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Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #46: Pharmacotherapy of Type 2 Diabetes, Part 5

May 11, 2014

Richard S. Beaser, MD


This week’s excerpt addresses the following topics:
  • What is the "Incretin Effect"?
  • The seven actions of GLP-1
  • Efficacy of DPP-IV inhibitors
  • Where do the bile acid sequestrants fit in?

Medications that Improve or Enhance Incretin Function: The Incretin Mimetics

The existence of the incretin system has been known for a number of years, but it is not until recently that this knowledge has translated into a mode of treating diabetes. It had been observed for many years that when glucose was taken orally, the resulting insulin stimulatory response was greater than when glucose was given intravenously — over 50% greater in many instances. This effect was noted in the differences in expected response between an oral and intravenous glucose tolerance test. This difference in response is referred to as the incretin effect. It is primarily due to the effects of two hormones secreted from cells in the small intestine when food enters the stomach and which stimulate insulin secretion and glucagon suppression, glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP). These hormones, constituting the incretin effect and playing significant roles in mealtime insulin secretion, are major controlling influences on postprandial glycemia.

GLP-1 is secreted by the L-cells in the distal small intestine (jejunum and ileum) upon stimulation by the presence of incoming nutrients. GLP-1 is rapidly metabolized by the enzyme dipeptidyl-peptidase IV, or DPP-IV. GIP is also metabolized by this enzyme, but less efficiently. Thus, the half-life of GLP-1 is about 4-5 minutes.

People with type 2 diabetes have been found to have a reduced incretin effect, primarily due to reduced GLP-1 secretion, but decreased GIP effect as well. As the efficacy of GLP-1 remains, and it is the secretion that is affected, replacement of GLP-1 was targeted as a potential treatment intervention. GLP-1 has a number of actions that have been identified to date:

  • stimulates insulin gene transcription and expression, and the resulting insulin synthesis
  • increases β-cell mass by stimulating new cell formation and inhibition of apoptosis
  • enhances glucose-dependent insulin secretion
  • suppresses glucagon secretion
  • slows gastric emptying (which blunts postprandial glucose excursions)
  • improves insulin sensitivity
  • reduces appetite and food intake

Thus, it seemed initially that with effects such as these, GLP-1 replacement would be a wonderful treatment option. However, as noted above, the rapid degradation by DPP-IV renders most of the GLP-1 inactive quite rapidly, and thus the natural form would not be a therapeutic option. To develop a pharmacologic means of replacing incretin function in people with type 2 diabetes, the options would be to find an alternative form of GLP-1 that was not degraded as rapidly as the natural form, or to inhibit the enzyme DPP-IV, so natural GLP-1 would remain active longer.

GLP-1 Agonists 
  • General comments: GLP-1 mimetic substances have been sought as a treatment to restore incretin function. The first one to reach the market was exenatide.

Exenatide was discovered when it was noted that a salivary protein from the Gila monster had properties similar to GLP-1. A synthetic version of this substance was produced and tested, and found to be effective. It has greater than 50% structural overlap with human GLP-1, binds to the human GLP-1 receptor on the β-cell, and is resistant to DPP-IV degradation, being measurable in plasma for as long as 10 hours after injection.

Exenatide is indicated for use as adjunctive therapy to achieve targeted glycemic control in people with type 2 diabetes who are taking metformin, a sulfonylurea, or a combination of the two. It increases first phase and augments second phase insulin secretion. It also reduces glucagon secretion, particularly in the presence of hyperglycemia, but does not blunt glucagon response to hypoglycemia. It slows gastric emptying, resulting in slower entry of meal-derived glucose into the circulation. It has been shown to reduce appetite, leading to decreased food intake.

  • Anticipated efficacy: Generally, exenatide is used in combination with a sulfonylurea and/or metformin and/or a TZD, and can achieve a reduction in A1C of up to 1%. It can also lead to a reduction in weight, most likely in combination with metformin alone where 3 kg reductions can be seen.
  • Clinical dosing: Exenatide is initiated as injection therapy in combination with sulfonylureas and/or metformin and/or TZDs. It is initiated at 5 mcg per dose, given with a prefilled pen device, twice daily within 60 minutes of the morning and evening meals. After about a month, based on clinical response and absence or amelioration of side effects, it is increased to 10 mcg per dose, twice daily.
  • Adverse effects: Other than hypoglycemia, the most common adverse effect was nausea, usually mild to moderate, sometimes associated with vomiting. These side effects usually subsided with continued therapy. Rarely, pancreatitis can be a more significant adverse event, and this is discussed in more detail in the drug detail sections at the end of the chapter.
DPP-IV Inhibitors 
  • General comments: At this writing, two DPP-IV inhibitors are available on the market: sitagliptin and saxagliptin. Others are in various stages of development. Normally, DPP-IV inactivates GLP-1, rapidly depleting the endogenous pool. DPP-IV inhibitors will block this degradation process, thus increasing the supply of endogenous GLP-1. Their blocking of GLP-1 degradation will lead to improved glucose dependent insulin release, reduced hepatic glucose production, and improved peripheral glucose utilization. Some of the other effects of GLP-1 replacement are less clear, such as the effect on satiety and β-cell preservation. Sitagliptin is indicated as an adjunct to diet and physical activity in the treatment of type 2 diabetes as monotherapy, or in combination with metformin or a thiazolidinedione. More recently, saxagliptin has been approved by the FDA for similar indications.
  • Anticipated efficacy: Improvements in A1C levels in initial studies have shown improvements of about 0.5–1.0%, the greater improvements seen with higher initial A1C levels.
  • Clinical dosing: DPP-IV inhibitors are oral medications, administered once daily. Sitagliptin is given as 100 mg tablets, although 50 mg tablets are used for people with moderate renal insufficiency, and 25 mg for those with severe renal dysfunction. The dose of saxagliptin is 5 mg daily and 2.5 mg for patients with impaired renal function or for those using other medications that are strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors.
  • Adverse effects: Studies with these medications showed no significant differences from placebo other than a slight increase in nasopharyngitis. A rare idiosyncratic side effect associated with sitagliptin is Stevens-Johnson Syndrome. Further details are available in the package inserts for these medications.

Bile Acid Sequestrants

Recently, a class of medications, the bile acid sequestrants, which has been available for many years as a lipid treatment, has been given the indication for use in glucose treatment as well. It will generally lower the A1C level up to about 0.5%. It is not absorbed, but rather works in the GI tract. There are a number of postulated mechanisms for this medication’s effect on glucose control.

Colesevelam is often used in people who are already on treatments for type 2 diabetes and dyslipidemia, but who may be short of goal for two key parameters for these conditions, A1C and LDL cholesterol. While not as effective as some other medications for hyperglycemia only or dyslipidemia only, its ability to be moderately effective for both metabolic parameters, thus allowing one medication to be used for two purposes, makes it a useful tool. It may also be used in treatment of either hyperglycemia or dyslipidemia when other mediations may be contraindicated


Next issue: Assembling a Treatment Program and A General Approach to Treatment

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