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This article originally posted 01 June, 2014 and appeared in  CardiovascularMedicationInsulinDiabetes Clinical Mastery Series Issue 191

Joslin's Diabetes Deskbook, Updated 2nd Ed., Excerpt #49: Pharmacotherapy of Type 2 Diabetes, Part 8

Richard S. Beaser, MD

Joslin_Diabetes_Deskbook

This week's excerpt covers the following topics:

  • Drug interactions with potential for clinical significance for metformin
  • Contraindications and precautions for metformin
  • Class contraindications and precautions for TZD's
  • Which TZD interactions are serious and how it is metabolized
 
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MEDICATIONS THAT INCREASE INSULIN SENSITIVITY
  1. BIGUANIDES
METFORMIN SUMMARY 

Brand name: Glucophage, Glucophage XR

Action: Decreases hepatic glucose production through a reduction in hepatic insulin resistance. Insulin secretion is unchanged, but fasting and daytime insulin response may actually decrease due to improved insulin sensitivity.

Indications and combination usage: To improve glucose control in people with type 2 diabetes, used as monotherapy, and combination therapy with sulfonylureas, repaglinide, nateglinide, thiazolidinediones, glp-1's, and insulin.

Required for efficacy: Insulin (exogenous or endogenous), insulin resistance

Manifestation on glucose patterns: Generalized improvement in glucose levels. Reduction in hepatic glucose production leads to reduced fasting glucose levels.

Metabolism and elimination: Excreted unchanged in the urine

Potential effect on A1C: A reduction of up to 1.8 % vs. placebo

Potential for hypoglycemia: Quite low in monotherapy. Increased in patients with marked reductions in caloric intake, undergoing strenuous exercise, using concomitant medications that increase insulin levels, and consuming excessive alcohol.

Significant adverse events/side effects:

  • diarrhea
  • flatulence
  • lactic acidosis

Other side effects of note:

  • subclinical reductions in vitamin B12 levels
  • infrequent hypoglycemia in people not adequately nourished

Typical patient with optimal efficacy: Type 2 diabetes with significant signs of insulin resistance syndrome, especially obesity, dyslipidemia

Typical starting dose: 500 mg BID, taken with breakfast and supper (mealtime dosing helps reduce GI side effects. Start with 500 or 850 mg once daily if GI side effects are bothersome).

Tablet sizes:
  • Glucophage (metformin)
    • 500 mg; 850 mg, 1000 mg
    • 500 mg/ml liquid
  • Glucophage XR (metformin extended release)
    • 500 mg; 750 mg
    • (Note, extended release system requires intact tablet. DO NOT split or crush.)
  • Combination Tablets (brand names in parentheses)
    • Metformin/glyburide (Glucovance)
      • metformin 250 mg and glyburide 1.25 mg
      • metformin 500 mg and glyburide 2.5 mg
      • metformin 500 mg and glyburide 5 mg
    • Metformin/glipizide (Metaglip)
      • metformin 250 mg and glipizide 2.5 mg
      • metformin 500 mg and glipizide 2.5 mg
      • metformin 500 mg and glipizide 5 mg
    • Metformin/rosiglitazone (Avandamet)
      • metformin 500 mg and rosiglitazone 1 mg
      • metformin 500 mg and rosiglitazone 2 mg
      • metformin 500 mg and rosiglitazone 4 mg
    • Metformin/pioglitazone (Actoplus Met)
      • Pioglitazone 15 mg and metformin 500 mg
      • Pioglitazone 15 mg and metformin 850 mg
    • Metformin/sitagliptin (Janumet)
      • metformin 500 mg and sitagliptin 50 mg
      • metformin 1000 mg and sitagliptin 50 mg
The utility of combination tablets includes:
  • Improved adherence to treatment regime
  • Addressing dual defects (for combinations with sulfonylureas, insulin resistance and insulin secretory deficiency, for combination with thiazolidinedione, hepatic and peripheral insulin resistance) that are likely present as early as the time of diagnosis of type 2 diabetes
  • For the lowest dose of the metformin/glyburide combination, the ability to utilize low doses of both medications concurrently Typical dose titration pattern for metformin: Start with 500 mg BID; increase in 2 to 6 weeks as needed to 1000 mg every morning and 500 mg at suppertime, then in 2–6 weeks more, if needed, increase to 1000 mg BID. If extended release is used, full dose can be given once daily, usually at suppertime.
Optimal daily dose: 1000 mg BID
 
