Insulin glargine once-daily versus insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs

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In Review
Swinnen SG, et al. "A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs". Diabetes Care. 2010. 33(6):1176-8.
PubMed • Full text • PDF

Clinical Question

Is insulin glargine noninferior to insulin detemir regarding the percentage of patients reaching A1c <7% without symptomatic hypoglycemia with plasma glucose ≤3.1 mmol/L?

Bottom Line

In insulin-naive patients with type 2 diabetes, insulin glargine taken once daily is noninferior to insulin detemir taken twice daily regarding the percentage of patients who reach a target A1c without hypoglycemia.

Major Points

Insulin glargine and insulin detemir result in similar improvement in A1c and similar risk of hypoglycemia. Insulin glargine leads to higher weight gain, lower daily insulin doses, and fewer drop-outs due to adverse events. Quality of life is positively affected by initiating insulin glargine or insulin detemir in patients with type 2 diabetes not achieving adequate control on oral glucose-lowering drugs (OGLDs).

Guidelines

No guidelines have been developed regarding which long-acting insulin is preferred over the other.

Design

  • Multinational, open-label, randomized trial
  • N=973
    • Insulin glargine-treated (n=478)
    • Insulin detemir-treated (n=486)
  • Setting: 20 centers in 20 different countries
  • Analysis: Noninferiority of glargine to detemir
  • Primary outcome: Percentage of patients reaching A1c <7% without symptomatic hypoglycemia confirmed by plasma glucose ≤3.1 mmol/L

Population

Inclusion Criteria

  • Insulin-naive patients with type 2 diabetes mellitus
  • Patients treated for three or more months with stable oral glucose-lowering drugs (including metformin of one or more grams per day)
  • Patients with A1c of 7.0-10.5%

Baseline Characteristics

  • Mostly white: ~78%
  • Age: 58 years old
  • Male: ~55%
  • Duration of diabetes: ~10 years
  • Duratation of oral glucose-lowering drug therapy: ~8.5 years
  • Weight: ~84 kg
  • BMI: ~30 kg/square meter
  • A1c: 8.7%
  • Laboratory fasting plasma glucose: ~10.5 mmol/L
  • Fasting C-peptide: ~1064 pmol/L
  • Macroangiopathy: ~17%
  • Nephropathy: ~12%
  • Neuropathy: ~27%
  • Retinopathy: ~20%
  • Previous Oral Glucose-Lowering Therapy:
    • Metformin: 100%
    • Sulfonylureas: ~86%
    • TZD's: ~17%
    • Alpha-glucosidase inhibitors: ~6%
    • Glinides: ~5%
    • DPP-4 inhibitor: ~0.1% (1 patient who stopped at randomization)

Interventions

Patients randomized to receive either glargine or detemir:

  • 24-week treatment with glargine in evening

    • Glargine doses increased every 2 days by 2 units until fasting plasma glucose reached <5.6 mmol/L
  • 24-week treatment with detemir at breakfast and dinner
    • Detemir titration with 3 steps to obtain fasting and predinner plasma glucose of <5.6 mmol/L

Outcomes

Comparisons are insulin glargine versus insulin detemir.

Primary Outcomes

27.5% of glargine-treated patients and 25.6% of detemir-treated patients reached A1c <7% without symptomatic hypoglycemia with plasma glucose ≤3.1 mmol/L

  • Difference of 1.85% (95% CI: -3.78 to 7.48%)
  • Noninferiority margin of -7.68%; therefore, noninferiority demonstrated

Secondary Outcomes

  • Similar mean improvement in A1c (p=0.149)
    • -1.46 +/- 1.09% for glargine
    • -1.54 +/- 1.11% for detemir
  • Insulin doses significantly lower with glargine versus detemir (p<0.001)
    • 43.5 +/- 29 units per day for glargine
    • 76.5 +/- 50.5 units per day for detemir
  • Similar proportions of patients achieving A1c <7% (p=0.254)
    • 44.1% for glargine
    • 47.8% for detemir
  • Significantly fewer glargine-treated patients reached A1c <6.5% (p=0.017)
    • 16.5% for glargine
    • 22.7% for detemir
  • Decrease in fasting plasma glucose significantly greater for glargine (p<0.001)
  • Significantly larger reductions in plasma glucose before and after lunch, before and after dinner, and at bedtime with detemir (p<0.001)
  • ~30% of patients in either treatment group experienced symptomatic hypoglycemia with plasma glucose < or equal to 3.1 mmol/L
  • Weight gain significantly higher with glargine versus detemir (p<0.001)
    • 1.4 +/- 3.2 kg with glargine
    • 0.6 +/- 2.9 kg with detemir
  • Quality of life improved with no difference between groups
  • Total satisfaction favored glargine (p<0.001)
    • 31.1 +/- 5.8 for glargine
    • 29.3 +/- 7.0 for detemir

Criticisms

One limitation of the study was open-label design, yet necessary with twice-daily dosing of detemir and separate titration target before dinner. In order to better understand intrapatient variability, a cross-over trial could have been utilized--especially regarding the difference in doses between the two groups. The patient population of mostly whites does not make the results generalizable to a patient population of various ethnicities which exist in many areas of the United States.

Funding

Study sponsored by Sanofi-Aventis, Paris, France who is the manufacturer of Lantus (insulin glargine)

Further Reading

Swinner SG, Dain M, Aronson R, et al. A 24-week, randomized, treat-to-target trial comparing initiation of insulin glargine once-daily with insulin detemir twice-daily in patients with type 2 diabetes inadequately controlled on oral glucose-lowering drugs. "Diabetes Care." 2010;33(6):1176-1178.

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