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Home / Resources / Clinical Gems / Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #47: Pharmacotherapy of Type 2 Diabetes, Part 6

Joslin’s Diabetes Deskbook, Updated 2nd Ed., Excerpt #47: Pharmacotherapy of Type 2 Diabetes, Part 6

Richard S. Beaser, MD


This week’s excerpt cover the following topics:
  • Why a patient should start with multiple medications
  • How much treatment is needed
  • When to use combination therapy

Assembling a Treatment Program

A General Approach to Treatment

When nonpharmacologic interventions are deemed insufficient to achieve treatment targets, treatment with antidiabetes medications is indicated. Initial medication selection can be made using the parameters to assess the predominance of the various pathophysiologic components of type 2 diabetes discussed earlier in this chapter. Selection of the initial medication, based on this assessment of pathophysiology, can then be made taking into consideration the characteristics of the various medications as outlined above and in the Medication Summaries.

With the array of new medications available, more precise treatments can be selected to target the predominant pathophysiologic defects and specific glucose pattern abnormalities. This evolution to a more precise targeting of pathophysiology with a carefully selected medication or medications has been occurring over the last decade. Keep in mind, also, that when hyperglycemia becomes manifest in someone with type 2 diabetes, there must be two significant defects present.

  • By definition, people with type 2 diabetes have some degree of insulin resistance
  • In order for glucose abnormalities to be present, there must be insulin secretory insufficiency. Even if there is hyperinsulinemia (excess insulin relative to normal), it is still insufficient to overcome that insulin resistance and normalize glycemia, and thus these patients have relative insulin secretory insufficiency.

The first key abnormality in insulin secretion usually seen is a blunting or loss of the first-phase insulin release. Early on, there may be a compensatory augmentation of the second-phase insulin release leading to hyperinsulinemia. Eventually, there may be a more complete loss of insulin secretory capacity.

Further, if there is significant hyperglycemia on presentation, one can anticipate that this hyperglycemia may also be causing glucose toxicity. Glucose toxicity, caused by significant hyperglycemia, paradoxically worsens insulin resistance and blunts insulin secretory capacity.

Therefore, one can and should assume that upon diagnosis of type 2 diabetes, there are multiple defects present and, thus, treatment with multiple pharmacologic agents with differing modes of action is not only reasonable, but in many instances may be recommended.

If the diagnosis of type 2 diabetes is truly made early in the natural history of the condition, the lifestyle changes of medical nutritional therapy and physical activity may be sufficient to achieve appropriate control. Improvements in nutrition and activity habits may reduce insulin resistance enough to restore insulin sensitivity to a level that corresponds to the insulin secretory capacity. If not, the combination of lifestyle changes and a single pharmacologic agent may be sufficient to achieve targeted levels of control.

However, in many cases, at the time of diagnosis, the condition has progressed significantly so that the impact of multiple defects can be considerable. Therefore, increasingly, clinicians have chosen to initiate combination therapy earlier in the natural history of this condition. Many are moving away from the traditional therapeutic approach of starting one medication and working it exclusively for a considerable period of time.

Now, with the recognition that multiple metabolic defects cause the glucose abnormalities, combination therapy is utilized sooner. While the selection of an initial medication may be made based on the usual clinical estimates of predominant metabolic defect, only a short time is allowed to pass during which clinical efficacy is measured and drug tolerance is assured. Shortly after initiation of this first medication, rather than increasing its dose, treatment with a second medication is initiated. Then, both are concurrently titrated to achieve optimal control, pharmacologically treating multiple defects concurrently. Third medications may also be added to the mix.

The advantages of this approach are: 
  • multiple defects are addressed, providing more effective treatment by more completely addressing the spectrum of underlying pathophysiologic components
  • use of lower doses of each medication reduces the likelihood of adverse effects from any one of the medications

Taking this approach one step further, combination medications have now become available to simplify such therapy. These medications are discussed in detail in the Medication Summaries at the end of this chapter. Undoubtedly, as well, additional combinations may become available following publication of this book. Various ratios of the component medications found in these combination tablets allow concurrent initiation of dual therapy using one tablet to optimize convenience and compliance. For tablets such as the glyburide/metformin combination, there are differences in the pharmacodynamics of the glyburide, leading to earlier rises in drug levels.