Maximal daily dose:2550 mg (850 mg TID)
 
Other clinical effects:
  • Weight: decreases
  • Lipids: reduces: triglycerides, LDL, total cholesterol
  • Coagulation: decreased plasminogen activator inhibitor

Drug interactions with potential for clinical significance:

  • Most clinically significant interaction is cimetidine/metformin, leading to increased metformin levels
  • Nifedipine enhances metformin absorption. Metformin has minimal effects on metformin
  • Metformin has minimal effect on nifedipine
  • Cationic drugs that are eliminated by the kidneys (including amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, trimethoprim) have the potential for interaction with metformin by competing for common renal tubular transport systems. Theoretically, they may increase the metformin levels.

Contraindications and precautions:

  • Known hypersensitivity to metformin
  • To reduce risk of lactic acidosis, avoid use in contraindicated patients:
    • renal disease (serum creatinine : >1.5 mg/dl in males, >1.4 mg/dl in females, or abnormal creatinine clearance)
    • hepatic dysfunction has been associated with some cases of lactic acidosis, so use of metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
    • congestive heart failure (CHF) requiring pharmacologic treatment
    • history of alcohol abuse/binge drinking
    • acute or chronic metabolic acidosis, including diabetic ketoacidosis
  • Metformin should be withheld in conditions predisposing to renal insufficiency and/or hypoxia, including:
    • cardiovascular collapse
    • acute myocardial infarction
    • acute CHF
    • severe infections
  • Metformin should be temporarily discontinued in patients undergoing radiologic studies or surgical procedures involving intravascular administration of iodinated contrast materials at the time of the procedure. Metformin should be withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been reevaluated and found to be normal.
  • May result in ovulation in anovulatory women
  • Not indicated for use in pregnancy
 
Key advice to patients:
  • Contact healthcare professional if deterioration of glucose control occurs.
  • Contact healthcare professional for symptoms of hepatic disease: jaundice, anorexia, unexplained abdominal pain, nausea, vomiting, fatigue, or dark urine.
  • Contact healthcare professional if anyone tells you that your kidneys are not working properly.
  • Discuss potential for GI symptoms early in treatment (in particular, diarrhea), and the possibility of slower dose titration to reduce symptoms.
  • Discuss symptoms of lactic acidosis (weakness, muscle pain, trouble breathing, stomach discomfort, dizziness or lightheadedness, irregular heart beat).
  • Avoid excessive alcohol.
  • Potential for resumed ovulation in anovulatory women.

2.   THIAZOLIDINEDIONES

CLASS SUMMARY: 

Action: Improves glucose control by improving insulin sensitivity. Works primarily to reduce peripheral insulin resistance (primarily muscle, adipose) but also can have hepatic effects. Thiazolidinediones are agonists for the peroxisome proliferators-activated receptor–gamma (PPAR_), which regulate transcription of insulin-responsive genes involved in glucose production, transport, and utilization, as well as fatty acid metabolism.

Required for efficacy: Insulin (exogenous or endogenous), insulin resistance

Manifestation on glucose patterns: General and postprandial glucose levels

Potential effect on A1C: -1%–2%

Titration: Because thiazolidinediones impact genes which are involved in glucose metabolism, their full clinical effect can take some time to be fully manifest. Upon treatment initiation or a change in dose, it may take as much as 2–4 months for the full clinical effect to be seen. Further, with this mode of action, if a patient has marked hyperglycemia requiring rapid reduction in glucose levels, thiazolidinediones should not be the primary mode of therapy, and a more rapid-acting treatment should be selected.

