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Primary endpoint (noninferiority) and secondary endpoint (superiority) of A1C reductions achieved

DUAL™ V: Xultophy® 100/3.6 demonstrated A1C reductions vs insulin glargine U‑1001,2


PRIMARY ENDPOINT

(noninferiority)


A1C REDUCTION

A1C reductions vs insulin glargine U‑1001,2

aEstimated treatment difference (ETD) (95% CI): –0.51 (–0.67; –0.34).

  • The difference in A1C effect observed in the trial may not necessarily reflect the effect that will be observed in the care setting where alternative insulin glargine dosage can be used
EXPLORATORY PRESPECIFIED ENDPOINT:
PATIENTS ACHIEVING A1C OF <7%

68%

with Xultophy®
100/3.6 + MET


VS

VS

46%

with insulin glargine U-100 + MET


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tertiary_msg

SECONDARY ENDPOINTS


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EPISODES OF HYPOGLYCEMIA

Rate of severe hypoglycemiab reported in the Xultophy® 100/3.6 arm1,2

treated with Xultophy® 100/3.6 reported severe hypoglycemia2,b

treated with Xultophy® 100/3.6 reported hypoglycemia with a glucose level <54 mg/dL (%)c

bSevere hypoglycemia: an event requiring assistance from another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
cEpisodes of hypoglycemia with a glucose level below 54 mg/dL that are associated with or without symptoms of hypoglycemia.

 

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SECONDARY ENDPOINT CHANGE IN WEIGHT

On average, patients experienced a significant change in weight1

Weight gain can occur with insulin-containing products, including Xultophy® 100/3.6, and has been attributed to the anabolic effects of insulin.1

dETD (95% CI): –7.1 lb (–8.3; –5.81). P<0.0001.

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PRESPECIFIED EXPLORATORY ENDPOINT



INSULIN DOSE

With Xultophy® 100/3.6, it took less insulin to lower A1C

  • Average pretrial insulin glargine U-100: 31 units for Xultophy® 100/3.6 arm; and 32 units for insulin glargine U-100 arm2
  • Average end-of-trial dose: 41 units Xultophy® 100/3.6; 66 units insulin glargine U-100
  • Trial doses could not be increased by more than 4 units per week. No maximum dose was set for insulin glargine U-100
  • Xultophy® 100/3.6 is a combination product that includes basal insulin and a GLP-1 RA

It is unclear whether these observed differences in insulin doses are clinically important.


SUMMARY


DUAL™ V RESULTS

Once-daily Xultophy® 100/3.6 vs insulin glargine U-100

insulin glargine U-100

insulin glargine U-100

PRIMARY ENDPOINT
Mean A1C reduction1

-1.7%

-1.2%

SECONDARY ENDPOINT
Weight change1

-3.1 lb

+4.0 lb

EXPLORATORY PRESPECIFIED ENDPOINT
Patients achieving A1C <7%1

68%

46%

Average insulin dose1

41 units

66 units

Weight gain can occur with insulin-containing products, including Xultophy® 100/3.6, and has been attributed to the anabolic effects of insulin.1

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Study design

A 26-week, randomized, parallel, open-label, treat-to-target trial in adult patients with type 2 diabetes inadequately controlled (A1C 7%-10%) on insulin glargine U-100 (20-50 units) + metformin, comparing the efficacy and safety of Xultophy® 100/3.6 (n=278) with continued up-titration of insulin glargine U-100 (n=279), both + metformin. The primary endpoint was change in A1C after 26 weeks of treatment. Exploratory prespecified endpoints included insulin dose, change from baseline in fasting plasma glucose (FPG) level, 9-point self-measured blood glucose (SMBG) profile, responders for A1C level (predefined targets of <7.0% and ≤6.5%), and for composite targets based on A1C level without hypoglycemia and/or without weight gain.1,2

Review the abstract of the DUAL™ V clinical study



“Fasting plasma glucose is an important part of glycemic control, but it’s not all of it. With Xultophy® 100/3.6, the combination of a basal insulin and a GLP-1 receptor agonist improves FPG and PPG control in just 1 injection.”

Pablo Mora, MD, FACE, MsSc, CDE

“Fasting plasma glucose is an important part of glycemic control, but it’s not all of it. With Xultophy® 100/3.6, the combination of a basal insulin and a GLP-1 receptor agonist improves FPG and PPG control in just 1 injection.”

Pablo Mora, MD, FACE, MsSc, CDE

Dosing and titration

Start your adult patients with type 2 diabetes on once-daily Xultophy® 100/3.6 and show them how to titrate their dose.

Xultophy® 100/3.6 coverage

See which commercial and Medicare Part D plans give your adult patients access to Xultophy® 100/3.6.


 

Selected Important Safety Information

WARNING: RISK OF THYROID C-CELL TUMORS

  • Liraglutide, one of the components of Xultophy® 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Xultophy® 100/3.6 causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.
  • Xultophy® 100/3.6 is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Xultophy® 100/3.6 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 Xultophy® 100/3.6.

