Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes

1
Addition of Biphasic, Prandial, or Basal
Insulin to Oral Therapy in Type 2 Diabetes

• Dr. Elizabeth Ferrenz
• Family and Community Medicine
• Resident at UCSF/SFGH
• February 6th, 2008

2
Background

• Type II DM is characterized by progressive
  worsening of glycated hemoglobin as beta cell
  function declines
• Normalizing glycemic levels decreases chance of
  diabetic complications
• Insulin is often necessary when diet, exercise
  and oral agents are insufficient
• Which insulin should be used initially?

3
Methods - Patients

• Nov 1, 2004 to July 31, 2006
• 58 clinical centers in Ireland and UK
• Men and women age 18 or older
• Type 2 DM at least 12 months
• Suboptimal HgbA1C (7-10)
• On max tolerated doses of metformin and
  sulfonlyurea for 4 months
• BMI 40

Exclusion Reasons
4
Methods Study Design

• Treating to Target in Type 2 Diabetes (4T)
• Three year study (data in this talk from year
  one)
• Open-label
• Randomized Controlled Trial
• Online Trial-management system
• Novo Nordisk and Diabetes UK supported

5
Methods Insulin Initiation/Titration

• Trial management system calculated starting doses
  using formula
• Visits at 2, 6, 12, 24, 38, 52 weeks and
  telephone contacts to adjust regimens
• Adjustments based on FSBG and self-reported
  hypoglycemia
• Before meal goal 72-99
• 2 hour after meal goal 90-126
• Hypoglycemia
• Grade 1 Symptoms and FSBG 56
• Grade 2 Symptoms and FSBG lt 56
• Grade 3 Third-party assistance required
• Unacceptable hyperglycemia - HgbA1c gt10 once
  or gt8 twice after 24 weeks of therapy -gt second
  type of insulin added sulfonlyurea stopped

6
Methods Insulin Initiation/Titration

• Biphasic Aspart 30
• Twice daily injections
• FSBG monitored before breakfast and before dinner
  (2)
• Added prandial to midday meal if unacceptable
  hyperglycemia
• Prandial - Aspart
• Thrice daily injections before meals
• FSBG monitored before each meal, 2 hours after
  each meal, bedtime (7)
• Added basal at bedtime if unacceptable
  hyperglycemia
• Basal - Detemir
• Once daily injection at bedtime
• FSBG monitored before breakfast and before dinner
  (2)
• Added morning injection when fasting controlled
  but before dinner not controlled and hypoglycemia
  limited dosage increase
• Added prandial at all meals if unacceptable
  hyperglycemia

7
Methods Outcomes

• Primary Outcome HgbA1c at 1 year
• Secondary Outcomes
• patients with HgbA1c 6.5
• patients with HgbA1c 6.5 without
  hypoglycemia (Grade 2 or 3) during weeks 48 to 52
• Median rate of hypoglycemia (events/patient/year)
• Weight Gain
• Eight-point glucose profiles (weeks 12, 24, 38,
  52)
• Proportion of patients requiring twice daily
  basal insulin
• Proportion of patients with unacceptable
  hyperglycemia
• Median of ratio of albumin to creatinine
• Quality of life

8
Methods Statistical Analyses

• Power 95 to detect difference in HgbA1C between
  groups if true difference of at least 0.4 with
  SD 1.1
• Mixed regression models and mixed-effect logistic
  models utilized
• Two-sided P value of lt 0.05 significant

9
(No Transcript)
10
Results Patients/Insulin

• Withdrawals Statistically significant P lt0.002
  all comparisons
• Biphasic 4 (1.7)
• Prandial 13 (5.4)
• Basal 3 (1.3)
• No meaningful differences measured between study
  completers and non-completers
• Required Additional Type of Insulin Plt0.001 all
  comparisons
• Biphasic 21 (8.9)
• Prandial 10 (4.2)
• Basal - 42 (17.9)
• Addition of morning basal required in 79 (33.8)

11
Results Primary Outcome HgbA1c at 1 year

• Maximal reduction at 24 weeks and then stable
• Reduction at 52 weeks
• Biphasic 1.3
• Prandial 1.4
• Basal 0.8
• Statistically significant difference Plt0.001
  basal vs. biphasic or prandial

12
Results Secondary OutcomesHgbA1c 6.5

• HgbA1c 6.5 or less at 52 weeks
• Prandial 24
• Biphasic 17
• Basal 8
• Basal v. biphasic P0.001
• Basal v. prandial Plt0.001
• Prandial v. biphasic P0.08 NS

