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One of the biggest challenges to optimal diabetes care is drug therapy that effectively lowers and maintains blood glucose without triggering hypoglycemia, causing weight gain, or contributing to complications.
Metformin perhaps has come closest to filling that bill, and now it appears the newest class of diabetes medications—the incretin drugs—is another viable contender, according to recent research. Endocrinologist Anastassios Pittas, MD, MSc, and colleagues at Tufts-New England Medical Center in Boston analyzed results from 29 incretin therapy trials and found the oral incretin-based drug sitagliptin (Januvia, Merck) and the injectable incretin mimetic exenatide (Byetta, Amylin/Eli Lilly) safely and effectively lower patients' glycated hemoglobin (A1C) levels by an average of 0.7 percentage points (for example, from 8.0% to 7.3%) and 1 percentage point, respectively.1
According to Pittas, metformin lowers A1C levels by an average of 1.5 percentage points; sulfonylureas lower A1C levels by an average of 1.5–2 percentage points; and thiazolidinediones (TZDs) reduce A1C levels by an average of 1–1.5 percentage points.
Incretin drugs mainly target the pancreas, where they increase insulin output and decrease glucagon secretion—actions that lower glucose.2 Exenatide may also slow gastric emptying and suppress appetite. All incretin-based therapies fight hyperglycemia most effectively when ingested after meals. Also, in animal models, incretin drugs appear to increase the amount of working beta-cells in the pancreas. This is key because, over time, beta-cells in the pancreas of people with type 2 diabetes gradually stop working or become less responsive, so medicines that initially control blood glucose eventually become ineffective.
Another benefit of incretins is their favorable effect on weight relative to sulfonylureas and TZDs—an important consideration given the high number of type 2 diabetes patients who are obese. Sulfonylureas and TZDs increase weight .91–4.99 kg (2–11 lb) on average over 3–6 months.3 Metformin is weight neutral, although it can be associated with a small amount of weight loss.3 The once-a-day pill sitagliptin has no impact on weight gain or loss, exenatide may even promote weight loss, and neither drug increases the risk of hypoglycemia, according to recent research on incretins by Pittas, published in JAMA.1
"Exenatide is consistently associated with weight loss of about 2–5%, although certain people lose much more than that," says Pittas.
NEWER ISN'T ALWAYS BETTER
While incretins appear a promising addition to the diabetes arsenal, many experts agree that traditional medicines such as metformin and sulfonylureas still are often the best and safest place to start—mainly because the long-term effects of the newer drugs are unknown.3
A recent study published in the Annals of Internal Medicine lends credence to this position. Diabetes researcher Shari Bolen, MD, MPH, and co-authors compared metformin and sulfonylureas with the newer lines of TZDs, alpha-glucosidase inhibitors, and meglitinides and found the traditional first-line therapies boast similar or better effects on blood glucose levels and cardiovascular outcomes.3 Their analysis excluded exenatide because it is an injectable and sitagliptin because it had not been approved by the FDA at the time.
"Our study gives clinicians vindication for using the older medications," says Bolen, an instructor in the Division of General Internal Medicine at Johns Hopkins School of Medicine in Baltimore. "For those who have started using TZDs a little more, hopefully we've shown them there's really no need to do that as a first-line treatment."
Physicians turn to newer medicines when patients cannot tolerate the older drugs or have certain contraindications that would make their use risky. For example, some people experience diarrhea, nausea, and occasional vomiting with the older drugs. And the sulfonylureas sometimes lower blood sugar too much in certain patients. In such cases, those at risk for hypoglycemia or its complications may benefit from incretin therapy or possibly from the alpha-glucosidase inhibitors or meglitinides, which also promote targeted post-meal—rather than sustained—insulin production.1
"I think there is definitely a role for the newer medicines; I just don't think we need to jump to them right away," adds Bolen. She does believe that incretin drugs hold promise, but she would like to see more data on their long-term effects before they become widely used, to preclude the possibility that they might possibly cause unanticipated adverse reactions, such as the negative cardiovascular effects now associated with TZDs (DOC News, June 2007, page 20).
TARGETING THERAPIES
One concern with sitagliptin is that it may alter the body's immune response to certain infections. The JAMA study showed a very slight increase in common infections, such as urinary tract infections and nasal pharyngitis, among those who took sitagliptin.1 Comparatively, nausea is the most commonly reported adverse side effect of exenatide.1
Moreover, the incretin drugs typically do not reduce A1C levels any further than older type 2 drugs—and they cost more as well. Costs to patients largely depend on their insurance coverage, and they can be prohibitive for people on a fixed income. According to J. Mark Beard, MD, assistant professor in the Department of Family Medicine at University of Washington in Seattle, a prescription for metformin 1,000 mg twice a day runs about $35 a month. By comparison, Byetta (Amylin, Eli Lilly) runs about $200 a month, and Januvia (Merck) costs approximately $165 per month.
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"They are expensive and there's a lack of long-term data," says Pittas. "Other medications—mostly metformin, sulfonylureas, and insulin—have proven their value in terms of decreasing complications and perhaps mortality."
But incretins can be a good add-on option for a patient whose A1C level is slightly above a target range of 7–8%, says Beard. The combination of sitagliptin with metformin or a sulfonylurea appears well tolerated. However, combining exenatide with metformin may cause unpleasant gastrointestinal side effects.1
"There's nothing dangerous about it," says Pittas. "It's just a matter of whether the patient can tolerate it."
As new drugs such as the incretins emerge, physicians can better customize therapeutic regimens to patients' unique drug reactions and diabetes cases—and that's the real benefit of the newer options, in Pittas's view.
"Not everybody with type 2 diabetes has the same types of
defects," says Pittas. "If we can somehow easily determine whether
a patient has insulin resistance or a defect in pancreatic beta-cells, then we
can use the appropriate medication. For example, a patient with beta-cell
insufficiency would be a good candidate for a medication such as incretins
that targets that defect." 
References
2. Levetan C: Oral antidiabetic agents in type 2 diabetes. Curr Med Res Opin 23:945–952, 2007.[Medline]
3. Bolen S, Feldman L, Vassy J, et al.: Systematic review: Comparative effectiveness and safety of oral medications for type 2 diabetes mellitus. Ann Intern Med [Epub ahead of print July 16] 2007. Available online at www.annals.org/cgi/content/full/0000605-200709180-00178v1. Accessed August 14, 2007.
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