Indications and Limitations of Use

Xultophy® 100/3.6 (insulin degludec and liraglutide injection) 100 units/mL and 3.6 mg/mL is a combination of insulin degludec and liraglutide and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

  • Xultophy® 100/3.6 is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise.
  • Xultophy® 100/3.6 is not recommended for use in combination with any other product containing liraglutide or another GLP-1 receptor agonist (GLP-1 RA).
  • Xultophy® 100/3.6 is not indicated for use in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
  • Xultophy® 100/3.6 has not been studied in combination with prandial insulin.

Important Safety Information

WARNING: RISK OF THYROID C-CELL TUMORS

  • Liraglutide, one of the components of Xultophy® 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Xultophy® 100/3.6 causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.
  • Xultophy® 100/3.6 is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Xultophy® 100/3.6 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 Xultophy® 100/3.6.

Contraindications

  • Xultophy® 100/3.6 is contraindicated during episodes of hypoglycemia and in patients with hypersensitivity to Xultophy® 100/3.6, either of the active substances, or any of its excipients. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide, one of the components of Xultophy® 100/3.6.

Warnings and Precautions

  • Risk of Thyroid C-cell Tumors: If serum calcitonin is measured and found to be elevated or thyroid nodules are noted on physical examination or neck imaging, the patient should be further evaluated.
  • Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide postmarketing. Observe patients carefully for signs and symptoms of pancreatitis (persistent severe abdominal pain, sometimes radiating to the back with or without vomiting). If pancreatitis is suspected, discontinue Xultophy® 100/3.6 promptly and if pancreatitis is confirmed, do not restart. Liraglutide, one of the components of  Xultophy® 100/3.6, has been studied in a limited number of patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at a higher risk for development of pancreatitis on liraglutide.
  • Never Share a Xultophy® 100/3.6 Pen Between Patients,  even if the needle is changed. Sharing of the pen poses a risk for transmission of blood-borne pathogens.
  • Hyper- or Hypoglycemia with Changes in Xultophy® 100/3.6 Regimen: Monitor blood glucose in all patients. Changes in Xultophy® 100/3.6 regimen may affect glycemic control. Changes should be made cautiously and under medical supervision. Adjustments in concomitant oral anti-diabetic treatment may be needed.
  • Overdose Due to Medication Errors: Instruct patients to check the label before each injection since accidental mix-ups with insulin containing products can occur. Do not administer more than 50 units of Xultophy® 100/3.6 daily. Do not exceed the 1.8 mg maximum recommended dose of liraglutide or use with other GLP-1 RAs.
  • Hypoglycemia: Hypoglycemia is the most common adverse reaction of insulin-containing products, including Xultophy® 100/3.6, and may be life-threatening. Increase monitoring with changes to: dose, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with hypoglycemia unawareness or renal or hepatic impairment.
  • Acute Kidney Injury: Acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis, have been reported postmarketing for liraglutide, usually in association with nausea, vomiting, diarrhea, or dehydration. Advise patients of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.
  • Hypersensitivity and Allergic Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur. If a hypersensitivity reaction occurs, discontinue and treat per standard of care. Anaphylaxis and angioedema have been reported with other GLP-1 RAs. Use caution in a patient with a history of anaphylaxis or angioedema with other GLP-1 RAs because it is unknown whether such patients will be predisposed to these reactions with Xultophy® 100/3.6.
  • Acute Gallbladder Disease: In a cardiovascular outcomes trial (LEADER trial) 3.1% of patients treated with liraglutide, one of the components of Xultophy® 100/3.6, versus 1.9% of placebo treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis. The majority of events required hospitalization or cholecystectomy. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
  • Hypokalemia: All insulin containing products, including Xultophy® 100/3.6 can lead to life-threatening hypokalemia, which may then cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated.
  • Fluid Retention and Congestive Heart Failure: Patients using insulin containing products, including Xultophy® 100/3.6, with thiazolidinediones (TZDs) should be observed for signs and symptoms of heart failure. If heart failure develops, dosage reduction or discontinuation of the TZD must be considered.

Adverse Reactions

  • The most common adverse reactions, reported in ≥5% of patients treated with Xultophy® 100/3.6 are nasopharyngitis, headache, nausea, diarrhea, increased lipase and upper respiratory tract infection.

Drug Interactions

  • Certain drugs may affect glucose metabolism, requiring dose adjustment and close monitoring of blood glucose. The signs and symptoms of hypoglycemia may be reduced or absent in patients taking anti-adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine).
  • Liraglutide-containing products, including Xultophy® 100/3.6, cause a delay of gastric emptying, and thereby have the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with liraglutide-containing products.

Use in Specific Populations

  • Xultophy® 100/3.6 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Please click here for Prescribing Information.

 

References:

  1. Xultophy 100/3.6 [package insert]. Plainsboro, NJ: Novo Nordisk Inc; February 2019.
  2. Lingvay I, Pérez Manghi F, García-Hernández P, et al; DUAL V Investigators. Effect of insulin glargine up-titration vs insulin degludec/liraglutide on glycated hemoglobin levels in patients with uncontrolled type 2 diabetes: the DUAL V randomized clinical trial. JAMA. 2016;315(9):898-907.