DUAL VII demonstrated A1C control and additional clinical benefits for adults with type 2 diabetes taking Xultophy® 100/3.6

DUAL VII demonstrated A1C control and additional clinical benefits for adults with type 2 diabetes taking Xultophy® 100/3.6

A1C (primary endpoint)▾   |   Hypoglycemica (confirmatory secondary endpoint)▾   |   Adverse reactions▾

Weight (confirmatory secondary endpoint)▾   |   Insulin dose (supportive secondary endpoint)▾

Number of injections (supportive secondary endpoint)▾   |   Once-daily Xultophy® 100/3.6 vs basal-bolus therapy (summary)▾

PRIMARY ENDPOINT OF NON-INFERIORITY ACHIEVED IN DUAL VII, A 26-WEEK, OPEN-LABEL TRIAL VS BASAL-BOLUS THERAPY, BOTH PLUS MET

Comparable A1C control vs basal-bolus therapy1

The difference in A1C effect observed in the trial may not necessarily reflect the effect that is observed in the care setting where alternative insulin glargine U-100 dosage can be used.

aEstimated treatment difference (ETD) (95% CI): –0.02 (–0.16; 0.12). P<0.0001 confirmed non-inferiority.


Mean A1C (%)
8.5
8.0
7.5
7.0
6.5
6.0
Xultophy® 100/3.6 + MET (n=252)
insulin glargine U-100 + insulin aspart + MET (n=254)
6.7%
6.7%
secondary_msg


Study design

Duration
26 weeks
Patient population
506 adults with type 2 diabetes inadequately controlled on insulin glargine U-100 (<50 units) + MET
Primary endpoint
Change in A1C
Select secondary endpoints
Insulin dose, episodes of hypoglycemia, change in body weight, and proportion of patients who achieved A1C <7%, had no hypoglycemia in the last 12 weeks of treatment, and/or had no weight gain
See full study designHide full 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=252) with basal-bolus therapy (insulin glargine U-100 + insulin aspart [n=254]), both + metformin. The primary endpoint was change in A1C after 26 weeks of treatment. Secondary endpoints included change in laboratory-measured FPG, dose, change in body weight, percent of patients achieving A1C <7%, and episodes of hypoglycemia.1

CONFIRMATORY SECONDARY ENDPOINT OF SEVERE OR BG-CONFIRMED SYMPTOMATIC HYPOGLYCEMIA ACHIEVED

Patients had a significantly lower rate of hypoglycemia1,b,c

  • 89% lower rate with Xultophy® 100/3.6

The clinical relevance of the difference in rates of severe or BG-confirmed hypoglycemia has not been established

bSevere or blood glucose (BG)-confirmed symptomatic hypoglycemia: an event requiring assistance from another person to actively administer carbohydrate, glucagon, or other resuscitative actions or BG-confirmed by a plasma glucose value (<56 mg/dL) with symptoms consistent with hypoglycemia.
cERR (95% CI): 0.11 (0.08; 0.17). P<0.0001.


Number of episodes/PYE
9.0
8.0
7.0
6.0
5.0
4.0
3.0
2.0
1.0
0.0
Xultophy® 100/3.6 + MET (n=252)
insulin glargine U-100 + insulin aspart + MET (n=253)
1.1
8.2
quaternary_msg

Reported in ≥5% of patients on Xultophy® 100/3.62

ADVERSE REACTIONS

XULTOPHY® 100/3.6
N=1881

Nasopharyngitis

9.6

Headache

9.1

Nausea

7.8

Diarrhea

7.5

Increased Lipase

6.7

Upper respiratory tract infection

5.7

CONFIRMATORY SECONDARY ENDPOINT OF CHANGE IN BODY WEIGHT IN DUAL VII

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.2

7.9 lb

DIFFERENCE BETWEEN

Xultophy® 100/3.6

and basal-bolus therapy

quinary_msg

SUPPORTIVE SECONDARY ENDPOINT OF TOTAL DAILY INSULIN DOSES IN DUAL VII

With Xultophy® 100/3.6, it took less insulin to lower A1C1

Average pretrial insulin glargine U-100 dose:
34 units for Xultophy® 100/3.6 arm;
33 units for basal-bolus arm

