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When many of us were in training, the pharmacological therapy of type 2 diabetes was relatively simple: We could choose sulfonylureas, which were introduced in the 1950s, and insulin, which of course has a more illustrious history.1 Both classes have had their times of intense controversy, but many of these concerns were resolved with the publication of the U.K. Prospective Diabetes Study (UKPDS) in 1998.2
Nine years after learning the results of UKPDS, we have new agents with different mechanisms of action for the treatment of type 2 diabetes. I'm not sure, however, that there's any less controversy. Physicians and patients seem to be passionate about one agent or another, with good reason. Individual and anecdotal results often convince individual physicians and patients differently about effectiveness.
Unfortunately, this is probably the worst way to assess drug efficacy and safety, since one requires randomized and blinded clinical trials to make appropriate conclusions. We recently witnessed an oral agent for type 2 diabetes (troglitazone [Rezulin, Warner-Lambert) gain Food and Drug Administration (FDA) approval only to learn later of a dangerous side effect resulting in potential death. Ideally, these types of problems are identified prior to release to the general public (muraglitazar [Pargluva, Bristol-Myers Squibb/Merck] and torcetrapib [Pfizer]), but there are times it takes many years to really learn the danger of a drug or drug combination after release to the public, as was seen in the Women's Health Initiative with estrogen and progesterone.
TZD ADDS TO THE THERAPY PUZZLE
The publication of the results of A Diabetes Outcome Progression Trial (ADOPT)3 presented at the International Diabetes Federation (IDF) 19th World Diabetes Congress last month in South Africa adds yet another piece of the puzzle to the role of thiazolidinediones (TZDs) in type 2 diabetes, although questioning what role rosiglitazone, compared with metformin or glyburide, should have in the initiation of therapy. This comes within 16 months of the announcement of the PROactive trial and only 3 months after the DREAM results were reported (DOC News, November 2006, page 1). Both of these trials, using a TZD, were controversial for different reasons, most notably for using different populations of study participants with different end points. PROactive, for example, had a primary end point of seven different macrovascular outcomes, including leg amputations and lower extremity revascularization. Using these primary end points, PROactive was a negative study.
In ADOPT, subjects were randomized if their type 2 diabetes was essentially drug naïve for hyperglycemia with <2 years' duration of diabetes. It is interesting that the primary end point was reaching a target plasma glucose of 180 mg/dl, since most of our "treat-to-target" type studies use glycated hemoglobin (A1C) as the clinical marker to evaluate the end points and primary treatment efficacy. The authors should be congratulated in reanalyzing the data to a more clinically relevant fasting plasma glucose level of 140 mg/dl, which is probably more consistent with most recommendations today. Still, A1C is (and has been) our gold standard, and therapeutic decisions ideally should have been matched to that end point.
Perhaps a more important criticism of ADOPT is that in all groups there was an approximate 40% study withdrawal rate. Some could argue that this reduces the generality of the study results, particularly when considering almost 90% of the study population was Caucasian, for a disease that certainly is well represented in all other ethnicities, particularly in the U.S.
The primary end point in ADOPT, monotherapy failure, showed that rosiglitazone was clearly beneficial over glyburide, with less impressive benefit when compared with metformin. Comparing rosiglitazone with glyburide and metformin, the risk of monotherapy failure was 63% and 37% respectively (P < 0.001 for both comparisons). Even less impressive is the analysis of A1C levels for the three groups. Mean A1C was 0.13% less in the rosiglitazone group than in those receiving metformin and 0.42% less than in those taking glyburide. Although one could debate the clinical significance of this analysis for glyburide, there seems to be no controversy that the rosiglitazone-metformin difference is not clinically important.
Drug "durability" is a term we use to describe how well a therapy does over time. In this regard, at the 4-year evaluation, 40% receiving rosiglitazone had an A1C <7%, compared with 36% for metformin and 26% for glyburide. The other (and to me more) relevant way to think about these same data is that A1C was maintained below 7% for 60 months with rosiglitazone, 45 months with metformin, and 33 months with glyburide. So rosiglitazone clearly was more effective and durable, particularly against metformin, at least in a well-performed statistical analysis. But what about other side effects of therapy... and cost?
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Although the ADOPT report holds several major surprises, the most interesting to me is the differences in major cardiovascular events. For serious cardiovascular events, glyburide had the least at 1.8%, compared with 3.2% for metformin and 3.4% for rosiglitazone (P < 0.05). Sulfonylureas, and in particular glyburide, were implicated with cardiotoxicity due to a process called "ischemic preconditioning." But, like UKPDS, this large clinical trial included no signal for this problem, perhaps further weakening if not putting to rest the concern over sulfonylureas. It needs to be emphasized, however, that ADOPT was not powered to look at cardiovascular end points.
A similar surprise was the congestive heart failure (CHF) results. There were no differences in CHF between rosiglitazone and metformin, but again, glyburide has less diagnosed heart failure. In all, these were very small numbers, so this point should not be overemphasized.
Another important end point, one that is of no surprise, is the added weight gain seen with rosiglitazone, particularly when compared with metformin: 6.9 kg! That is >15 pounds of added weight compared with metformin. The difference in weight was 2.5 kg (5.5 lb) of added weight with rosiglitazone compared with glyburide.
ADDRESSING WEIGHT-GAIN CONCERNS
So where does that leave clinicians as we try to understand this important study? Every study has limitations, and ADOPT is no different, but does this study change the way we should be initiating drug therapy in type 2 diabetes? I think not.
First, let's look at the drug costs, with the understanding that prices fluctuate. For the agents used in ADOPT, a month's supply of drug cost $211 for rosiglitazone, $56 for metformin, and $18 for glyburide.4 Do 15 additional months prior to drug failure (comparing rosiglitazone with metformin) and a change in A1C of 0.13% favoring rosiglitazone justify this added cost, particularly since no added cardiovascular benefits have been proven for this population?
Besides, the 6.9 kg weight gain with rosiglitazone (compared with metformin) is the fundamental reason I can't recommend this therapy as first-line for this obese population. We need to look at type 2 diabetes differently now than we did a decade ago, before so many drug therapy options existed. With drugs that are generally weight-neutral (metformin, dipeptidyl peptidase-IV inhibitors, alpha-glucosidase inhibitors) and even weight-losing (exenatide), these agents must at least be considered in anyone's algorithm. The results reported at the IDF meeting of Sanofi-Aventis's SERENADE study using rimonabant—a powerful antiobesity agent for patients with type 2 diabetes—and A1C rather than weight as a primary end point likely will give us yet another option in the near future.
At the very least, even though I don't agree with all aspects of the
American Diabetes Association/European Association for the Study of Diabetes
algorithm for the treatment of type 2 diabetes published last
summer,5 ADOPT, when
reviewed in its entirety, further supports the aggressive use of metformin as
first-line therapy early in the course of type 2 diabetes. 
Footnotes
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References
2. 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]
3. Kahn SE, Haffer SM, Heise MA, et al.: Glycemic durability of
rosiglitazone, metformin, or glyburide monotherapy. N Engl J
Med 355:2427–2443, 2006.
4. Cost comparison search using an online pharmaceutical company. Published online at http://www.drugstore.com. Accessed December 6, 2006.
5. Nathan DM, Buse JB, Davidson MB, et al.: Management of hyperglycemia in type 2 diabetes: A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 49:1711–1721, 2006.[Medline]
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