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Home / Conditions / Type 2 Diabetes / Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #52: Pharmacotherapy of Type 2 Diabetes, Part 11

Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #52: Pharmacotherapy of Type 2 Diabetes, Part 11

Richard S. Beaser, MD

Joslin_Diabetes_Deskbook

This week’s excerpt covers the following topics:

  • What drugs restore incretin function
  • How to titrate GLP-1 agonists
  • Learn the contraindications and precautions for the DPP-IV inhibitors
  • The typical doses for the different DPP-IV’s….

MEDICATIONS THAT RESTORE INCRETIN FUNCTION
 
GLP-1 AGONISTS
 
EXENATIDE SUMMARY

Brand name: Byetta

  • Indications: Monotherapy or in combination with a sulfonylurea and/or metformin
  • Action: Enhances glucose-dependent insulin secretion by the beta-cells, suppresses inappropriately elevated glucagon secretion, and slows gas­tric emptying
  • Pharmacology: Injected drug reaches peak plasma concentration in 2.1 hours. Elimination by glomerular titration with subsequent proteolytic degradation. Concentrations measurably present for 10 hours post-administration.
  • Required for efficacy: Beta-cells with some functional capacity remain­ing
  • Manifestation on glucose patterns: Generalized improvement in glucose levels, particularly postprandially. Reduction in hepatic glu­cose production leads to reduced fasting glucose levels.
  • Metabolism and elimination: Excreted unchanged in the urine
  • Potential effect on A1C: Lowering of 0.4–0.9%, depending on starting A1C and use of combination therapeutic agents
  • Potential for hypoglycemia:
    • Hypoglycemia: primarily when used in combination with a sulfon­ylurea. Not increased over placebo in combination with metformin alone.
  • Significant adverse events/side effects:
    • Nausea: usually moderate and dose dependent. Decreased over time with continued therapy. Leads to withdrawal of therapy in 3% of pa­tients.
    • Pancreatitis: The use of exenatide has been very rarely associated with the development of pancreatitis. As a more common side effect of exenatide use is nausea unassociated with pancreatitis, clinicians should be cognizant of the need to differentiate GI symptoms that are and are not caused by pancreatitis. Clinicians are encouraged to discuss possible GI symptoms with their patients, and tell them to watch in particular for any persistent, unexplained abdominal pain, which could be quite severe and possibly accompanied by vomiting. The discomfort may or may not be accompanied by vomiting. In in­stances of such severe pain, the use of exenatide should be stopped if pancreatitis is suspected and the diagnosis of pancreatitis should be confirmed, including by the performance of enzyme testing. If pan­creatitis is confirmed, exenatide should not be restarted unless an al­ternate cause of the pancreatitis is identified.
  • Typical patient with optimal efficacy: Type 2 diabetes, overweight, with postprandial hyperglycemia
  • Typical starting dose: 5 mcg per dose administered twice daily at any time within the 60-minute period before the morning and evening meals. Do not administer after a meal. Injection by prefilled pen SC into the thigh, abdomen, or upper arm.
  • Prefilled pen dosage sizes:
    • 5 mcg per dose, 60 doses, 1.2 ml
    • 10 mcg per dose, 60 doses 2.4 ml
  • Titration and optimal daily dose: After 1 month of therapy at 5 mcg/ dose level, if patient is without significant problems with nausea or hypoglycemia, increase to 10 mcg/dose which is the usual maintenance dose. When given with metformin, the dose of metformin usually does not need to be reduced. When given with sulfonylurea, a reduction in dose is often warranted initially to reduce the risk of hypoglycemia.
  • Maximal daily dose: 10 mcg/dose, given BID
  • Other clinical effects:
    • Reduces appetite
    • Slows gastric emptying
  • Drug interactions with potential for clinical significance:
    • The effect of exenatide to slow gastric emptying may reduce the ab­sorption of other orally administered medications. Use with caution in combination with medications which require rapid gastrointesti­nal absorption. Medications that are dependent on threshold concen­trations for efficacy such as contraceptives and antibiotics should be taken at least 1 hour before an injection of exenatide. If such medica­tions are to be taken with food, have the person take them with a snack at which exenatide is not administered.
  • Contraindications and precautions:
    • Persons with hypersensitivity to exenatide or one of its components
    • In patients with mild to moderate renal impairment (creatinine clear­ance 30–80 ml/min) clearance was only mildly reduced, and no dose reduction is needed. However, exenatide is not recommended in people with end-stage renal disease/dialysis (creatinine clearance < 30 ml/min).
    • Not recommended for use in people with severe gastrointestinal dis­ease
    • Pregnancy Category C
  • Key advice to patients:
    • Explain use of prefilled pen devices, injection technique, and titration plan.
    • Explain use of detachable needles and equipment disposal tech­niques.
    • Explain potential for adverse events, including nausea and hypogly­cemia.
    • Advise regarding potential reduction in appetite.
    • Advise that they should inform their physician if they become preg­nant or plan pregnancy.
Please note that liraglutide (Victoza) is also an FDA-approved GLP-1 for treating type 2 diabetes but at the time of this text excerpt’s original publication had not yet received approval from the FDA. We are working to contact Joslin to obtain their updated information on liraglutide and will add it to this list as soon as we have it.
 
