Side effects of Tresiba® (insulin degludec) and other hypoglycemia data
What are the most common adverse reactions associated with Tresiba®?
In the SWITCH 2 trial in patients with T2D at increased risk of hypoglycemia
In a separate study designed to further evaluate the safety profile, hypoglycemia rates of Tresiba® U-100 were compared to insulin glargine U-1001
Primary endpoint: Rate of severea or BG-confirmedb symptomatic hypoglycemia events in adult patients with type 2 diabetes in the maintenance period
Patient population was considered to be at increased risk for hypoglycemia
Tresiba® U-100
185.6 events
per 100 patient-years1,c
22.5%
of patients experienced severe or BG-confirmed symptomatic hypoglycemia1,a,b
Insulin glargine U-100
265.4 events
per 100 patient-years1,c
31.6%
of patients experienced severe or BG-confirmed symptomatic hypoglycemia1,a-c
Achieved with similar glycemic control: Tresiba® U-100 vs insulin glargine U-100
- In the separate type 2 diabetes adult trials within the BEGIN clinical trial program, the percentage of patients experiencing at least 1 episode ranged from 0% to 4.5% for severe hypoglycemia and 28.5% to 80.9% for Novo Nordisk–defined hypoglycemia in trials with Tresiba® U-100 ± OADs or in a basal bolus regimen2,a,d
- The American Diabetes Association classifies hypoglycemia <54 mg/dL as sufficiently low to indicate clinically important hypoglycemia and to warrant investigation and review of a patient's medical regimen.3
aSevere hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.2
bBG-confirmed symptomatic hypoglycemia was defined as a BG measurement of <56 mg/dL with symptoms; nocturnal hypoglycemia was defined as any episode occurring between 12:01 AM and 5:59 AM, both inclusive; and severe hypoglycemia was defined per American Diabetes Association 2013 guidelines.
cDifference in percentage: –9.1% (95% CI: –13.1% to –5.0%).
dNovo Nordisk–defined hypoglycemia: a severe hypoglycemia event or an event where laboratory or self-measured glucose calibrated to plasma was <56 mg/dL or where whole blood glucose was <50 mg/dL (ie, with or without the presence of hypoglycemic symptoms).2
SWITCH 2 study design1
Hypoglycemia rates of Tresiba® U‑100 and insulin glargine U‑100 were compared in a randomized, double-blind, crossover study1
20% dose reduction
from twice-daily dosing. If switching from once-daily dosing, the starting dose was the pretrial dose.e
721 adult patients
with type 2 diabetes taking basal insulin ± OADs.
- Patient population was considered to be at increased risk for hypoglycemia
Hypoglycemia may be happening more often than you think
Treatment arm 1
Treatment arm 2
Full treatment period: 64 weeks
A1C noninferiority in both treatment periods was a prerequisite1
- Primary endpoint achieved: Tresiba® U-100 demonstrated superiority vs insulin glargine U-100 in terms of rates of severe or BG-confirmed symptomatic hypoglycemicf,g episodes during the maintenance period of each treatment period
- This study design ensured that all patients were exposed to each trial medication for the same amount of time
- Mean A1C at the end of treatment period 1: Tresiba® U-100, 7.06%; insulin glargine U-100, 6.98%1
- Mean A1C at the end of treatment period 2: Tresiba® U-100, 7.08%; insulin glargine U-100, 7.11%1
All patients required to meet ≥1 of these criteria for developing hypoglycemia:
- ≥1 episode of severe hypoglycemiah in previous year
- Moderate chronic renal failure (eGFR: 30 to 59 mL/min/1.73 m2)
- Hypoglycemic symptom unawareness
- Insulin exposure >5 years
- Episode of hypoglycemiai within previous 12 weeks
eThe starting dose for treatment period 2 was the dose from the end of treatment period 1.
fSevere hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.2
gBG-confirmed symptomatic hypoglycemia was defined as a BG measurement of <56 mg/dL with symptoms; nocturnal hypoglycemia was defined as any episode occurring between 12:01 AM and 5:59 AM, both inclusive; and severe hypoglycemia was defined per American Diabetes Association 2013 guidelines.
hBased on ADA definition.
iSymptoms and/or BG level ≤70 mg/dL.
Secondary endpoints achieved1
Secondary confirmatory endpoints
- The rate of nocturnal symptomatic hypoglycemiaj during the maintenance period was 42% lower with Tresiba® U-100 vs insulin glargine U-100 (55.2 vs 93.6 episodes/100 PYE, respectively; ERR=0.58 [95% CI, 0.46 to 0.74]; P<0.001; rate difference, –7.41 episodes/100 PYE [95% CI, –11.98 to –2.85])
- The rate of severe hypoglycemiak during the maintenance period was 46% lower with Tresiba® U-100 vs insulin glargine U-100 (5.3 vs 9.1 episodes/100 PYE, respectively; ERR=0.54 [95% CI, 0.21 to 1.42]; P=not significant; rate difference, –1.18 episodes/100 PYE [95% CI, –2.77 to –0.41])
- The percentage of patients experiencing at least 1 episode of severe hypoglycemia in the maintenance period was: Tresiba® U-100 1.6%; insulin glargine U-100 2.4% (P=not significant)
Achieved with similar glycemic control: Tresiba® U-100 vs insulin glargine U-100
jNocturnal hypoglycemia was defined as any episode occurring between 12:01 AM and 5:59 AM, both inclusive; and severe hypoglycemia was defined per American Diabetes Association 2013 guidelines.
kSevere hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.2
BG=blood glucose; OADs=oral antidiabetic drugs.
Once-daily Tresiba®: Provide your patients with proven A1C control2
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:
- Wysham C, Bhargava A, Chaykin L, et al. Effect of insulin degludec vs insulin gargine U100 on hypoglycemia in patients with type 2 diabetes: The SWITCH 2 randomized clinical trial. JAMA. 2017;318(1):45-56.
- Tresiba [package insert]. Plainsboro, NJ: Novo Nordisk Inc; July 2022.
- American Diabetes Association. Standards of Care in Diabetes - 2023. Diabetes Care. 2023;46(suppl 1):S1-S291.