13
Results Secondary OutcomesHgbA1c 6.5
without hypoglycemia

• patients with HgbA1c 6.5 without
  hypoglycemia (Grade 2 or 3) during weeks 48 to 52
• Prandial 44
• Biphasic 53
• Basal 79
• P0.001 for all comparisons

14
Results Secondary OutcomesHgbA1c 7.0

• HgbA1c 7.0 or less at 52 weeks
• Prandial 48.7
• Biphasic 41.7
• Basal 27.8
• Basal v. biphasic Plt0.001
• Basal v. prandial Plt0.001
• Prandial v. biphasic PNS

15
Results Additional Outcomes

• Starting HgbA1c 8.5 achieve HgbA1c lt 6.5
• Biphasic is reference
• Prandial OR 1.76 (CI 0.96 to 3.26) P0.07
• Basal OR 0.50 (CI 0.24 to 1.03) P0.06
• Starting HgbA1c gt 8.5 achieve HgbA1c lt 6.5
• Biphasic is reference for calculation
• Prandial OR 1.24 (CI 0.62 to 2.51) P0.54
• Basal OR 0.21 (CI 0.07 to 0.65) P0.007
• Did not test if difference in OR for basal vs.
  biphasic significantly different between 2
  groups. May be chance finding.

16
Results Secondary OutcomesWeight Gain

• Baseline all participants
• Weight 85.8 kg /-15.9
• BMI 29.8 /-4.6
• Weight Gain in kg
• Prandial 5.7 /- 4.6
• Biphasic 4.7 /- 4.0
• Basal 1.9 /- 4.2
• Statistical significance for all comparisons
  P0.005 or less
• Weight is another intermediate outcome in
  cardiovascular disease studies

17
Results Secondary OutcomesHypoglycemia

• Hypoglycemia grade 2 or 3 by definition
• Significant differences between groups
• Group Median (interquartile range)
• Prandial 8.0 (3.0-18.0) Prandial vs. Basal
  Plt0.001
• Biphasic 3.9 (1.0-9.0) Prandial vs. Biphasic
  P0.002
• Basal 0 (0-2.0) Biphasic vs. Basal
  P0.01

18
Results Secondary Outcomes

• Proportion of patients requiring twice daily
  basal insulin 33.8
• Albumin/Creatinine ratio not significant
• Quality of Life not significant

19
Results Adverse Events
20
Discussion

• One year reduction from baseline HgbA1c 0.8-1.4
• biphasic prandial gt basal
• HgbA1c reduction with minimizing the risk of
  hypoglycemia favors starting with basal regimen
• Though number of injections may be considered
  when picking a starting regimen in this study
• 1/3 of patients started on basal required at
  least 2 injections
• 1/5 of patients started on basal required at
  least 5 injections
• 1/10 of patients started on biphasic required at
  least 3 injections
• 1/25 of patients started on prandial required at
  least 4 injections
• Weight gain occurs on all regimens and may affect
  other clinically important outcomes less weight
  gain on basal
• Using cutoff of starting HgbA1c of 8.5
  stratifies data so that there is no difference in
  the regimens for patients starting below 8.5 to
  get to below 6.5 but if patients start above
  8.5 starting a basal regimen is less effective
  in getting to below 6.5 compared to biphasic or
  prandial

21
Evaluation of Study

• Strengths
• Clinically relevant question
• Sufficiently powered
• Well designed and randomized
• Clearly documented (exclusions, withdrawals, etc)
  
• Clear primary and secondary outcomes

22
Evaluation of Study

• Weaknesses
• Pharmaceutical company supported
• Not upfront about frequency of injections in each
  group
• Did not report on all defined secondary outcomes
• Not blinded patients/investigators unclear
  about reviewers
• Complicated dose adjustment unlikely to work
  outside study setting
• Can results be applied to our insulin
  preparations?

23
Bottom Line

• One year reduction from baseline HgbA1c 0.8-1.4
• i.e. from baseline HgbA1c 8 to 6.6-7.2
• Multifactorial decision-making on starting
  regimen
• Patient preference
• Insurance coverage (medi-cal covers basal, CHN
  does only after repeated hypoglycemia on NPH)
• Level of concern for hypoglycemia in particular
  patient
• Level of concern for weight gain less gain on
  basal
• HgbA1c at time of starting insulin if very far
  from goal unlikely to achieve sufficient
  reduction on basal alone
• Ongoing challenge to discuss initiating insulin
  therapy

24
Citations

• Holman RR et al. Addition of Biphasic, Prandial,
  or Basal Insulin to Oral Therapy in Type 2
  Diabetes N Engl J Med 2007 3571716-30.