The benefits of combination tablets should not be underappreciated. In this era of polypharmacy and of pharmaceutical plans doling out prescription refills in one-month aliquots, fewer pills to take not only reduces the chance for erroneous dosing and missed doses, but also may reduce the onerous timed trips to the pharmacy or the mailed-in request forms to refill a prescription at the precise time in a refill cycle. 

How Much Treatment Is Needed?

To determine the answer to this question, there are a number of questions to be answered and steps to be taken:

  • What is the goal? In general, the goal for glucose control for people with type 2 diabetes is an A1C level that is at least <7% (with normal 4%–6%), and ideally as low as can be safely and practically achieved. Aside from individualized situations where there might be contraindications to attempting to reach this goal, achieving an A1C level of <7% should be the target. The concerns about being too aggressive with control raised by recent studies such as the ACCORD trial seem to be related to people with long-standing type 2 diabetes and likely increased cardiovascular disease risk, and while general target recommendations of <7% may still hold, the avoidance of hypoglycemia is also recommended and adjustment of A1C targets should be considered to optimize safety.
  • What is the starting point? For a given patient, what is their starting A1C level? How far above a level of 7% is it? Anyone with an A1C >7% despite optimized medical nutrition therapy and exercise will probably need pharmacologic intervention, and the higher the starting A1C, the more likely monotherapy will not be sufficient.
  • What is the impact of nonpharmacologic therapy? Have medical nutrition therapy and activity optimization been attempted? How long ago and with what impact? Would a "refresher" course be useful?
  • How acutely is intervention needed? Is the patient markedly hyperglycemic with symptoms? Is there a complicating factor such as an acute or chronic infection or other physiologic stress? The presence of an infection might be leading to increased glucose levels, and thus infection treatment may be indicated. However, even with infection treatment, the resulting hyperglycemia may need more aggressive treatment.

Let’s assume that nonpharmacologic interventions are optimized, that the hyperglycemia is not so excessive that it warrants acute aggressive intervention (usually insulin), and there are no complicating conditions such as infections. The key piece of information in determining the needed pharmacotherapy is the "distance" between the patient’s current A1C and the target A1C. This information will give a sense as to how much therapy is needed — whether one medication is sufficient or multiple medications are required. Then, the next steps are to:

  • Assess the predominance of the various pathophysiologic abnormalities as discussed earlier.
  • Assess each of the appropriate medications to determine how much strength in A1C lowering they are likely to bring to that patient. Keep in mind when doing so that the data found in studies is based on differing A1C starting points. In clinical practice, most agents have more A1C-lowering effect when used in patients with higher initial A1C levels.
  • Review the patient’s overall medical condition in light of contraindications to the use of any medications.

Examples: We have provided a few examples below to give a sense as to how one might approach selecting therapy, and the various considerations that go into the decision-making process.

In an otherwise uncomplicated patient with optimized non-pharmacologic treatment parameters, if the A1C is 9%, the achievement of adequate control would require pharmacologic interventions that could lower the A1C by more than 2%. The assessment would therefore focus on what medications will address the predominant pathophysiologic components of his or her diabetes and can provide enough strength to lower the A1C to less than 7%.

In the example given above, with an A1C of 9%, there are likely to be multiple factors: insulin resistance, decreased insulin secretory reserve (both first phase leading to postprandial hyperglycemia and, to some degree, second phase, and also there is likely to be some glucose toxicity). Thus, the likelihood of one medication succeeding in lowering the A1C to 7% is relatively low, and this patient will likely need multiple medications. One might start with one medication but initiate the second fairly early in the treatment progression, or even initiate the combination together. Conversely, if this patient had shorter duration diabetes and was markedly overweight, suggesting more predominant insulin resistance, one could consider early initiation of a combination of metformin and a thiazolidinedione, provided the weight issues associated with the thiazolidinediones could be managed. If concern about insulin secretory reserve was present, but peripheral insulin resistance was also a concern, with more predominant hyperglycemia later in the day, a combination of a thiazolidinedione and sulfonylurea could be considered. In many of these situations, combination tablets are available, which would improve compliance and ease of administration.

