SYMPOSIUM ON DIABETES

PREVIEW
Early initiation of therapy to decelerate the decline in beta cell function and achieve low hemoglobin A

1c levels is advantageous in patients with type 2 diabetes. In this first of two articles on treatment of type 2 diabetes, the authors share their experience in optimizing therapy and advocate fixed-dose oral combinations because of lower cost, improved efficacy, better compliance, and fewer side effects. The second article (on page 15) looks at the use of injection therapy when oral therapy is not enough.

When type 2 diabetes is diagnosed, the time for lifestyle change (diet and exercise) as monotherapy has passed. However, lifestyle change must and should be the foundation to which all other diabetes therapies are added.

Once diabetes has been diagnosed, it can be assumed that beta cell function is severely compromised and that unless beta cell function can be preserved or improved, the production of endogenous insulin will take a predictable downhill course. The progressive deterioration in beta cell function will result not only in the need for additional therapies, but also in worsening of glycemic control and more frequent development of diabetic complications.1

Use of thiazolidinedione combined with metformin

The United Kingdom Prospective Diabetes Study (UKPDS) showed that at the time of diagnosis of adult-onset diabetes, 50% of endogenous beta cell function remained. After 6 years, only 25% remained, and the decline in beta cell function occurred with an equal velocity whether monotherapy consisted of lifestyle change, metformin, insulin, or sulfonylureas.2

At this time, the only available oral therapy that can decelerate the decline in beta cell function and that may preserve or even increase the beta cell mass is a thiazolidinedione (TZD).3 Therefore, when type 2 diabetes is diagnosed, a TZD should be the first drug to be used.

In most situations, a TZD should be combined with metformin (figure 1). When used as monotherapy, especially in larger doses, TZDs are associated with weight gain. However, metformin combined with a TZD results in minimal weight gain, weight stabilization, or even weight loss. Furthermore, the ability to use smaller doses of both TZD and met- formin results in less edema (a potential side effect of TZD) and less diarrhea (a possible side effect of metformin).4

Another reason for early initiation of a metformin-TZD combination is the ability to achieve very low hemoglobin (Hb) A1c levels. Achieving an HbA1c of 7% effectively prevents the development or the progression of diabetic retinopathy, neuropathy, and nephropathy.5 However, at an HbA1c level of 7%, the cardiovascular benefits of better glycemic control have just started.

The UKPDS showed that the lower the HbA1c was to a level of 5.5%, the lower the risk of a myocardial infarction.6 The Norfolk cohort of the European Prospective Investigation of Cancer and Nutrition (Norfolk-EPIC),7 which studied a population in the English county of Norfolk, showed that for every 1% the HbA1c was above 5%, there was an increase of 27% in cardiac events. Furthermore, in the diabetic range (above a level of 7%), there was a 40% increase in cardiac events for each 1% increase in HbA1c.

Therefore, the goal of attaining an HbA1c level below 7% (according to the American Diabetes Association) or below 6.5% (according to the American College of Endocrinology and International Diabetes Federation) does not result in the maximal decrease in cardiac risk. However, the Canadian Diabetes Association's goal of an HbA1c of 6.5%, or as low an HbA1c as can be attained without causing hypoglycemia, is clearly the most logical.8

In the diabetic patient, cardiac protection is not maximized at the current HbA1c goals because there is no lower threshold for cardiac risk. Because of this, the target HbA1c level should be as low as can be safely attained.

Unfortunately, when therapy for type 2 diabetes includes insulin or a secretagogue (ie, sulfonylureas and metaglitinides), lower HbA1c levels cannot be attained because of the increased frequency and severity of hypoglycemia.9 Fortunately, neither metformin nor the TZDs are associated with frequent or severe hypoglycemia, and especially with a combination of the two drugs, lower HbA1c levels can be attained without the risk of severe hypoglycemia. Furthermore, because metformin and TZDs have different sites of action, the HbA1c level that can be attained with smaller doses of these drugs used in combination is lower than could be attained when larger doses of either drug are used as monotherapy.4

What if metformin is contraindicated?

Metformin use is contraindicated in patients who are older than 80 years unless normal creatinine clearance is documented; in patients with renal or hepatic problems; and in patients who are taking pharmacologic therapy for congestive heart failure. In such patients, the lowest possible HbA1c should be sought using a combination of a TZD and a sulfonylurea (see figure 1).

However, glyburide, the most commonly used se-cretagogue, should not be used because of increased frequency and severity of hypoglycemia.9 In the UKPDS, the frequency of hypoglycemia was greatest in the group that was using glyburide, in spite of achieving with glyburide HbA1c levels that were similar to those obtained with insulin, metformin, and chlorpropamide.10

A randomized prospective study comparing a glyburide plus metformin with metformin plus the TZD rosiglitazone showed significantly better A1c lowering with glyburide plus metformin.9 However, this improved glycemic control was accompanied by a much greater frequency and severity of hypoglycemia. With metformin plus rosiglitazone, 1.3% of subjects reported hypoglycemia, whereas with glyburide plus metformin, 38.3% had hypoglycemic episodes.

