Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes

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Incomplete
Marso SP, et al. "Efficacy and Safety of Degludec versus Glargine in Type 2 Diabetes". New England Journal of Medicine. 2017. 377(8):723-732.
PubMed • Full text

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Clinical Question

In patients with type 2 diabetes at high risk for cardiovascular events, is degludec, in comparison to glargine, more effective in treating type 2 diabetes and safer with respect to the incidence of major cardiovascular events?

Bottom Line

In patients with type 2 diabetes at high risk for cardiovascular events, there is no difference between degludec and glargine in terms of cardiovascular events, but degludec does have lower rates of severe and nocturnal hypoglycemia.

Major Points

Patients with type 2 diabetes are at a much higher risk of experiencing a cardiovascular event or a cardiovascular related death compared to patients without type 2 diabetes. The results of trials exploring the effect of glycemic control on cardiovascular risk have been mixed. UKPDS, ADVANCE, and VADT show a neutral effect on cardiovascular risk with reducing glycemic level, while the ACCORD study showed a greater cardiovascular risk with intensive glycemic control.1-4 Focus on cardiovascular outcomes in patients with type 2 diabetes has increased since the FDA issued guidelines in 2008 recommending establishing cardiovascular safety in antihyperglycemic therapies.5

The double-blinded, event-driven cardiovascular outcomes Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) was comprised of two study groups which were given either insulin degludec or insulin glargine. After the mean follow-up of 1.99 years, there was no difference in the primary outcome of a major cardiovascular event. The insulin degludec group did have significantly lower rates of severe hypoglycemia (rate ratio, 0.60; 95% CI, 0.48 to 0.76; P<0.001 for superiority).

Furthermore, after 24 months the mean glycated hemoglobin level was the same in each group (7.5±1.2%). There was no significant difference between the two groups in terms of adverse events with the insulin degludec group having 44.7 events per 100 patient-years and the insulin glargine group having 50.1 events per 100 patient-years.

Based on the results of the DEVOTE study, insulin degludec offers a lower risk of hypoglycemia compared to glargine, but offers no other benefits over glargine. Therefore, in adult patients with type 2 diabetes with a history or a high risk of hypoglycemia, degludec might be a preferable option compared to glargine. However, patients should be advised that degludec is much more expensive than glargine.

Guidelines

As of April 2018, the American Diabetes Association’s guidelines recommends that a longer acting basal insulin, such as U-300 glargine or degludec, may offer a lower risk for hypoglycemia compared to U-100 glargine when used in combination with an additional antihyperglycemic medication.6

Design

  • Trail type: double-blind, treat-to-target, event-driven cardiovascular outcomes trial
  • N = 7637 patients randomized
    • Experimental n = 3818 received degludec
    • Standard n = 3819 received glargine
  • Setting: 438 sites in 20 countries
  • Enrollment: November 2013 - November 2014, 7637 patients were randomly assigned
  • Mean Follow-up: 1.99 years (exposure time 1.83 years)
  • Analysis: Intention-to-treat for primary outcome for noninferiority
  • Primary outcome: first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke)

Population

Inclusion Criteria

  • Type 2 diabetes
  • HbA1c ≥7.0 %
  • OR HbA1c <7.0 % and current insulin corresponding to ≥20 U/day of basal insulin
  • Current treatment with one or more oral or injectable antidiabetic agents
  • Age ≥50 years at screening and at least one of the following conditions:
    • Prior myocardial infarction
    • Prior stroke or prior TIA
    • Prior coronary, carotid or peripheral arterial revascularization
    • >50% stenosis on angiography or other imaging of coronary, carotid or lower extremity artery
    • History of symptomatic coronary heart disease documented by positive exercise stress test or any cardiac imaging, or unstable angina pectoris with ECG changes
    • Asymptomatic cardiac ischemia documented by positive nuclear imaging test or exercise test or dobutamine stress echo
    • Chronic heart failure NYHA class II–III
    • Chronic kidney disease corresponding to estimated glomerular filtration rate 30–59 mL/min/1.73m2 per CKD-EPI
  • OR Age ≥60 years at screening and at least one of the following risk factors:
    • Microalbuminuria or proteinuria
    • Hypertension and left ventricular hypertrophy by ECG or imaging
    • Left ventricular systolic and diastolic dysfunction by imaging
    • Ankle/brachial index <0.9

