of study | 32 U | 36 U | 35 U |
| Daily bolus insulin dose | |||
| Baseline mean | 29 U | 33 U | 32 U |
| Mean dose at end of study | 27 U | 30 U | 35 U |
| TRESIBA+ Insulin aspart | Insulin detemir + Insulin aspart | |
|---|---|---|
| N | 174 | 176 |
| HbA 1c (%) | ||
| Baseline | 8.2 | 8.0 |
| End of 26 weeks | 8.0 | 7.7 |
| Adjusted mean change from baseline after 26 weeks ± | -0.19 | -0.34 |
| Estimated treatment difference [95%CI] TRESIBA v. Insulin detemir | 0.15 [ -0.03; 0.33] | |
| FPG (mg/dL) | ||
| Baseline | 162 | 151 |
| End of 26 weeks | 150 | 160 |
| Adjusted mean change from baseline after 26 weeks | 52.0 | 59.6 |
| Daily basal insulin dose | ||
| Baseline mean | 15 U (0.37 U/kg) | 16 U (0.41 U/kg) |
| Mean dose after 26 weeks | 16 U (0.37 U/kg) | 22 U (0.51 U/kg) |
| Daily bolus insulin dose | ||
| Baseline mean | 20 U (0.50 U/kg) | 20 U (0.52 U/kg) |
| Mean dose after 26 weeks | 23 U (0.56 U/kg) | 22 U (0.57 U/kg) |
| TRESIBA + OAD(s) | Insulin glargine U-100 + OAD(s) | ||
|---|---|---|---|
| N | 773 | 257 | |
| HbA 1c (%) | |||
| Baseline | 8.2 | 8.2 | |
| End of trial | 7.1 | 7.0 | |
| Adjusted mean change from baseline | -1.06 | -1.15 | |
| Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100 | 0.09 [-0.04;0.22] | ||
| Proportion Achieving HbA 1c < 7% at Trial End | 51.7% | 54.1% | |
| FPG (mg/dL) | |||
| Baseline | 174 | 174 | |
| End of trial | 106 | 115 | |
| Adjusted mean change from baseline | -68.0 | -60.2 | |
| Daily insulin dose | |||
| Baseline mean (starting dose) | 10 U | 10 U | |
| Mean dose after 52 weeks | 56 U | 58 U | |
| TRESIBA U-200 + Met ± DPP-4 | Insulin glargine U-100 + Met ± DPP-4 | ||
|---|---|---|---|
| N | 228 | 229 | |
| HbA 1c (%) | |||
| Baseline | 8.3 | 8.2 | |
| End of trial | 7.0 | 6.9 | |
| Adjusted mean change from baseline | -1.18 | -1.22 | |
| Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100 | 0.04 [-0.11;0.19] | ||
| Proportion Achieving HbA 1c < 7% at Trial End | 52.2% | 55.9% | |
| FPG (mg/dL) | |||
| Baseline | 172 | 174 | |
| End of trial | 106 | 113 | |
| Adjusted mean change from baseline | -71.1 | -63.5 | |
| Daily insulin dose | |||
| Baseline mean | 10 U | 10 U | |
| Mean dose after 26 weeks | 59 U | 62 U | |
| TRESIBA + OAD(s) | Insulin glargine U-100 + OAD(s) | |
|---|---|---|
| N | 289 | 146 |
| HbA 1c (%) | ||
| Baseline | 8.4 | 8.5 |
| End of trial | 7.2 | 7.1 |
| Adjusted mean change from baseline | -1.42 | -1.52 |
| Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100 | 0.11 [-0.03; 0.24] | |
| Proportion Achieving HbA 1c < 7% at Trial End | 40.8% | 48.6% |
| FPG (mg/dL) | ||
| Baseline | 152 | 156 |
| End of trial | 100 | 102 |
| Adjusted mean change from baseline | -54.6 | -53.0 |
| Daily insulin dose | ||
| Baseline mean (starting dose) | 9 U | 9 U |
| Mean dose after 26 weeks | 19 U | 24 U |
| TRESIBA at the same time each day ± OAD(s) | TRESIBA at alternating times ± OAD(s) | Insulin glargine U-100 ± OAD(s) | |
|---|---|---|---|
| N | 228 | 229 | 230 |
| HbA 1c (%) | |||
