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Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #45: Pharmacotherapy of Type 2 Diabetes, Part 4

May 4, 2014

Richard S. Beaser, MD


This week’s excerpt covers the following topics:

  • Which medications slow glucose absorption?
  • Which medications increase insulin secretion?
  • What is first phase insulin response?
  • Who are the patient candidates for the different drug classes?
  • Nateglinide vs. Repaglinide


Medications that Slow Glucose Absorption

The effect of this class of medications — slowing glucose absorption — is particularly helpful in improving glucose control for patients for whom the loss of first-phase insulin secretion is a predominant abnormality, often accompanied by a delay in second-phase and insulin resistance. The slowed glucose absorption and delayed rise in postprandial glucose absorption results in a better match between this glucose influx and the second — or later — phase of insulin release.

Normal insulin response occurs in two phases. The first phase is a rapid insulin release immediately following the ingestion of food. It is postulated that this phase is the result of release of pre-made insulin from β-cells and occurs after exposure of the cell to rising blood glucose levels. Loss of first-phase insulin release is a characteristic abnormality seen in people with type 2 diabetes. Subsequently, there is a more gradual, longer-lasting rise in insulin levels representing newly manufactured insulin, referred to as the second phase.

The loss of first-phase insulin release typically occurs early in the natural history of type 2 diabetes. The first-phase insulin response is also blunted by glucose toxicity, caused by the hyperglycemia present prior to food ingestion. When the first-phase insulin response is lost, the postprandial glucose levels rise unopposed and reach a higher-than-normal level. In the patient who still has otherwise adequate β-cell function and number, the second-phase of insulin release, stimulated by this elevated postprandial glucose level, is often augmented. The result is the increased insulin secretion that leads to the hyperinsulinemia that has been noted previously.

Interestingly, some people who may not yet have diabetes, but have parts of the insulin resistance constellation, will begin to lose their first-phase insulin response. In fact, people with impaired glucose tolerance who demonstrate a loss of first-phase insulin secretion are more likely to develop frank diabetes, as compared with those who retain that first phase. With absent first-phase insulin release, a significant second-phase release can lead to reactive hypoglycemia hours after eating. This can be particularly significant if a rapidly absorbed glucose source is consumed, resulting in a sharp rise in postprandial glucose levels and marked second-phase insulin production.

Early phases of diabetes will be manifest by this pattern of insulin secretory abnormality and the resulting glucose pattern of postprandial hyperglycemia. In fact, about 50% of people destined to get type 2 diabetes, who have not yet met diagnostic criteria based on the fasting glucose level, will show some postprandial abnormality. In spite of the promulgation of the new diabetes diagnostic criteria based on a fasting glucose level, intended to make diagnosis easier, there is some evidence that the early clinical manifestation of an insulin secretory abnormality — postprandial hyperglycemia — might be an important marker of the insulin resistance syndrome and all of the inherent risks of earlier morbidity and mortality that it carries with it.

For patients who have diabetes and are at the stage at which this early insulin secretory defect is present, one can reduce the need for that missing or blunted first-phase of insulin secretion if the incoming glucose load is absorbed more slowly. This is how the medications that slow glucose absorption work to improve glucose control. They blunt a sharp postprandial glucose rise that cannot be effectively held at appropriate levels by a first-phase insulin response, and then prolong the absorption of that glucose into the timeframe of the second-phase insulin release, when the presence of blood glucose more closely matches the presence of secreted insulin.

Thus, these medications have a specific niche in treatment for insulin resistant patients who have progressed to that phase in the natural history of the condition where first-phase insulin secretion is significantly decreased, and often, also, there is a delay or reduction in the second phase.

Similarly, while reactive hypoglycemia is over-diagnosed and used as an explanation of many unrelated symptoms, for the patient with insulin resistance and a true reactive pattern, these medications are sometimes used to help ameliorate untoward symptoms.

Glucosidase Inhibitors

  • General comments: α-Glucosidase inhibitors are the class of medications that are currently used to slow glucose absorption. The members of this class that are currently available in the United States are acarbose and miglitol. These medications are competitive inhibitors of intestinal brush border α-glucosidases, which leads to the prolongation of carbohydrate absorption time from the gastrointestinal tract. The usual effect on lowering A1C levels is about 0.5 to 1%.
  • Anticipated efficacy: As these medications are optimally effective in early stages of type 2 diabetes when glucose abnormalities are not as great as they may be later, the resulting impact on A1C-lowering is less than that seen with other classes of medications. However, there have been some suggestions that these medications may demonstrate greater A1C-lowering effect when used in patients with more advanced diabetes and higher initial A1C levels. In addition, not surprisingly, these medications are more effective in people who consume a diet higher in carbohydrates. Further, a study ("Stop NIDDM") showed that the use of one of these medications, acarbose, can reduce the progression from impaired glucose tolerance to type 2 diabetes by about 25% and also can reduce the incidence of cardiovascular events.
  • Clinical dosage: The usual starting dose of miglitol and acarbose is 25 mg TID. However, some physicians start with 12.5 mg before meals (although the tablet is not scored) and some elect to suggest 25 mg before just one or perhaps two meals initially. Usually, the medication is taken with the first bite of food at the 3 main daily meals. Doses are then gradually titrated upward, if necessary, based on the results of self-blood glucose testing and A1C, to 50 mg.TID, then 100 mg.TID.
  • Adverse effects: Use may be limited by the typical side effects of flatulence, which is usually mild and self-limited, or diarrhea. These occur in about 56% of people using acarbose, with 15% discontinuing use as a result; there are similar occurrences for miglitol. For most people, these symptoms subside after about three to four weeks of use. Mild elevations of liver enzymes (transaminases) are quite rarely seen with these medications, usually at higher doses.