If the patient’s starting A1C is 8%, it is possible that the targeted A1C level could be achieved using only one medication, so single-drug therapy initially would be quite appropriate. Nevertheless, with the trend toward earlier combination therapy and the likely presence of dual or multiple defects, even this patient may benefit from combination therapy, probably at less than maximum doses. It can certainly be argued that using combination therapy earlier in the natural history of type 2 diabetes can establish targeted levels of glucose control in the early years when much of the potential damage of hyperglycemia goes on silently. In addition, many of the medications used often show better efficacy early on, before the pathophysiology of this condition progresses, allowing smaller doses of multiple medications to be effectively used.

Further, we are now seeing the clinical impact of incretin replacement therapy. Exenatide, while it must be administered by injection, is easily dosed and the injections are relatively easy, and with its potential for weight loss, it is becoming a reasonable option as an add-on therapy to sulfonylureas and/or metformin and/or TZDs. The DPP-IV inhibitors are also a good option, and may produce a more physiologic insulin and glucagon effect than a sulfonylurea, either alone or in a combination program. Their A1C lowering capacity may not be quite as much as for sulfonylureas, but they work in a glucose dependent manner which could have advantages in that they precisely target the insulin action when it is needed, and suppress glucagon. This may allow more physiologic restoration of insulin secretory patterns and could be effective, particularly in a combination treatment program. Colesevelam may also be considered to help move the A1C down a bit further toward target, particularly when concurrent LDL-lowering effects are also desired.

Similarly, if the starting A1C were 9.7%, dual or even triple therapy might be needed, and the use of combination therapy quite early in the dosing progression would be strongly suggested.

Keep in mind that insulin may be needed as an initial treatment in a patient with:

  • a markedly elevated A1C level
  • significant symptoms of hyperglycemia, ketoacidosis, or hyperosmolar coma
  • the need for rapid establishment of glucose control such as someone with an infection, imminent surgery, or other extenuating medical conditions
  • contraindications to use of enough of the antidiabetes medications such that it is unlikely

Specific Medication Combinations

Although combination antidiabetes medication therapy has become much more popular in recent years, it is not a new idea. The first oral combination to achieve widespread use was treatment with the sulfonylurea chlorpropamide plus the biguanide phenformin (originally described by this author’s father, Samuel Beaser, MD in 1958). This combination was in widespread use through the 1960s until phenformin was removed from the market for concerns that its use increased the risk of developing lactic acidosis. However, in spite of this safety concern, this early combination was quite successful, improving control and prolonging the duration of time people could achieve adequate control before needing insulin therapy.

Typically, people would titrate one medication to optimal dosage. If treatment goals were reached, the patient was continued on that dose until goals no longer were achievable. This was referred to as "secondary failure" — failure to achieve goals with a medication after initially succeeding.

With the introduction of the safer biguanide, metformin, early studies of its combination therapy with sulfonylureas also demonstrated efficacy. It was through these studies that the term "secondary failure" fell into disuse and was replaced with "treatment insufficiency" as people realized that the first therapy did not fail per se. Rather, it was no longer able to achieve targeted control. However, it did not necessarily fail to work at all. In the case of metformin added to glyburide, for example, the loss of the ability of glyburide to achieve targeted control, where it might have done so in the past, is not surprising. The progression of type 2 diabetes involves loss of β-cell mass resulting in reduced pancreatic insulin secretory capacity, and it makes sense that a medication that stimulates insulin production from β-cells would lose efficacy. Thus, with treatment insufficiency, the approach is not to substitute one new medication for the old, but rather to combine their effects.

From this initial classic combination, the list has grown to include many other combinations that have been tried and proven useful. Some are sanctioned by the FDA as having official usage indications; others are reported in the medical literature. Still a few others have less scientific basis for their use, but have been tried by practicing physicians and, because of therapeutic success and absence of adverse events, continue to be used. This list of combinations is in flux, as new indications or studies are being reported. Table 8-2 includes combinations with proven utility. This list will undoubtedly grow in the future.


Next issue: Achieving A Proper Balance

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