| Baseline | 8.4 | 8.5 | 8.4 |
| End of trial | 7.3 | 7.2 | 7.1 |
| Adjusted mean change from baseline | -1.03 | -1.17 | -1.21 |
| Estimated treatment difference [95%CI] TRESIBA alternating- Insulin glargine U-100 | 0.04 [-0.12;0.20] | ||
| Estimated treatment difference TRESIBA alternating – TRESIBA same | -0.13 | ||
| Proportion Achieving HbA 1c < 7% at Trial End | 40.8% | 38.9% | 43.9% |
| FPG (mg/dL) | |||
| Baseline | 158 | 162 | 163 |
| End of trial | 105 | 105 | 112 |
| Adjusted mean change from baseline | -54.2 | -55.0 | -47.5 |
| Daily insulin dose | |||
| Baseline mean | 21 U | 19 U | 19 U |
| Mean dose after 26 weeks | 45 U | 46 U | 44 U |
| TRESIBA + Insulin aspart ± OAD(s) | Insulin glargine U-100 + Insulin aspart ± OAD(s) | |
|---|---|---|
| N | 744 | 248 |
| HbA 1c (%) | ||
| Baseline | 8.3 | 8.4 |
| End of trial | 7.1 | 7.1 |
| Adjusted mean change from baseline | -1.10 | -1.18 |
| Estimated treatment difference [95%CI] TRESIBA - Insulin glargine U-100 | 0.08 [-0.05;0.21] | |
| Proportion Achieving HbA 1c < 7% at Trial End | 49.5% | 50.0% |
| FPG (mg/dL) | ||
| Baseline | 166 | 166 |
| End of trial | 122 | 127 |
| Adjusted mean change from baseline | -40.6 | -35.3 |
| Daily basal insulin dose | ||
| Baseline mean | 42 U | 41 U |
| Mean dose after 52 weeks | 74 U | 67 U |
| Daily bolus insulin dose | ||
| Baseline mean | 33 U | 33 U |
| Mean dose after 52 weeks | 70 U | 73 U |
| TRESIBA + OAD(s) | Sitagliptin + OAD(s) | |
|---|---|---|
| N | 225 | 222 |
| HbA 1c (%) | ||
| Baseline | 8.8 | 9.0 |
| End of trial | 7.2 | 7.7 |
| Adjusted mean change from baseline | -1.52 | -1.09 |
| Estimated treatment difference [95%CI] TRESIBA - Sitagliptin | -0.43 [-0.61;-0.24] 1 | |
| Proportion Achieving HbA 1c < 7% at Trial End | 40.9% | 27.9% |
| FPG (mg/dL) | ||
| Baseline | 170 | 179 |
| End of trial | 112 | 154 |
| Adjusted mean change from baseline | -61.4 | -22.3 |
| Daily insulin dose | ||
| Baseline mean | 10 U | N/A |
| Mean dose after 26 weeks | 43 U | N/A |
| TRESIBA | Insulin glargine U-100 | ||||
|---|---|---|---|---|---|
| N | 3,818 | 3,819 | |||
| Number of Patients (%) | Rate per 100 PYO* | Number of Patients (%) | Rate per 100 PYO* | Hazard Ratio (95% CI) | |
| Composite of first event of CV death, non-fatal MI, or non-fatal stroke (3-Point MACE) | 325 (8.5) | 4.41 | 356 (9.3) | 4.86 | 0.91 [0.78; 1.06] |
| CV death | 136 (3.6) | 1.85 | 142 (3.7) | 1.94 | |
| Non-fatal MI | 144 (3.8) | 1.95 | 169 (4.4) | 2.31 | |
| Non-fatal stroke | 71 (1.9) | 0.96 | 79 (2.1) | 1.08 | |
| TRESIBA | Insulin glargine U-100 | |
|---|---|---|
| N | 3,818 | 3,819 |
| Severe Hypoglycemia | ||
| Percent of patients with events | 4.9% | 6.6% |
| Estimated odds ratio [95%CI] TRESIBA/Insulin glargine U-100 | 0.73 [0.60; 0.89] | |
| Events per 100 Patient Years of Observation | 3.70 | 6.25 |
| Estimated rate ratio [95%CI] TRESIBA/Insulin glargine U-100 | 0.60 [0.48; 0.76] | |
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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