DEVOTE: a landmark safety outcomes trial for Tresiba® U-1001
The landmark DEVOTE study compared Tresiba® U-100 vs insulin glargine U-100 in adults with T2D and ASCVD.1,2
In patients with T2D and ASCVD
DEVOTE is the first safety outcomes trial evaluating the noninferiority in risk of major adverse cardiovascular events (MACEa) with Tresiba® U-100 vs insulin glargine U-100.1,2 Tresiba® U-100 achieved the primary composite outcome, demonstrating no increased risk of MACE vs insulin glargine U-100.1 The secondary confirmatory endpoints compared rates and incidence of severeb hypoglycemia between the 2 products.1
Percentage of patients experiencing MACE1,a:
8.5% in the Tresiba® U-100 group
9.3% in the insulin glargine U-100 group
aMACE=cardiovascular death, nonfatal MI, or nonfatal stroke.
bSevere 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.1
Secondary confirmatory endpoint
In adult patients with type 2 diabetes and ASCVD
Tresiba® U-100 is a basal insulin that has demonstrated significantly lower rates of severe hypoglycemia vs insulin glargine U-1001,3-5
Rate of severe hypoglycemia events1
Tresiba® U-100
3.70 events
per 100 patient-yearsc
4.9%
of patients experienced ≥1 severe hypoglycemia event(s)d
Insulin glargine U-100
6.25 events
per 100 patient-yearsc
6.6%
of patients experienced ≥1 severe hypoglycemia event(s)d
cEstimated rate ratio: 0.60 (95% CI, 0.48 to 0.76); P<0.001 for superiority.1,2
dAbsolute difference: 1.7%. Estimated odds ratio, 0.73 (95% CI, 0.60 to 0.89); P<0.001 for superiority.1,2
Glycemic control between the 2 groups was similar at baseline and throughout the trial.2
Study design
DEVOTE: a landmark safety outcomes trial for Tresiba® U-100
DEVOTE was a landmark treat-to-target trial of 7637 patients with inadequately controlled type 2 diabetes and ASCVD.1
7637 patients
Inclusion criteria1,2,e:
- Type 2 diabetes1
- Current treatment with ≥1 oral or injectable antidiabetic agent2
- A1C ≥7.0% OR A1C <7.0% and current treatment with ≥20 U/day basal insulin2
- Age ≥50 years and ≥1 coexisting cardiovascular or renal condition OR age ≥60 years and ≥1 cardiovascular risk factor1,2
Exclusion criteria6,e:
- Acute coronary or cerebrovascular event in previous 60 days
- Planned coronary, carotid, or peripheral artery revascularization
- Chronic heart failure NYHA class IV
- Current hemodialysis or peritoneal dialysis or eGFR <30 mL/min/1.73 m2 per CKD-EPI
- End-stage liver disease
eThis is not an exhaustive list of the inclusion and exclusion criteria.
Duration 2.0 years (median)
Primary composite endpoint
Time to first MACE composed of:
CV death
Nonfatal MI
Nonfatal stroke
FPG target was 71 to 90 mg/dL with an alternative target of 90 to 126 mg/dL for vulnerable patients, at investigators’ discretion.2,f
fPatients determined their FPG by performing 3 pre-breakfast SMBG tests on the 2 days before and on the day of dose adjustment each week. The lowest of the 3 pre-breakfast SMBG values was used to adjust their dose of basal insulin each week.
Secondary confirmatory endpoints:
The number and incidence of severe hypoglycemic events1
Patient characteristics at baseline1,2:
- Mean age: 65 years1
- Mean diabetes duration: 16.4 years1
- Mean A1C: 8.4%1
- % of patients on insulin therapy: 83.92
Change in A1C level2:
There was no significant difference between treatment groups throughout the trial; at 24 months, A1C was 7.5% in both groups. ETD 0.01% (95% CI, –0.05 to 0.07); P=0.78 in post hoc analysis.
ASCVD=atherosclerotic cardiovascular disease; CKD-EPI=Chronic Kidney Disease Epidemiology Collaboration; CV=cardiovascular; eGFR=estimated glomerular filtration rate; MI=myocardial infarction; NYHA=New York Heart Association; T2D=type 2 diabetes.
In a separate study designed to further evaluate the safety profile of Tresiba® U-100
Find out what SWITCH 2 revealed about the efficacy and safety of Tresiba®
Important Safety Information for Tresiba®
Contraindications
- Tresiba® is contraindicated during episodes of hypoglycemia and in patients with hypersensitivity to insulin degludec or any of the excipients in Tresiba®
Warnings and Precautions
- Never Share a Tresiba® FlexTouch® Pen, Needle, or Syringe 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, or 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. 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). 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, changes in level of physical activity, or changes to concomitant drugs. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia. Patients and caregivers must be educated to recognize and manage 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, always 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.
- 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 and treat if indicated.
- Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Tresiba®. Patients should be observed for signs and symptoms of heart failure. If heart failure occurs, dosage reduction or discontinuation of the TZD must be considered.
Adverse Reactions
- Adverse reactions commonly associated with Tresiba® are hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain.
Drug Interactions
- There are certain drugs that may cause clinically significant drug interactions with Tresiba®.
- Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors
- Drugs that may decrease the blood glucose lowering effect: 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
- Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine
- Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine
Please click here for Tresiba® Prescribing Information.
Important Safety Information for Tresiba®
Contraindications
- Tresiba® is contraindicated during episodes of hypoglycemia and in patients with hypersensitivity to insulin degludec or any of the excipients in Tresiba®
Warnings and Precautions
- Never Share a Tresiba® FlexTouch® Pen, Needle, or Syringe 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, or 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. 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). 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, changes in level of physical activity, or changes to concomitant drugs. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia. Patients and caregivers must be educated to recognize and manage 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, always 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.
- 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 and treat if indicated.
- Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists: Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including Tresiba®. Patients should be observed for signs and symptoms of heart failure. If heart failure occurs, dosage reduction or discontinuation of the TZD must be considered.
Adverse Reactions
- Adverse reactions commonly associated with Tresiba® are hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain.
Drug Interactions
- There are certain drugs that may cause clinically significant drug interactions with Tresiba®.
- Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors
- Drugs that may decrease the blood glucose lowering effect: 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
- Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine
- Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine
Please click here for Tresiba® Prescribing Information.
References:
- Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc.
- Marso SP, McGuire DK, Zinman B, et al. N Engl J Med. 2017;377(8):723-732.
- Lantus [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; June 2022.
- Toujeo [package insert]. Bridgewater, NJ: sanofi-aventis US LLC; March 2023.
- Basaglar [package insert]. Indianapolis, IN: Lilly USA LLC; July 2021.
- Marso SP, McGuire DK, Zinman B, et al. N Engl J Med. 2017;376(suppl):1-70.