Significant adverse effects/side effects:

  • Edema, anemia (probably dilutional), potential unmasking or exacerbation of congestive heart failure, weight gain.
  • Based on meta-analyses, concerns have been biased about the relationship between rosiglitazone and coronary events. These fears seem to have been allayed by a subsequent double blind trial. Other trials still suggest concern with rosiglitazone, but not pioglitazone, and the literature should be monitored for further resolution of this issue.
  • Concern about increased fracture rate/increased risk of osteoporosis in post-menopausal women.
Other potential adverse effects of note: Rare hepatotoxicity (see below)

Typical patient with optimal efficacy: type 2 diabetes with significant signs of insulin resistance syndrome

Other effects:
  • Weight: increases
  • Lipids: variable among members of class, as studies have different inclusion parameters and results are not consistent. Ultimately many of the patients who would be candidates for thiazolidinedione treatment would also benefit from a statin, and one of these medications should be used in addition, if indicated.
  • Procoagulant state: probable decrease

Class contraindications and precautions:

  • Hepatic disease
  • With the class tendency to produce edema and unmask/exacerbate congestive heart failure (CHF), use caution in the setting of current or potential CHF. Medications should be used with caution and careful monitoring in patients with mild to moderate heart failure (New York Heart Association (NYHA) Class 1 or 2) and not used in patients with more severe heart failure (NYHA Class 3 or 4).
  • New onset or worsening macular edema has been noted very rarely with use of rosiglitazone. It is unclear if this is unique to rosiglitazone, or could be related to the class. Consider discontinuation of thiazolidinedione use, particularly rosiglitazone, if macular edema is diagnosed, and if a patient using a thiazolidinedione reports decreased visual acuity, consider the possibility of macular edema.

INDIVIDUAL MEDICATION SUMMARIES: 

A. ROSIGLITAZONE (GENERIC)

Brand name: Avandia

Indications: Use as monotherapy, or in combination with sulfonylureas, metformin, or insulin.

Metabolism and elimination: Exclusively metabolized by cytochrome P450, CYP2C8 mostly, with CYP2C9 having a minor role. Excreted 64% in urine, 28% in feces.

Potential for hypoglycemia: Low when used as monotherapy. Increased when used in combination, particularly with an agent that increases insulin levels. Reduction of the dose of that other medication may be needed.

Possible adverse effects: Based on meta-analyses, concerns have been raised about the relationship between rosiglitazone and coronary events. A subsequent double blind, controlled trial did not find any increased risk, but other data may still suggest an increased risk compared to pioglitazone. This concern remains under discussion, and it is recommended that the literature be monitored for the latest opinions. See class effects for other possible issues.

Tablet sizes:
  • 2 mg, 4mg, 8 mg
  • Combination Tablets (brand names in parentheses):
    • Rosiglitazone/metformin (Avandamet)
      • rosiglitazone 1 mg and metformin 500 mg
      • rosiglitazone 2 mg and metformin 500 mg
      • rosiglitazone 4 mg and metformin 500 mg
    • Rosiglitazone/glimepiride (Avandaryl)
      • rosiglitazone 4 mg and glimepiride 1 mg
      • rosiglitazone 4 mg and glimepiride 2 mg
      • rosiglitazone 4 mg and glimepiride 4 mg

Typical starting dose of rosiglitazone: 4 mg per day, given at breakfast or in divided doses, 2 mg each at breakfast and suppertime

Typical dose titration pattern: increase every 4 to 8 weeks or more, as needed, to either 8 mg every morning, or 4 mg BID

Maximum daily dose: 8 mg daily, in single or divided dose; can be taken with or without food. While initial recommendations were that better control could be achieved with BID dosing, long-term studies now suggest that this difference may not be significant, and once-daily dosing is probably adequate.

Drug interaction/metabolism: As rosiglitazone is primarily metabolized by CYP2C8, which is an uncommon pathway for drug metabolism, there are no clinically significant interactions with drugs metabolized by CYP3A4 such as nifedipine or oral contraceptives. Nevertheless, if changes in glucose control are noted with initiation or discontinuation of certain drugs which are metabolized by CYP3A4 (gemfibrozil inhibits, and may thus increase rosiglitazone effect, rifampin induces, and may decrease rosiglitazone effect), dose adjustments of diabetes treatments may be needed.

