- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Assoc
- CrCl - Creatinine clearance
- PI - Manufacturer's package insert
- RCT - Randomized controlled trial
- T2DM - Type 2 diabetes
- DRUGS IN CLASS
- Meglitinides
- Nateglinide (Starlix®)
- Repaglinide (Prandin®)
- Combination products with metformin
- PrandiMet® (repaglinide + metformin)
- MECHANISM OF ACTION
- Meglitinides stimulate insulin secretion from the pancreas. Because of this, they are sometimes referred to as "insulin secretagogues."
- Insulin secretion is enhanced in response to a meal, but does not appear to be increased during periods of fasting
- Because meglitinides enhance insulin secretion, they can cause low blood sugars (hypoglycemia) [1,2]
- TYPE TWO DIABETES
| 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 |
- Repaglinide (Prandin®)
- The effects of repaglinide on blood sugars were compared to nateglinide in the randomized controlled trial detailed below
- STUDY
- Design: Randomized controlled trial (N=150 | length = 16 weeks) in type 2 diabetics who were not taking diabetes medications
- Treatment: Repaglinide 0.5 - 4 mg at mealtime (median dose was 6 mg/day) vs Nateglinide 60 - 120 mg at mealtime (median dose was 360 mg/day)
- Primary outcome: Change in HgA1C from baseline
- Results:
- Primary outcome (decrease in A1C): Repaglinide - 1.57%, Nateglinide - 1.04% (p=0.002)
- Decrease in fasting blood sugar: Repaglinide - 57 mg/dl, Nateglinide - 18 mg/dl (p<0.001)
- Weight gain: Repaglinide - 3.96 lbs (1.8 kg), Nateglinide - 1.54 lbs (0.7 kg) (p=0.04)
- Patients who experienced hypoglycemia: Repaglinide - 7%, Nateglinide - 0%
- Findings: In patients previously treated with diet and exercise, repaglinide and nateglinide had similar postprandial glycemic effects, but repaglinide monotherapy was significantly more effective than nateglinide monotherapy in reducing HbA(1c) and FPG values after 16 weeks of therapy.
- Body weight effects
- Meglitinides tend to cause a small amount of weight gain
- In placebo-controlled trials lasting 24 weeks, nateglinide-treated patients (120 mg) gained 2 pounds compared to a weight loss of 1.5 pounds in placebo-treated patients
- In the Diabetes Care study detailed above, the repaglinide group gained 4 pounds over 16 weeks of treatment compared to 1.5 pounds in the nateglinide group
- Cholesterol effects
- Meglitinides do not appear to have a significant effect on cholesterol (lipid parameters) [3]
- Clinical outcomes
- There have been no studies in diabetics that have evaluated clinical outcomes with meglitinides [3]
- ADA recommendations
- TYPE 2 DIABETES PREVENTION
- SIDE EFFECTS
- Low blood sugar (hypoglycemia)
- Because meglitinides stimulate insulin secretion, they can cause low blood sugars
- When meglitinides are taken with other diabetes medications, the risk of low blood sugars increases
- See hypoglycemia for a review of low blood sugar and its treatment
- Weight gain
- Meglitinides tend to cause weight gain
- See weight gain above
- Upper respiratory infections (URI)
- In placebo-controlled trials, patients on meglitinides had a higher incidence of upper respiratory infections (URI) when compared to placebo
- In repaglinide trials (N=460), the incidence of URI was 16% in repaglinide-treated patients compared to 8% in placebo-treated patients
- In nateglinide trials (N=1899), the incidence of URI was 10.5% in nateglinide-treated patients compared to 8.1% in placebo-treated patients
- CONTRAINDICATIONS
- Nateglinide
- Type 1 diabetes
- Diabetic ketoacidosis
- Repaglinide
- Concomitant use with gemfibrozil (Lopid®)
- Type 1 diabetes
- Diabetic ketoacidosis
- PRECAUTIONS
- 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 is a CYP2C9 sensitive substrate. Poor CYP2C9 metabolizers may have increased exposure to nateglinide and may be at higher risk of hypoglycemia.
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Nateglinide (Starlix®)
- CYP2C9 inhibitors and inducers - nateglinide is a CYP2C9 sensitive substrate. CYP2C9 inhibitors and inducers may affect exposure to nateglinide.
- 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
- LONG-TERM SAFETY
- Repaglinide was FDA approved in 1997
- Nateglinide was FDA approved in 2000
- They are not as widely prescribed as other diabetes medications
- No long-term concerns have arisen from available information
- DOSING
- BIBLIOGRAPHY
- 1 - Repaglinide PI
- 2 - Nateglinide PI
- 3 - PMID 17443551
- 4 - PMID 15161773
- 5 - PMID 11790217
- 6 - PMID 20228402
- 7 - ADA 2016 Standards of Care in Diabetes
- 8 - Clopidogrel PI