Medications that Increase Insulin Secretion

Traditionally, the group of medications that increase insulin secretion were referred to as insulin secretagogues. The sulfonylureas, one class of medication in this grouping, were the first types of oral treatments for diabetes in common usage. Subsequently, the short-acting secretagogues became available with more immediate postprandial secretory effects.

There is now a new group of medications that work to increase insulin secretion, referred to by various names including the incretin mimetics or incretin replacement therapies. While technically also secretagogues, we will consider them in a separate grouping due to their differences in mode of action.

The traditional insulin secretagogues

As noted above, the "traditional" insulin secretagogues are divided into the longer-acting sulfonylureas, and the shorter-acting or prandial secretagogues, the meglitinides and D-phenylalanine derivatives. While the medications that decrease insulin resistance require the presence of insulin from any source in order to be effective, medications that increase insulin secretion require the presence of the functioning β-cells, as they act upon these cells to increase their insulin production.

These insulin secretagogues work by binding to the SUR binding site on the wall of the pancreatic β-cell. This triggers a closing of potassium channels, and a resulting depolarization leads to opening of the calcium channels. This, in turn, leads to an increase in intracellular Ca++, which causes insulin release. The binding of these medications to the SUR binding sites can be tight or loose. Sulfonylureas tend to bind tightly, and thus there is a more tonic, longer acting insulin secretory response. Some of the other shorter-acting secretagogues bind more loosely, and thus have an immediate effect only, then come loose and the effect subsides. Thus, when taken before meals, their effect can be targeted to the postprandial period and also tend to be more dependent on glucose levels to modulate insulin secretion. Even within the sulfonylurea group, the binding affinity can vary, with glyburide binding the most tightly, thus leading to the most tonic, ongoing insulin secretory stimulation, with glimepiride and then glipizide binding somewhat less tightly.

While the primary impact of these medications is increased insulin secretion, the reduction of glucose levels can decrease glucose toxicity, and, indirectly, also reduce insulin resistance. This fact may explain the phenomenon that insulin levels do increase upon initiation of therapy with a sulfonylurea, one class of insulin secretagogues. However, after a number of months of therapy with improvement in glucose control, insulin levels often return to pretreatment levels. The reduction in glucose toxicity from the improvement in diabetes control may have the indirect effect of reducing insulin resistance, resulting in reduced insulin requirements. However, the direct effect of sulfonylureas to potentiate insulin action in liver and peripheral tissues (muscle and adipose) has also been proposed, and the actual clinical impact of these possible actions remains debatable.

  • General comments: As their primary mode of action, sulfonylureas increase insulin secretion in response to rising glucose levels. They also exhibit the indirect effects noted above, possibly increasing insulin action and decreasing hepatic insulin clearance.

The sulfonylureas were the first class of oral medications for diabetes treatment that achieved widespread use throughout the world, and their availability is considered to be one of the significant milestones in the modern history of diabetes treatment.

The first medication in this class, tolbutamide, became available for clinical use in 1955. Subsequently, three other medications, acetohexamide, tolazamide, and chlorpropamide became available. For two decades, these "first-generation" medications dominated the oral diabetes therapy market, shared, only briefly, but significantly, with the biguanide phenformin, which is no longer available. By the early 1980s, however, modifications of the basic sulfonylurea molecule led to the introduction of a second generation of sulfonylureas.

These agents include glyburide (also known as glibenclamide), glipizide, and gliclazide. Glimepiride followed a few years later.

The second-generation sulfonylureas (listed in Table 8-1) have essentially replaced the first generation agents in common usage due to numerous advantages:

  • high level of potency relative to therapeutic dosage due to high affinity for the sulfonylurea receptor on the cell surface
  • short half-life, yet 24-hour duration of action
  • compared with many of the first-generation agents, these second generation agents can be given less frequently, increasing adherence
  • theoretically fewer drug interactions and side effects

In addition, differing formulations of some of these agents (glipizide GITS, micronized glyburide, and combination tablets) can affect their pharmacologic action. (See Medication Summaries.)