Contraindications and precautions:

  • Can be used with renal impairment
  • Contraindicated with hepatic dysfunction (ALT >2.5 ULN)
  • As a precaution, it is recommended that liver enzymes be checked prior to initiation of therapy, and then periodically thereafter per the clinical judgment of the healthcare professional
  • Rosiglitazone should not be initiated in people with elevated baseline liver enzyme levels (ALT >2.5 X the upper limit of normal)
  • Patients with mild elevations (ALT levels < 2.5 X upper limit of normal) at baseline or during therapy should be evaluated to determine the cause of the liver enzyme elevation. Treatment can continue with caution and more frequent monitoring, per the judgment of the physician.
  • If at any time, ALT levels increase to 3 X ULN, recheck enzyme levels as soon as possible. If ALT levels remain > 3 X ULN, therapy should be discontinued.
  • Due to tendency for edema formation, rosiglitazone should not be used in people with New York Heart Association Class 3 or 4 cardiac status, unless the benefit is judged to outweigh the potential risk.
  • Not indicated in pregnancy (Category C)
  • May result in ovulation in an anovulatory female

Key advice to patients:

  • Contact healthcare professional if deterioration of glucose control occurs.
  • Liver function should be screened periodically when using rosiglitazone.
  • Contact healthcare professional for symptoms of liver disease: jaundice, anorexia, unexplained abdominal pain, nausea, vomiting, fatigue, or dark urine.
  • Use of this medication with oral contraceptives could decrease the efficacy of birth control medications.
  • This medication is not indicated in pregnancy — contact healthcare professional if you become pregnant.
  • This medication should not be used with severe heart failure, referred to as New York Heart Association Class 3 and 4 cardiac status, unless the benefit is judged to outweigh the potential risk. If heart failure develops, carefully consider the risks of continuing this medication vs. its benefits. Consult a healthcare professional to discuss this issue.
  • Use of this medication may result in ovulation in anovulatory women.
B. PIOGLITAZONE (GENERIC) 
 
Brand name: Actos

Indications: Monotherapy and combination therapy with sulfonylureas, metformin, and insulin

Metabolism and elimination: Hepatic metabolism via cytochrome P450 (CYP2C8, CYP3A4). Most goes to bile and is excreted. A remaining 15 to 30% is eliminated in the urine.

Potential for hypoglycemia: Low when used as monotherapy. Increased when used in combination, particularly with an agent that increases insulin levels. Reduction of the dose of that other medication may be needed.

Possible adverse effects: See class effects.

Tablet sizes:
  • 15 mg, 30mg, 45 mg
  • Combination Tablets (brand names in parentheses):
    • Pioglitazone/metformin (Actoplus Met)
      • pioglitazone 15 mg and metformin 500 mg
      • pioglitazone 15 mg and metformin 850 mg
    • Pioglitazone/glimepiride (Duetact)
      • pioglitazone 30 mg and glimepiride 2 mg
      • pioglitazone 30 mg and glimepiride 4 mg

Typical starting dose: 15 mg/day, given once daily before breakfast, for monotherapy or combination therapy. Can be given with or without food.

Typical dose titration pattern: Increase every 4 to 8 weeks or more, as needed, to 30 mg, and then 45 mg daily. Full doses can be given at once before breakfast.

Maximal daily dose: 45 mg

Drug interaction/metabolism: Three active metabolites via CYP3A4 and CYP2C8. In vitro, ketoconazole inhibits the metabolism of pioglitazone by 85%; with unknown clinical significance, but more frequent evaluation of glycemic control is recommended. Further drug interaction studies with drugs metabolized by the CYP3A4 pathway are not available at this writing.