 
DPP-IV INHIBITORS CLASS SUMMARY
  • Action: These medications are competitive inhibitors of DPP-IV, an enzyme that normally inactivates the incretin hormones (GLP-1). As a result of their action, there are increased concentrations of these incretin hormones released into the bloodstream from the small intestine in response to meals. These hormones enhance glucose-dependent in­sulin secretion by the beta-cell. They also suppress inappropriately ele­vated glucagon secretion seen with type 2 diabetes which reduces hepatic glucose production.
  • Required for efficacy: β-cells with some functional capacity remaining
  • Manifestation on glucose patterns: Improvement in glucose levels, fasting and, in particular, postpran­dially.
  • Typical patient with optimal efficacy: Type 2 diabetes, particularly those with postprandial hyperglycemia
INDIVIDUAL MEDICATION SUMMARIES:
 
SITAGLIPTIN
 
Brand name: Januvia
  • Indications: Monotherapy or in combination with a metformin or a thiazolidinedione
  • Pharmacology: Sitagliptin reaches its peak plasma concentration in 1–4 hours post administration. The absolute bioavailability is 87%. It may be administered with or without food. Approximately 79% of the drug is excreted unchanged in the urine, with metabolism being a minor pathway of elimination.
  • Potential effect on A1C: decrease of 0.5–1.0%, depending on starting A1C and use of combination therapeutic agents
  • Potential for hypoglycemia: Hypoglycemia is not a significant problem with normal usage
  • Significant adverse events/side effects: Not significantly different from placebo. Details in package insert.
  • Typical dose:
    • 100 mg once daily for people with creatinine clearance > 50
    • 50 mg daily for patients with moderate renal insufficiency as defined as creatinine clearance < 50 but > 30
    • 25 mg daily for patients with severe renal insufficiency as defined as creatinine clearance < 30 or end stage renal disease.
    • No dose titration.
  • Also available as a combination tablet with metformin:
    • Sitagliptin/metformin (Janumet)
    • sitagliptin 50 mg and metformin 500
    • sitagliptin 50 mg and metformin 1000 mg
  • Other suggested clinical effects:
    • May reduce appetite and promote weight loss
    • Slows gastric emptying
  • Drug interactions with potential for clinical significance: None significant
  • Contraindications and precautions: 
    • No contraindications
    • Precaution, with dose adjustment, in patients with mild to moderate renal impairment
SAXAGLIPTIN
 
Brand name: Onglyza
  • Indications: Monotherapy
  • Pharmacology: Saxagliptin reaches its peak plasma concentration in 2 hours post ad­ministration, and 4 hours for its active metabolite. Administration with a high fat meal increased this by about 20 minutes. It may be administered with or without food. Metabolism is primarily medi­ated by cytochrome P450 3A4/5 (CYP3A4/5). The major metabolite is also a DPP-IV inhibitor which is 1/2 as potent as saxagliptin. It is eliminated by both active renal and hepatic pathways as drug and active metabolite.
  • Potential effect on A1C: decrease of 0.5–1.0%, depending on starting A1C
  • Potential for hypoglycemia: Hypoglycemia is not a significant problem with normal usage as monotherapy
  • Significant adverse events/side effects: Not significantly different from placebo. Details in package insert.
  • Typical dose:
    • 5 mg once daily for people with creatinine clearance > 50
    • 2.5 mg daily for people with moderate to severe renal insufficiency as defined by a creatinine clearance < 50 or who are also using strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (ex: ketocon­azole, atazanavir, clarithromycin – see package insert for full list).
    • No dose titration at either dose level
  • Other suggested clinical effects:
    • May reduce appetite and promote weight loss
    • Slows gastric emptying
  • Drug interactions with potential for clinical significance: Strong CYP3A4/5 inhibitors (see above and package insert)
  • Contraindications and precautions:
    • Not studied in pregnant women
    • Dose adjustment in patients with mild to moderate renal impair­ment
VILDAGLIPTIN
Brand name: Galvus
Under FDA review at the time of this writing
 
BILE ACID SEQUESTRANTS (BINDING MOLECULE)
 
COLESEVELAM
 
Brand name: Welchol
  • Action: Binds bile acids in the intestine without being absorbed. Re­duced reabsorption of the bile acids leads to depletion of cholesterol. Postulated mechanisms of glucose-lowering include: alteration of bile acid composition which affects intestinal glucose absorption, increased cholesystokiniin release which stimulates insulin release, decreased enterhepatic bile acid pool decreases FXR enzymatic activity which re­duces inhibition of enzyme LXR which leads to a reduction in hepatic insulin resistance, suppresses hepatic gluconeogenesis, and improves hepatic glucose utilization and uptake, and/or other mechanisms to stimulate increased insulin secretion.
  • Indications and combination usage: As an adjunct to diet and exer­cise to improve glucose control in adults with type 2 diabetes, particu­larly in combination therapy
  • Required for efficacy: Insulin (exogenous or endogenous)
  • Metabolism and elimination: Non absorbed, eliminated in the stool
  • Potential effect on A1C: A reduction of about 0.5 % vs. placebo
  • Potential for hypoglycemia: Low
  • Side effects of note:
    • Constipation or heartburn
    • May cause increase in triglyceride levels
  • Typical patient with optimal efficacy: Type 2 diabetes. Particularly useful in people who also have dyslipidemia, and who may be short of treatment goal for both A1C and LDL cholesterol
  • Tablet sizes: 625 mg tablets
  • Optimal daily dose:
    • Three tablets (1875 mg) taken twice daily with meals (total 3750 mg) or 6 tablets once a day with a meal.
  • Drug interactions with potential for clinical significance: 
    • Decreases absorption of fat soluble vitamins (A, D, K, and E), glyburide, levothyroxine, and birth control pills containing ethinyl estradiol
    • May decrease absorption of phenytoin and warfarin
  • Contraindications and precautions:
    • Bowel obstruction
    • Triglycerides > 500 mg/dL or history of triglyceride-induced pancre­atitis
    • Category B for use in pregnancy
    • Not absorbed, so will not pass into breast milk
    • Do not use to treat type 1 diabetes or ketoacidosis

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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.

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