Contraindications to the use of sulfonylureas include:

  • type 1 diabetes or diabetes due to pancreatic resection
  • pregnancy
  • significant renal or hepatic disease
  • a history of adverse reactions to sulfonylureas or related compounds
  • treatment during acute stress such as infections, trauma, surgery
  • acute hyperglycemia with ketosis or hyperosmolar states
  • tendencies to develop severe hypoglycemia


  • Anticipated efficacy: Generally, sulfonylureas can be expected to lower A1C levels by about 1–2 percentage points in a person with adequate β-cell function remaining.
  • Clinical dosage: The dosing ranges for the various agents in this class are listed in Table 8-1 and in the Medication Summaries. Most of the therapeutic efficacy of sulfonylureas is seen in the first half of the usual dosing range. Dose titration is accomplished based on the results of SMBG and A1C levels.
  • Adverse effects: There are relatively few adverse effects from sulfonylureas. The most common concerns are allergic reactions in people with sensitivity to sulfa drugs. Hypoglycemia is more likely to occur with the use of the sulfonylureas than with the use of medications from any other class due to the potential for generalized increases in insulin levels.
  • General comments: Meglitinides are a newer class of non-sulfonylurea insulin secretagogues. These medications are benzoic acid analogues, and the first drug introduced from this class is repaglinide. Repaglinide is a β-cell sensitizer that primes the cell for glucose-dependent release of insulin in the immediate postprandial period. Thus, from a clinical standpoint, the key difference is that the insulin release is more predominantly glucose-dependent, as opposed to the effect of sulfonylureas, in particular glyburide, which initiate insulin release more independent of the presence of glucose.

This medication can be effective in patients with the characteristic loss of first-phase insulin release. However, with a longer effect than nateglinide (see below), these medications probably can boost insulin response in the timeframe of the second phase of insulin release as well. Therefore, they would be useful for patients who are at the point in the natural history of their type 2 diabetes at which they are losing the glucose-stimulated insulin secretory function and are beginning to develop significant postprandial hyperglycemia. For patients needing an insulin secretagogue but who often eat meals on erratic schedules, of variable quantities, or who even skip meals, this medication can be adjusted based on these variables, with doses being omitted if a meal is missed.

  • Anticipated efficacy: Generally, repaglinide, the meglitinide currently available, can be expected to lower A1C levels by about 1.6 to 1.9 A1C percentage points in a person with adequate β-cell function remaining.
  • Clinical dosing: Repaglinide is indicated for use as monotherapy or in combination with metformin. It is given preprandially, titrated to doses between 0.5 and 4 mg prior to each meal, and can be used for up to four meals per day for a maximum dose of 16 mg/day. (See Medication Summaries).
  • Adverse effects: Relatively few. As with sulfonylureas, hypersensitivity and hypoglycemia are adverse effects that might occur.

D-Phenylalanine Derivatives

  • General comments: The representative medication of the class of D-phenylalanine is nateglinide. In spite of the similarity of the generic name to repaglinide, this medication is really in a separate structural class from repaglinide and, for that matter, from the sulfonylureas.

The name similarity stems from the similarity of its clinical effects to those of repaglinide — the rapid, glucose-mediated stimulation of postprandial insulin release — and often people mistakenly include this in the meglitinide group, when technically it is not. Nateglinide has an essentially flat dose-response curve, so the usual dose recommendation is 120 mg, with the 60-mg dose reserved for patients who are close to their therapeutic target. The glucose levels dictate the degree of response more than does the dose of medication.

Nateglinide has a strong affinity for beta-cells. If it is taken before eating, its glucose-dependent effect in stimulating insulin release is extremely rapid, analogous to the first-phase insulin release that is lost in people with type 2 diabetes. Used as monotherapy in non-drug-naïve patients, data suggest an A1C drop of about 0.45%. As with other medications, drug-naïve patients, and those with higher pretreatment A1C levels, may have a greater response. For example, combined therapy with metformin may achieve an A1C drop of 1.5% or more. As with repaglinide, treatment can be tailored to meal schedules with respect to timing and the omission of the medication if a meal is skipped.

The key clinical difference between this medication and repaglinide is the time-course of action. Compared with repaglinide, nateglinide has a more rapid onset and results in a postprandial insulin secretory peak that comes even closer to the natural first-phase pattern than repaglinide would stimulate. Its shorter duration of action makes it less likely to cause hypoglycemia hours after the meal than is seen with repaglinide and considerably less likely than with sulfonylureas. However, the other side of this issue is that with less late efficacy, it might be less effective in patients who have developed significant defects in second-phase insulin secretion. Therefore, one would expect this medication to have clinically significant efficacy in patients with early type 2 diabetes, where the characteristic loss of first-phase insulin release has occurred, but before the condition has progressed further to include a significant second-phase insulin secretory deficiency or a reduction in β-cell mass as well.

Next Issue: Medications that Improve or Enhance Incretin Function: The Incretin Mimetics



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