Contraindications and precautions:

  • Known hypersensitivity to thiazolidinediones
  • Contraindicated in patients with impaired hepatic function as reflected by ALT > 2.5 X the upper limit of normal (ULN)
  • Measurement of liver enzymes:
    • Determine baseline ALT, and then periodically thereafter, per the judgment of the physician.
    • People with mildly elevated liver enzymes (ALT 1 to 2.5 X ULN) at baseline or at any time during therapy should be evaluated to determine the cause.
    • Initiation of, or continuation of, therapy with pioglitazone should proceed with caution and should include appropriate follow-up and more frequent liver monitoring.
    • If ALT > 2.5 X ULN liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values.
    • If ALT >3 X ULN during pioglitazone therapy, retest promptly and discontinue if ALT remains >3 X ULN or if patient shows signs of liver disease such as jaundice.
  • Can be used to treat patients with renal insufficiency. No dose adjustment is usually needed.
  • Not indicated in pregnancy (Category C)
  • Due to tendency for edema formation, rosiglitazone should not be used in people with New York Heart Association Class 3 or 4 cardiac status, unless the benefit is judged to outweigh the potential risk.
  • May result in ovulation in anovulatory women

Key advice to patients:

  • Contact healthcare professional if deterioration of glucose control occurs.
  • You need to have your liver function screened with a blood test every 2 months for the first month of the use of this medication and periodically thereafter. Be sure you have made these arrangements with your healthcare provider.
  • Contact healthcare professional for symptoms of hepatic disease: jaundice, anorexia, unexplained abdominal pain, nausea, vomiting, fatigue, or dark urine.
  • Use of this medication with oral contraceptives could decrease the efficacy of these birth control medications.
  • This medication is not indicated in pregnancy — contact healthcare professional if you become pregnant.
  • This medication should not be used with severe heart failure, referred to as New York Heart Association Class 3 and 4 cardiac status, unless the benefit is judged to outweigh the potential risk. If heart failure develops, carefully consider the risks of continuing this medication vs. its benefits. Consult a healthcare professional to discuss this issue.
  • Use of this medication may result in ovulation in anovulatory women.

EDUCATION SUMMARIES

IMPORTANT NOTE: These Summaries are provided for the convenience of the reader, for general education purposes, and as a clinical guide only. They reflect the author's compilation of information and general usage patterns that were accurate at the time of manuscript preparation. They should not be a substitute for the latest package insert. All categories listed below, particularly indications, precautions, screening recommendations, side effects, and other usage recommendations are subject to change without notice. For expected effects on A1C levels based on published data, be aware that some studies may reflect change with respect to placebo or change with respect to baseline. A1C improvements are also usually greater in magnitude with a higher starting value, and studies often vary with respect to the initial A1C of the treatment groups. Drug interactions listed are only those with specific relationship to the medication(s) in question, and do not list the many medications that might generally increase or decrease glucose levels. Ultimately, clinicians should use these medications based on the latest available information in the package insert, and not the potentially dated information in these Summaries.

Next Issue part 9:  MEDICATIONS THAT BLOCK GLUCOSE ABSORPTION

Copyright © 2010 by Joslin Diabetes Center. All rights reserved. Reprinted with permission. Neither this book nor any part thereof may be reproduced or distributed in any form or by any means without permission in writing from Joslin. Note: Joslin does not endorse products or services.

You can purchase the updated 2nd Edition of JOSLIN'S DIABETES DESKBOOK at:

https://www.joslin.org/jstore/books_for_healthcare_professionals.html

Please Note: Reasonable measures have been taken to ensure the accuracy of the information presented herein. However, drug information may change at any time and without notice and all readers are cautioned to consult the manufacturer's packaging inserts before prescribing medication. Joslin Diabetes Center cannot ensure the safety or efficacy of any product described in this book.

Professionals must use their own professional medical judgment, training and experience and should not rely solely on the information provided in this book to make recommendations to patients with regard to nutrition or exercise or to prescribe medications.

This book is not intended to encourage the treatment of illness, disease or any other medical problem by the layperson. Any application of the recommendations set forth in the following pages is at the reader's discretion and sole risk. Laypersons are strongly advised to consult a physician or other healthcare professional before altering or undertaking any exercise or nutritional program or before taking any medication referred to in this book.         

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This article originally posted 01 June, 2014 and appeared in  CardiovascularMedicationInsulinDiabetes Clinical Mastery Series Issue 191

Past five issues: Issue 739 | GLP-1 Special Editions July 2014 | Diabetes Clinical Mastery Series Issue 198 | Issue 738 | Diabetes Clinical Mastery Series Issue 197 |

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