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The explosion of obesity, both in the United States and in the rest of the developed world, has resulted in a dramatic increase in type 2 diabetes that is well appreciated by primary care clinicians. Therefore it should not be surprising that the options for drug therapy used to treat type 2 diabetes (and obesity, for that matter) are increasing at tremendous speed.
Not long ago, some of the greatest clinical debates involved which sulfonylurea should be preferred for the therapy of type 2 diabetes: glyburide or glipizide. In the past decade, we have added not only new drugs, but also several new classes of agents to treat hyperglycemia. Of course this is good news, but it does lead to confusion: Which pharmacological option should be used for each of the clinical situations we all see in our daily practice?
Some of this confusion has been addressed in an American Diabetes Association (ADA) consensus statement about this important topic.1 The authors of this document note that the guidelines and algorithm presented are based on clinical trials and the authors' clinical experience and judgment. They go on to note the lack of high-quality evidence that directly compares different diabetes treatment regimens. For example, at the recent ADA Scientific Sessions, held June 9–13 in Washington, D.C., it was not uncommon to have trials comparing an active agent with a placebo.2 There are also many examples of the comparator of the study agent being used at less than maximal dose or, in the case of insulin, of comparing two basal analogs at once-daily for one and twice-daily for the other. The playing field is not level! This obviously makes any set of recommendations subject to disagreement, and the authors acknowledge that the consensus statement will engender debate.
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The authors mention several key factors to be taken into account when considering pharmacological therapy for type 2 diabetes. First, with high levels of glycemia (e.g., glycated hemoglobin [A1C] >8.5%), drug classes with greater and more rapid glucose-lowering effectiveness or potentially earlier initiation of combination therapy are recommended. Conversely, with more modest hyperglycemia (e.g., A1C <7.5%), medications with lesser potential to lower glycemia and/or with a slower onset of action may be considered.1 Finally, because of the progressive nature of type 2 diabetes, addition of medications is the rule, not the exception, if treatment goals are to be met over time.
The potentially controversial aspect of the statement is the treatment algorithm shown in the figure. After diagnosis, lifestyle modification is still the initial and more important therapy. Unfortunately, many patients will not reach glycemic targets with lifestyle change alone, and thus pharmacological therapy needs to be added, usually within 2–3 months. First-line therapy, when no contraindications exist, should be metformin, according to the algorithm. I agree with this. Metformin is inexpensive, has an excellent glycemic response compared with other oral agents, is weight-neutral, and has demonstrated a beneficial effect on cardiovascular outcomes in the U.K. Prospective Diabetes Study.3
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Much more controversial is the choice of a second agent. The authors point out that the choices include sulfonylureas, which are inexpensive and generally as effective as metformin; thiazolidinediones, which, when used with metformin, will not result in hypoglycemia; and insulin, which is the most effective. It is reasonable to choose a therapy based on the patient's A1C level at the time. Perhaps one could use a sulfonylurea or insulin if the A1C were still >8.5%, but I would strongly consider insulin for an A1C >9%.
However, even though I find so many advantages for insulin therapy in terms of effectiveness, flexibility in the case of illness or dietary indiscretions, and ease of use after so many years of experience, I have found myself increasingly using exenatide (Byetta, Lilly/Amylin) over the past year. The authors of the consensus statement point out that exenatide, along with pramlintide (Symlin, Amylin), alpha-glucosidase inhibitors (acarbose [Precose, Bayer] and miglitol [Glyset, Bayer]), and glinides (repaglinide [Prandin, Novo Nordisk] and nateglinide [Starlix, Novartis]), is not included in the algorithm because of "lower overall glucose lowering effectiveness, limited clinical data, and/or relative expense."1
Although it is true all of these drugs are expensive, I feel more emphasis needs to be placed on the potential for weight loss in an obese population. Should an agent be considered a higher priority if A1C drops 1% and weight is reduced by 2.3 kg (5 lb)? What if weight is reduced by 4.5 kg (10 lb)? In a 30-week study, exenatide in combination with metformin therapy has been shown to result in a mean weight loss of 2.8 kg (6.2 lb).4 When do we decide that factors other than glycemic control should be used in the decision-making process of choosing an agent? Although this is anecdotal evidence, I have several patients who have lost >9.1 kg (20 lb) and one who lost >18.1 kg (40 lb) on exenetide. Of course, this type of weight loss is exceptional; yet it has added to the enthusiasm of many of us as we struggle with obesity in the majority of our patients.
The addition of new agents for the treatment of type 2 diabetes provides us
with greater opportunities to reach glycemic targets, but we also have, for
the first time, better tools for weight loss. Even more agents will become
available over the next few years, and as more data are generated, it seems
likely that algorithms for the treatment of type 2 diabetes will need to be
modified accordingly. 
Footnotes
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References
2. Rosenstock J, Brazg R, Andryuk PJ, et al.: Addition of sitagliptin to pioglitazone improved glycemic control with neutral weight effect over 24 weeks in inadequately controlled type 2 diabetes (Abstract). Diabetes 55 (Suppl. 1): A132–A133, 2006.
3. U.K. Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: 837–853, 1998.[Medline]
4. DeFronzo RA, Ratner RE, Han J, et al.: Effects of exenatide
(exendin-4) on glycemic control and weight over 30 weeks in metformin-treated
patients with type 2 diabetes. Diabetes Care 28: 1092–1100, 2005.
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