Skip to main content

WHY I INTENSIFY WITH XULTOPHY® 100/3.6

An alternative intensification option: Comparable efficacy vs basal-bolus, but with only 1 injection per day


Jodi Strong

DNP, FNPBC, APNP, CDE, BCARM

Stevens Point, WI

For the more than 10 years I’ve been practicing, when I had an adult patient with type 2 diabetes who was not reaching his/her A1C goal on basal insulin, I would almost always intensify treatment with basal-bolus therapy.

Even though a basal-bolus regimen helps my patients gain control of their blood sugar, there are other things to consider, like hypoglycemia and weight gain, that come with basal-bolus treatment. Additionally, my patients don’t like injecting themselves as it is, so getting them to buy into a 4-5 shot-per-day basal-bolus regimen can be a struggle.

In light of these considerations, I was particularly interested in seeing the results of the DUAL™ VII trial. DUAL™ VII evaluated the efficacy and safety of once-daily Xultophy® 100/3.6 compared to basal-bolus therapy in adult patients with type 2 diabetes who were uncontrolled on insulin glargine U-100 (20-50 units daily) and metformin.1

Xultophy® 100/3.6 is indicated for adult patients with type 2 diabetes as an adjunct to diet and exercise. There’s a lot of information in this study, so you can use the links below to learn more about the trial:

primary_msg

For the more than 10 years I’ve been practicing, when I had an adult patient with type 2 diabetes who was not reaching his/her A1C goal on basal insulin, I would almost always intensify treatment with basal-bolus therapy.

Even though a basal-bolus regimen helps my patients gain control of their blood sugar, there are other things to consider, like hypoglycemia and weight gain, that come with basal-bolus treatment. Additionally, my patients don’t like injecting themselves as it is, so getting them to buy into a 4-5 shot-per-day basal-bolus regimen can be a struggle.

In light of these considerations, I was particularly interested in seeing the results of the DUAL™ VII trial. DUAL™ VII evaluated the efficacy and safety of once-daily Xultophy® 100/3.6 compared to basal-bolus therapy in adult patients with type 2 diabetes who were uncontrolled on insulin glargine U-100 (20-50 units daily) and metformin.1

Xultophy® 100/3.6 is indicated for adult patients with type 2 diabetes as an adjunct to diet and exercise. There’s a lot of information in this study, so you can use the links below to learn more about the trial:



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 had no weight gain
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 from baseline to week 26 of treatment. Confirmatory secondary endpoints included number of treatment-emergent severe or BG-confirmed symptomatic hypoglycemic episodes during 26 weeks of treatment and change in body weight from baseline after 26 weeks of treatment. Supportive secondary efficacy endpoints included total, basal, and bolus daily insulin doses; responders for A1C <7.0% and ≤6.5% after 26 weeks of treatment; and proportion of patients achieving these A1C targets without severe or BG-confirmed symptomatic hypoglycemia in the last 12 weeks and/or weight gain.1

PRIMARY ENDPOINT OF NONINFERIORITY ACHIEVED: A1C REDUCTION

Comparable A1C control to basal-bolus therapy1

Previously, basal-bolus therapy was the only option that could get some of my patients’ A1C below the American Diabetes Association’s recommended A1C target of <7%.2 But this trial showed that patients on Xultophy® 100/3.6 can achieve a similar A1C reduction as basal-bolus, but with just 1 injection vs up to 5 per day.1

Of course, 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 and insulin aspart dosage can be used.3

These A1C results show that Xultophy® 100/3.6 should be considered as an alternative to basal-bolus therapy for patients who need more than a basal insulin but would prefer not to add more injections.


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%
Achieved with only 1 injection per day
Achieved with up to 5 injections per day
aETD (95% CI): –0.02 (–0.16; 0.12). P<0.0001.
ETD=estimated treatment difference.
secondary_msg

When I had an adult patient with type 2 diabetes who was not reaching his/her A1C goal on basal insulin, I would almost always intensify treatment with basal-bolus therapy.

CONFIRMATORY SECONDARY ENDPOINT: EPISODES OF SEVERE OR BG-CONFIRMED HYPOGLYCEMIA

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

In the DUAL™ VII study, patients experienced on average 1.1 hypoglycemic episodes per patient-year with Xultophy® 100/3.6 vs 8.2 with basal-bolus therapy—an 89% lower rate.1

Other adverse reactions reported in ≥5% of patients on Xultophy® 100/3.6 in this trial were nauseac (11.1%), influenza (7.1%), diarrheac (6.3%), upper respiratory tract infection (6.0%), and headache (5.6%).4

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.
cGastrointestinal adverse events tended to diminish within a few days or weeks on continued treatment.
PYE=patient-year of exposure.
ERR=estimated rate ratio.


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
ERR (95% CI): 0.11 (0.08; 0.17). P<0.0001.


Hypoglycemia rates observed in DUAL™ VII may not reflect the rates observed in clinical practice. Individual results may vary.