The increased frequency of hypoglycemia that occurs with glyburide is due to suppressed release of both glucagon and growth hormone, which play key roles in avoiding and correcting hypoglycemia.11 The suppression of these hormones, in turn, may be due to closure of the K+ ATPase channels in the hypothalamus, so that hypoglycemia is not recognized and the release of these counterregulatory hormones needed to correct the hypoglycemia does not occur.12 Closure of the K+ ATPase channels in the pancreatic beta cells results in release of insulin. Unfortunately, glyburide also closes the K+ ATPase channels in the myocardium, which results in worsening of myocardial ischemia due to the loss of “ischemic preconditioning.� Ischemic preconditioning is the progressive decrease in myocardial ischemia that occurs with each ischemic episode as a result of opening of the K+ ATPase channels. Because the K+ ATPase channels cannot open in the presence of glyburide, outcomes following a cardiac event can be worsened.13

Alternatively, use of another sulfonylurea, glimepiride, through K+ ATPase channel closure, results in a physiologic release of insulin when eating occurs and decreased or no insulin release when glimepiride is administered in the fasting state or during or before exercise. In addition, glimepiride does not close the K+ ATPase channels in the myo-cardium.14,15 The phenylalanine derivative secretagogue nateglinide also has no effect on K+ ATPase channels in the myocardium and is associated with little or no hypoglycemia, but because of its exclusive postprandial activity, it cannot lower HbA1c to the levels that can be attained with glimepiride.12

Finally, glimepiride has the potential to further improve insulin sensitivity, as has been shown with hyperinsulinemic euglycemic clamp studies in the insulin-resistant offspring of subjects with type 2 diabetes.16 Adiponectin levels, which are proportional to insulin sensitivity, have also been shown to increase in elderly type 2 diabetic patients with glimepiride use.17

Therefore, when metformin is contraindicated, the best choice is a fixed-dose combination of a sulfonylurea, preferably glimepiride, and a TZD.

When TZDs are not appropriate

When TZDs are not appropriate or are contraindicated, such as with hypersensitivity or the presence of New York Heart Association class III or IV heart failure (the inability to walk 200 yards or two blocks without dyspnea), the best starting regimen is a combination of metformin and a sulfonylurea (see figure 1). Because of the disadvantages of metformin plus glyburide already discussed, metformin plus glipizide in a fixed-dose oral combination is preferred.

Both TZD and metformin are contraindicated in the presence of congestive heart failure. If the patient has class III or IV heart failure, the only remaining choices at this time are a secretagogue with or without insulin therapy or insulin therapy alone (see figure 1).

Why not use oral agents separately rather than in fixed-dose combinations?

In general, the disadvantages of fixed-dose oral combination therapies are (1) a lack of flexibility and (2) if a side effect occurs, the potential inability to determine which drug is causing the problem. With regard to flexibility, most fixed-dose oral diabetic combinations have an adequate selection of dosage combinations.

Regarding side effects, a time-consuming and potentially dangerous rechallenge with the separate agents is required to determine which agent caused the adverse event. However, identifying the cause of an adverse event is seldom a problem with fixed-dose oral antidiabetic therapies if the side-effect profile of the individual components is known. For example, hypoglycemia would be due to a secretagogue or insulin or both, gastrointestinal problems (especially diarrhea) would be attributable to metformin, and weight gain or edema would be caused by TZD.

The advantages of fixed-dose oral antidiabetic combinations, compared with their components taken separately, are lower cost and better compliance. In most situations, the cost of combination therapy is less than the cost of the individual components, and in some cases the price is similar to that of one of the drugs in the combination so that the second drug is “free.�4 In addition, one copay rather than two copays can be economically advantageous. In some situations, the number of nongeneric drugs that are covered by a third-party payer is limited, and if an oral combination is classified as one rather than two nongeneric drugs, the patient will be allowed an additional, often much needed, nongeneric drug.

Studies of the use of fixed-dose combination therapy for hypertension, respiratory diseases, and postmenopausal hormone replacement have shown significant improvement in compliance, often as much as 30%, compared with use of the combination components separately.18 Improved compliance has also been shown with fixed-dose oral antidiabetic therapies, which is therefore another advantage.19

When a fixed-dose oral antidiabetic regimen is failing

When a TZD-metformin combination is no longer able to achieve the targeted levels of HbA1c, the addition of a sulfonylurea is required. This should result in a further decrease in the HbA1c of 1% to 2%. A combination of fixed-dose metformin and a sulfonyl-urea can be used in the morning and fixed-dose metformin and a TZD in the evening. If a greater reduction is needed, then the addition of insulin likely will be required.

When is the addition of insulin needed?

When the targeted HbA1c level is not being reached with a TZD-sulfonylurea combination or a metformin-sulfonylurea combination, and the third agent cannot be added, then advancement to insulin injection therapy is required. When the triple oral therapy regimen of a TZD, metformin, and a secretagogue is failing, injection therapy is also required. In all of these situations, injection therapy is an addition to, rather than a replacement for, the oral antidiabetic agents.

Conclusion

When type 2 diabetes is diagnosed, oral diabetic therapy should be initiated and diet and exercise therapy should be continued. Use of combination therapy at this stage and later on is advantageous because of improved efficacy, fewer side effects, lower cost, and better compliance with fixed-dose combination oral hypoglycemic agents. When maximal oral therapy fails, an injectable incretin-mimetic or a once-daily insulin injection should be added to the existing oral regimen.

Dr Bell has served on the advisory boards for GlaxoSmithKline and on the speakers' bureau for GlaxoSmithKline, Bristol-Myers Squibb, AstraZeneca, and Novo Nordisk. Dr Bell is an adjunct clinical professor of medicine, University of Alabama at Birmingham School of Medicine. Dr Wyne is on the advisory board for GlaxoSmithKline, Novo Nordisk, and Sanofi-Aventis; is on the speakers' bureau for Abbott, Boehringer, Bristol-Myers Squibb, Novartis, Novo Nordisk, and Sanofi-Aventis; is a consultant for GlaxoSmithKline, Novo Nordisk, and Sanofi-Aventis; and has received research support from Novo Nordisk. Dr Wyne is associate professor of medicine, University of Texas Southwestern Medical School, Dallas.

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