Average end-of-trial dose:
40 units Xultophy® 100/3.6
52 units basal + 32 units bolus

Xultophy® 100/3.6 and basal insulin could not be increased by more than 4 units per week and bolus insulin could not be increased by more than 2 units per injection per week.

tertiary_msg

SUPPORTIVE SECONDARY ENDPOINT OF INJECTIONS PER DAY IN DUAL VII

Fewer injections were needed with Xultophy® 100/3.6 to achieve similar efficacy to basal-bolus therapy1

senary_msg
Xultophy® 100/3.6 injection vs basal-bolus therapy
Xultophy® 100/3.6 injection vs basal-bolus therapy

Summary: Once-daily Xultophy® 100/3.6 vs basal-bolus therapy

insulin glargine U-100

insulin glargine U-100 + insulin aspart

insulin glargine U-100 + insulin aspart

PRIMARY ENDPOINT

Mean A1C reduction1,e

-1.5%

-1.5%

SECONDARY ENDPOINTS

Severe or BG-confirmed symptomatic hypoglycemia reported1,f

1.1 events/PYE

8.2 events/PYE

Weight change1

7.9 LB DIFFERENCE

-2.0 lb

+5.7 lb

Average insulin dose1,g

40 units

84 units

Number of injections1

1 injection

At least 3 injections

Weight gain can occur with insulin-containing products, including Xultophy® 100/3.6, and has been attributed to the anabolic effects of insulin.2

eThe difference in A1C effect observed in the trial may not necessarily reflect the effect that may be observed in the care setting where alternative insulin glargine and insulin aspart dosage can be used.

fSevere or BG-confirmed symptomatic hypoglycemia: an event requiring assistance from another person to actively administer carbohydrate, glucagon, or other resuscitative actions or BG-confirmed by a plasma glucose value (<56 mg/dL) with symptoms consistent with hypoglycemia.

gAverage end-of-trial dose was 40 units of Xultophy® 100/3.6 vs 52 units basal + 32 units bolus.

BG=blood glucose; CI=confidence index; ERR=estimated rate ratio; MET=metformin; PYE=patient-year of exposure.

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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 in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2), 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.
  • 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.
  • 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. Severe hypoglycemia can cause seizures, may be life threatening or cause death. Hypoglycemia can impair concentration ability and reaction time which may place the patient and others at risk in situations where these abilities are important. 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, diabetic neuropathy, and in patients using drugs that block the sympathetic nervous system, or who experience recurrent hypoglycemia. The long-acting effect of insulin degludec may delay recovery from hypoglycemia compared to shorter acting insulins. Increase monitoring with changes to: dose, co-administered glucose lowering medications, concomitant drugs, 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 with insulins, including Xultophy® 100/3.6. There have been postmarketing reports of serious hypersensitivity reactions (e.g. anaphylactic reactions and angioedema) in patients treated with liraglutide, one of the components of Xultophy® 100/3.6. If a hypersensitivity reaction occurs, discontinue and treat promptly per standard of care, and monitor until signs and symptoms resolve. 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: Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In a cardiovascular outcomes trial (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. 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, including Boxed Warning.

References:

  1. Billings LK, Doshi A, Gouet D, et al. Efficacy and safety of IDegLira versus basal-bolus insulin therapy in patients with type 2 diabetes uncontrolled on metformin and basal insulin: the DUAL VII randomized clinical trial. Diabetes Care. 2018;41(5):1009-1016.
  2. Xultophy 100/3.6 [package insert]. Plainsboro, NJ: Novo Nordisk Inc.; June 2022.