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Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #42: Pharmacotherapy of Type 2 Diabetes, Part 1

Richard S. Beaser, MD

Joslin_Diabetes_Deskbook

This week’s excerpt covers the following topics:

  • Knowing the options for treatment
  • Determining medication selection
  • Clinical markers for the dominant underlying pathophysiology
  • The three stages to glucose patterns

INTRODUCTION

The development of oral medications to treat type 2 diabetes has been one of the major milestones in the modern era of diabetes treatment. Since the 1950s, it has been possible to treat type 2 diabetes with tablets. In recent years, newer medications have become available targeting specific components of the spectrum of pathophysiologic abnormalities, regulating glucose input, and also addressing glucose utilization and disposal through impacts on insulin resistance and insulin deficiency. This broadening of the reach of non-insulin medical therapies also now includes a non-insulin injectable medication. The power that these treatment tools bring to diabetes treatment has allowed more people with type 2 diabetes than ever before to approach a level of glucose control and near normalization of glucose patterns that can significantly reduce their risk of complications.

The availability of antidiabetes medications for treatment of type 2 diabetes was one of the significant milestones in the history of diabetes treatment. When oral medications first became available, there were thousands of people who suspected or actually knew that they had diabetes, but, fearing insulin injections, did not seek medical attention. Physicians practicing at that time recall the many patients who suddenly appeared once oral treatments were available. Today, modern insulin administration is easier, provides better control, is more widely accepted by patients, and can be very appropriate for many with type 2 diabetes. Yet, the antidiabetes medication treatment boon has achieved widespread acceptance among people with diabetes and has contributed immensely to improved health and reduced disease impact. In fact, as is discussed in the chapter on macrovascular complications, comprehensive treatment of type 2 diabetes often involves the use of many medications to treat other metabolic abnormalities in an attempt to reduce macrovascular risk.

Using pills to treat diabetes was not a new concept even in the 1950s. German scientists found compounds with hypoglycemic effects as far back as 1920, although many of those early compounds were too toxic for human use. In many parts of the world, natural substances have been used for years as medications to lower glucose levels, and the search continues today for others that may be effective.

The comments at the end of the previous chapter on the treatment of type 2 diabetes provide the medical indications for pharmacotherapy for type 2 diabetes. Other than states of acute hyperglycemia, the primary indication for treatment with antidiabetes medications is the inability to achieve goals of therapy after no more than 3 months of nonpharmacologic intervention. The goals should be those of a diabetes organization such as Joslin Diabetes Center (see Joslin’s Clinical Guidelines, www.joslin.org), the American Diabetes Association (ADA) or the American Association of Clinical Endocrinologists (AACE), but such goals should otherwise be individualized for a particular patient.

The recent introduction of the many new pharmacologic agents to treat type 2 diabetes has taken some of the "pressure" off nonpharmacologic treatments as the only treatment modality short of insulin. Nevertheless, medical nutrition therapy and increased activity are still the primary therapies for type 2 diabetes. Unfortunately, many patients cannot alter these lifestyle parameters sufficiently to overcome metabolic abnormalities and optimize glucose control. In the past, this inability to make long-term lifestyle changes resulted in suboptimal control. Now, pharmacology can circumvent the inability to optimize the impact of lifestyle changes, and patients do not have to suffer the consequences of hyperglycemia resulting from inadequate pharmacology and the inability to change their habits. However, it does not mean that medical nutrition therapy and activity are any less important. This point must be emphasized to patients at the initiation of pharmacologic treatment, as well as throughout the course of their treatment. Pharmacologic management is not likely to be sufficiently effective — if effective at all — without some conscientious attention to lifestyle changes as well.

Options for Therapy

The medications available at this writing to treat type 2 diabetes can be grouped according to their chemical class and function:

  • Medications that improve insulin action
    • Biguanides
    • Thiazolidinediones
  • Medications that increase insulin secretion
    • Sulfonylureas
    • Meglitinides
    • D-phenylalanine derivatives
  • Medications that restore or replicate incretin action and increase insulin secretion and suppress glucagon secretion
    • GLP-1 agonists (injected)
    • DPP-IV inhibitors
  • Medications that slow glucose absorption
    • αGlucosidase inhibitors
  • Medications that provide additional insulin
    • Exogenous pharmacologic insulin (injected)

It is important to note that insulin is included in this list. Insulin should not be thought of as a treatment of last resort when other antidiabetes medications fail to work, or when the patient is perceived to be nonadherent. Insulin is an important part of this medication list with specific indications. It has typically been used when there is decreased endogenous insulin secretion or to decrease glucose toxicity. However, in recent years with the recognition that postprandial glycemia is a major contributor to elevated A1C levels on the lower end of the scale, and also may be a marker of increased macrovascular risk, the incentive to provide prandial insulin coverage has increased. Thus, it is possible that we will see the use of insulin not just reserved for the time when the absolute insulin secretory capacity has decreased, but also earlier in the natural history when it is the first phase insulin secretion that has diminished in capacity and it is needed to provide adequate prandial coverage. 