The clinical relevance of the difference in rates of hypoglycemia has not been established.

quaternary_msg

This trial showed that patients on Xultophy® 100/3.6 can achieve a similar A1C reduction as basal-bolus, but with just 1 injection vs up to 5 per day.1

CONFIRMATORY SECONDARY ENDPOINT: CHANGE IN BODY WEIGHT FROM BASELINE

Weight reduction vs basal-bolus therapy1

While A1C reductions and the potential of hypoglycemia are my primary concerns when intensifying, I may also consider the effect of treatment on my patients’ weight.

We know that weight gain can occur with insulin-containing products, including Xultophy® 100/3.6, because it has been attributed to the anabolic effects of insulin.5

In the DUAL™ VII trial, on average, Xultophy® 100/3.6 patients experienced a 2.0-lb weight reduction while basal-bolus patients experienced weight gain of 5.7 lb.1 The estimated treatment difference was 7.9 lb.1 These results help support my decision to choose Xultophy® 100/3.6 over basal-bolus for appropriate patients.


Change in body weight (lb)
6.0
4.0
2.0
0.0
-2.0
-4.0
-6.0
Xultophy® 100/3.6 + MET (n=252)
insulin glargine U-100 + insulin aspart + MET (n=254)
–2.0 lb
+5.7 lb
7.9 lb estimated treatment difference
ETD (95% Cl): –7.92 (–9.24; –6.38) P<0.0001.


Weight change observed in DUAL™ VII may not reflect what is observed in clinical practice. Individual results may vary.

quinary_msg

SUPPORTIVE SECONDARY ENDPOINT: TOTAL DAILY INSULIN DOSES

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

ETD (95% CI): -44.5 units [-48.3, -40.7]

Insulin doses observed in DUAL™ VII may not reflect what is observed in clinical practice. Individual results may vary.

In addition to the number of injections my patients have to take, I am always mindful of how much insulin my patients are taking.

Pre-trial, the average insulin glargine U-100 dose was 34 units in the Xultophy® 100/3.6 arm and 33 units in the basal-bolus arm. By the end of the trial, patients in the Xultophy® 100/3.6 arm were taking an average of 40 units, while patients in the basal-bolus arm were taking an average of 84 units total (52 units basal + 32 units bolus).

That’s 52% less insulin with Xultophy® 100/3.6, but still with similar A1C reductions to basal-bolus.1 It’s important to note that patients could not increase their basal insulin or Xultophy® 100/3.6 dose by more than 4 units per week and patients could not increase their bolus insulin dose by more than 2 units per injection per week.1

tertiary_msg

SUPPORTIVE SECONDARY ENDPOINT: TRIPLE COMPOSITE

More patients reached the composite endpoint vs basal-bolus therapy1

Patients who achieved the triple composite endpoint achieved all 3 prespecified criteria:

Glycemic control (A1C <7%)

No hypoglycemia in the last 12 weeks of treatment

No weight gain


When choosing a therapy for my patients, I like to look at the big picture.

A prespecified analysis of DUAL™ VII examined a triple composite endpoint focused on the combined effect of Xultophy® 100/3.6 compared to basal-bolus therapy in achieving A1C control (<7%), reducing hypoglycemic episodes, and preventing weight gain.1

With Xultophy® 100/3.6, significantly more patients were able to achieve the composite endpoint vs with basal-bolus therapy.1

It’s important to note that composite endpoints should be examined with caution, as each individual endpoint may not be equally important or contribute equally to the combined endpoint. The link between this composite endpoint and patient outcomes has not been established.


Percent of patients who achieved the triple composite endpoint1
38%
6%
OR (95% CI): 10.39 (5.76, 18.75). P<0.0001.
OR=odds ratio.

as many patients achieved the triple composite endpoint with Xultophy® 100/3.6 vs basal-bolus therapy1

senary_msg

Jodi Strong

DNP, FNPBC, APNP, CDE, BCARM


Dr Jodi Strong has been working as a board-certified nurse practitioner specializing in diabetes care for over a decade. In 2015, she earned a doctorate of nurse practice (DNP). As an advanced diabetes manager and a certified diabetes educator, Dr Strong shares her knowledge and research in diabetes management by speaking at conferences in the US and around the world.

septenary_msg

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. 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. American Diabetes Association. Standards of medical care in diabetes—2018. Diabetes Care. 2018;41(suppl 1):S1-S172.
  3. 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(suppl):1-17.
  4. Billings LK, Doshi A, Gouet D, et al. Efficacy and safety of insulin degludec/liraglutide (IDeglira) vs. basal-bolus (BB) therapy in patients with type 2 diabetes: DUAL VII trial. Presented at: 53rd Annual Meeting of the European Association for the Study of Diabetes; September 11-15, 2017; Lisbon, Portugal.
  5. Xultophy 100/3.6 [package insert]. Plainsboro, NJ: Novo Nordisk Inc; February 2019.