Exclusion Criteria

  • An acute coronary or cerebrovascular event in the 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/1.73m2
  • End-stage liver disease, defined as acute or chronic liver disease and history of one or more of the following:
    • Ascites
    • encephalopathy
    • variceal bleeding
    • bilirubin ≥2.0 mg/dL
    • albumin level ≤3.5 g/dL
    • prothrombin time ≥4 seconds prolonged
    • international normalized ratio ≥1.7
    • prior liver transplant
  • Hypersensitivity to trial products or related products
  • Pregnant, breast-feeding or intends to become pregnant
  • Simultaneous participation in any other clinical trial of a medicinal product
  • Receipt of any investigational medicinal product within 30 days before randomization. Brazil: Receipt of any investigational medicinal product within 1 year
  • Malignant neoplasms (except basal cell and squamous cell skin carcinoma)
  • Unable to adhere to the initial trial visit schedule and procedures

Baseline Characteristics

From Degludec group. Groups were similar.

  • Age: 64.9, >75 years old: 10%, men: 62.8%, body weight: 211.8lbs, BMI: 33.6
  • Ethnicity
    • Hispanic/Latino: 15.2%
  • Race
    • White: 76%, Black/African American: 10.5%, Asian: 10.2%, Other: 3.2%
  • Region
    • North America: 68.8%, Europe 11.5%, South America 8.0%, Asia excluding India 4.0%, Africa 3.5%
  • Diabetes duration in years: 16.6
  • Smoking status
    • Current 11.3%, Previous 44.4%, 44.3%
  • Renal status
    • Normal: 19.4%, mild impairment: 41.8%, moderate impairment: 34.6%, severe impairment: 2.8%
  • PMH
    • >50 years old and CV or CKD: 85.5%, >60 years old and risk for CV event: 14.1%
  • Alternative titration target at baseline 17.4%, Switched to alternative titration target after baseline 9.6%

Interventions

  • Patients with type 2 diabetes at high risk for cardiovascular events were randomly assigned to receive either degludec or glargine daily between dinner and bedtime. Patients could continue their pretrial antihyperglycemic therapy except for basal and premixed insulins.
  • Participants adjusted their dose of basal insulin weekly on the basis of the lowest of three self-measured blood-glucose readings, as measured before breakfast 2 days before and on the day of dose adjustment, with the aim of reaching a target of 71 to 90 mg per deciliter.
  • If patients were considered vulnerable, their target was 90 to 126 mg per deciliter. Each drug was given in an identical bottle to avoid selection or ascertainment bias.

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Any major fatal cardiovascular event including death from cardiovascular event, nonfatal myocardial infarction, or nonfatal stroke
8.5% v.s. 9.3% (RR 0.91; 95% CI 0.78-1.06; P<0.001)

Secondary Outcomes

Severe Hypoglycemia
4.9% v.s. 6.6% (RR 0.60; 95% CI 0.48-0.76; P<0.001; NNH 59)
Unconsciousness or coma
1.4% v.s. 1.6% (RR 0.81; 95% CI 0.55-1.19; P=0.28)
Annual rate of death from any cause
1.41% vs. 1.14% (HR 1.22; 95% CI 1.01-1.46; P=0.04)
Seizure
0.2% v.s. 0.3% (RR 1.02; 95% CI 0.38-2.73; P=0.97)
Nocturnal severe hypoglycemia
1.0% v.s. 1.9% (RR 0.47; 95% CI 0.31-0.73; P<0.001; NNH 112)

Subgroup Analysis

Severe Hypoglycemia analyses
Male: 1.4% v.s. 3.1% (RR 0.46; 95% CI 0.32-0.66; P=0.038; NNH 59)
Female: 2.2% v.s. 2.9% (RR 0.76; 95% CI 0.56-1.02; P=0.038)

Adverse Events

The most prevalent severe adverse event was severe hypoglycemia but did not result in any deaths. Other ADE’s were not discussed in this trial.

Rate of ADE’s: 44.7 % v.s. 50.1 %

Criticisms

  • Many adverse events were not discussed.
  • Novo Nordisk funded this article who happen to be the manufacturers of Tresiba, which is an insulin degludec product.

Funding

The trial was funded and conducted by Novo Nordisk. Statogen Consulting and Novo Nordisk both independently analyzed the data only after the database lock.

Further Reading

Citations

1.) UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.

2.) The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.

3.) Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.

4.) The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.

5.) Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes: guidance for industry. December 2008 (http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatory- Information/Guidances/ucm071627.pdf).

6.) American Diabetes Association. Standards of Medical Care In Diabetes- 2018. Diabetes Care. 2018;41:S82.

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