Medication Selection for Treatment of Type 2 Diabetes

There are a number of considerations in selecting a medication to treat type 2 diabetes:

  • Underlying pathophysiology
    • severity of abnormalities
    • degree of insulin resistance vs. insulin deficiency
    • presence and severity of glucose toxicity
    • degree of postprandial hyperglycemia
  • Overall patient condition
    • age
    • coexisting diseases, conditions, or abnormalities
    • the presence of contraindications to certain medications
    • patient lifestyle considerations
    • willingness and ability to use injected medication (exenatide, exogenous insulin)
  • Characteristics and precautions of potential medications

Currently, there is no easy method in common clinical use to measure insulin resistance or insulin secretory capacity. Insulin clamp studies that are used in research protocols to measure insulin resistance are not practical in the outpatient office. Measurement of C-peptide can be used as a marker of endogenous insulin production. C-peptide is the connecting peptide that is severed from the proinsulin molecule in the final stage of insulin production. Unfortunately, patients for whom the clinical signs that reflect insulin secretory capacity are equivocal often have equivocal C-peptide levels, thus not helping clinical decisions. However, if future trends lead to treatment of insulin resistance in the absence of hyperglycemia, and hyperinsulinemia is reflective of insulin resistance, then measuring C-peptide may become useful. At present, however, most clinicians do not feel it adds much to the medication selection decisions.

Clinical Markers 

There are clinical markers that can reflect the predominance of the various pathophysiologic components that contribute to type 2 diabetes. While these markers cannot be relied on to provide completely accurate information about the dominant underlying pathophysiology, they can help give the healthcare professional enough of a clinical sense of the predominance of the various defects to guide selection of treatments. They might also signal the need for additional attention to potential problems. These markers include:

Body habitus: The so-called apple-shaped body (big belly) suggests insulin resistance. Overweight in general suggests insulin resistance. Presence of a skin condition called acanthosis nigricans can also be a marker of insulin resistance.

Age: Aging promotes insulin resistance. Therefore, the older the person, the more likely he or she is to have insulin resistance. Also, insulin secretion can decline with age as well.

Weight change: Recent loss of weight, particularly concurrent with poorly controlled diabetes, suggests insulin deficiency. Weight gain tends to lead to insulin resistance. BMI (Body Mass Index) greater than 27 is invariably associated with insulin resistance.

Duration of diabetes: The longer the patient has had type 2 diabetes, the more likelihood that there is significant insulin deficiency.

Gender: Women with type 2 diabetes lose the protection against macrovascular disease that being female would normally bring. Attention to macrovascular risk factor reduction is important.

Ethnic group: Groups with an above-average incidence of type 2 diabetes and insulin resistance may benefit from treatment with a medication that reduces insulin resistance.

Coexisting diseases: The presence of other components of the insulin resistance syndrome suggest the presence of insulin resistance. These might include dyslipidemia, hypertension, or gout.

Side effect profile: The development of side effects from use of a medication might preclude its use. Similarly, the presence of another condition that might be exacerbated by a side effect might preclude use of the offending medication. (e.g., liver toxicity potential in someone with underlying hepatic disease)

Glucose patterns: Glucose patterns, can be suggestive of more specific underlying pathophysiology.

  • Fasting hyperglycemia, with lower values before lunch and supper, is reflective of hepatic insulin resistance. The presence of other factors suggesting insulin resistance would support this conclusion. (Keep in mind that values that are generally elevated throughout the day may be more reflective of both insulin resistance as well as a more significant reduction in insulin secretory capacity.)
  • Postprandial hyperglycemia is also a hallmark of type 2 diabetes, usually reflecting the loss of first-phase insulin release (insulin release in the first minutes after starting food consumption). Absent first-phase insulin release allows the postprandial glucose level to rise to higher levels, primarily in response to nutrients provided in the meal. However, first-phase insulin loss may also lead to a less effective suppression of hepatic glucose production as well.
  • Glucose values that are unresponsive to antidiabetes therapy and lifestyle changes may suggest significant insulin deficiency. As insulin deficiency increases, patterns may progress through a number of stages that suggest declining insulin secretory capacity.

Note that not all patients will demonstrate all stages and stages are often not as clear as described.

These stages might include:
  • Elevated fasting glucose (greater than those seen in earlier stages that may be responsive to antidiabetes medication therapy. Generally, fasting values _200 mg/dl suggest absolute insulin deficiency which could be transient due to glucose toxicity.)
  • Rising glucose levels during the day (a general up-trend in glucose levels suggests that insulin secretion cannot keep up with needs)
  • Marked postprandial hyperglycemia (suggests marked reductions in insulin secretory capabilities in response to meals, probably beyond loss of first-phase insulin release that is present early in the natural history of diabetes.)
  • Marked hyperglycemia throughout the day (probably heralds generalized insulin deficiency)
  • General lability in response to daily activities (the patterns typically seen with type 1 diabetes)

Using these markers to gauge the presence and predominance of the various pathophysiologic components of type 2 diabetes, the clinician can then select pharmacologic treatments to target these specific defects. A discussion of selecting medications based on this information will follow later in this chapter.

In a general sense, all non-insulin therapies used to treat type 2 diabetes require the presence of insulin or functional beta-cells in order to be effective. The source of that insulin may not necessarily be the pancreas (it could be exogenous), but significant differences exist among medications that reduce insulin resistance. Some exert their effect directly. All will have some effect on reducing insulin resistance by virtue of a reduction in glucose toxicity that accompanies reduced hyperglycemia.

Next Excerpt: How the Various Antidiabetes Medications Work

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