MEGLITINIDES















  • All values are expressed as average change from baseline. FBS (fasting blood sugar) expressed as mg/dl.
  • Baseline A1C ∼ 8.2% in all studies
  • Reference [2]
Effects of Nateglinide on blood sugars in trials lasting 24 weeks
Drug A1C
(monotherapy)
FBS
(monotherapy)
A1C
(added to metformin)
FBS
(added to metformin)
Nateglinide 60 mg 3 times daily -0.3% +0.4 -0.4% N/A
Nateglinide 120 mg 3 times daily -0.5% -4.5 -0.6% N/A









Overview
  • Nateglinide was compared to placebo for the prevention of type 2 diabetes in a large study that enrolled prediabetics. The study is detailed below.
NAVIGATOR study - Nateglinide vs Placebo for the Prevention of T2DM, NEJM (2010) [PubMed abstract]
  • The NAVIGATOR study enrolled 9306 patients with impaired glucose tolerance and either cardiovascular disease or risk factors for cardiovascular disease
Main inclusion criteria
  • Age ≥ 50 years
  • Fasting glucose of 95 - 126 mg/dl
  • Documented CVD or risk factors for CVD
Main exclusion criteria
  • Significant liver disease
  • Serum creatinine > 2.5 mg/dl
  • Current use of ACE inhibitor or ARB
  • Use or oral DM med or insulin within past 5 years
  • NYHA class III or IV heart failure
Baseline characteristics
  • Average age 64 years
  • Average BMI - 30.5
  • Average BP - 140/83
  • History of cardiovascular disease - 24%
  • Average HgA1C - 5.8%
  • Average fasting glucose - 110 mg/dl
Randomized treatment groups
  • Group 1 (4645 patients) - Nateglinide 60 mg three times a day before meals
  • Group 2 (4661 patients) - Placebo three times a day
  • Nateglinide was started at 30 mg before meals and increased to 60 mg after 2 weeks
  • Fasting blood sugar was measured every 6 months for 3 years, then annually. Oral glucose tolerance tests were also performed annually.
  • All participants were required to participate in a lifestyle modification program
  • Another factor in the trial randomized patients to valsartan
Primary outcomes:
  • 1. Progression to diabetes
  • 2. Composite of death from a cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina
Results

Duration: Progression to diabetes - median of 5 years | Composite cardiovascular outcome - median of 6.3 years
Outcome Nateglinide Placebo Comparisons
Primary outcome (diabetes incidence) 36% 33.9% HR 1.07 95%CI [1.0 - 1.15], p=0.05
Primary outcome (cardiovascular outcomes) 14.2% 15.2% HR 0.93 95%CI [0.83 - 1.03], p=0.16
Myocardial infarction 2.9% 3.1% HR 0.95 95%CI [0.75 - 1.20], p=0.66
Overall mortality 6.7% 6.7% HR 1.0 95%CI [0.85 - 1.17], p=0.98
Hypoglycemia incidence 19.6% 11.3% p<0.001
Drug discontinuation at 5 years 30.1% 29% N/A

Findings: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes.



Low blood sugar (hypoglycemia)

Weight gain

Upper respiratory infections (URI)






Kidney disease
Nateglinide (Starlix®)
  • No adjustment is necessary in mild-to-severe kidney disease [2]
Repaglinide (Prandin®)
  • CrCl > 40 ml/min: no adjustment necessary
  • CrCl 20 - 40 ml/min: start therapy at 0.5 mg dose, titrate slowly
  • CrCl < 20 ml/min: - has not been studied [1]

Liver disease
Nateglinide (Starlix®)
  • Nateglinide has not been studied in patients with moderate-to-severe liver disease
  • Nateglinide should be used with caution in these patients [2]
Repaglinide (Prandin®)
  • Repaglinide should be used with caution in patients with moderate-to-severe liver disease
  • In studies, repaglinide levels have been increased in patients with moderate-to-severe liver disease
  • Manufacturer states that dosage adjustments will be necessary, but gives no specific recommendations [1]

Poor CYP2C9 metabolizers (nateglinide)



Nateglinide (Starlix®)


Repaglinide (Prandin®)

  • Clopidogrel (Plavix®)
    • The acyl-β-glucuronide metabolite of clopidogrel is a CYP2C8 strong inhibitor
    • Repaglinide is a sensitive CYP2C8 substrate. Clopidogrel increases repaglinide exposure by 4 - 5 fold.
    • Repaglinide should not be given with clopidogrel
    • If concomitant use cannot be avoided, initiate repaglinide at a dose of 0.5 mg before each meal and titrate based on blood sugars. Do not exceed 4 mg/day.
    • When clopidogrel is added to repaglinide, repaglinide doses should be reduced to no more than 4 mg/day [8]
  • Cyclosporine - Cyclosporine increases repaglinide levels. Do not exceed 6 mg/day of repaglinide if given concomitantly.
  • CYP3A inducers and inhibitors - CYP3A inducers and inhibitors may affect repaglinide blood levels. Dose adjustments may be necessary.
  • CYP2C8 inducers and inhibitors - CYP2C8 inducers and inhibitors may affect repaglinide blood levels. Dose adjustments may be necessary.
  • Gemfibrozil (Lopid®) - DO NOT COMBINE. Gemfibrozil may increase repaglinide levels and they should not be taken together
  • OATP inhibitors - OATP inhibitors may affect repaglinide blood levels

Metabolism and clearance
Nateglinide (Starlix®)
  • CYP2C9 - sensitive substrate and inhibitor
  • CYP3A - substrate
Repaglinide (Prandin®)
  • CYP2C8 - sensitive substrate
  • CYP3A - sensitive substrate
  • OATP - substrate