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Microvascular complications of diabetes are a major concern for both health care provider and patient. A study of 24,151 patients with type 2 diabetes in 33 countries found that 39% had evidence of microalbuminuria and 10% showed indications of macroalbuminuria.1 Up to 21% of those with type 2 diabetes have retinopathy when they are first diagnosed with diabetes, and most will eventually develop some degree of retinopathy.2 Although numerous studies have shown that good control of blood glucose levels helps reduce the incidence of these complications, there is still a need for adjunctive medications and treatments to stop or slow the processes once they begin. Ruboxistaurin (Arxxant, Lilly) is one such alternative currently under review by the Food and Drug Administration (FDA). Ruboxistaurin selectively inhibits the function of protein kinase C (PKC)-ß, which may have a role in the treatment of diabetic microvascular disease. "In organs susceptible to developing microvascular complications—retina of the eye, kidney, aorta, and heart—hyperglycemia induces increased levels of diacylglycerol, which is an activator of PKC," says Donna Myers, MD, assistant professor of medicine in the nephrology division of Johns Hopkins School of Medicine in Baltimore. "In addition, hyperglycemia selectively activates the gene that codes for the beta isoforms. Thus, in theory, selective blockage of PKC-ß may run `interference' between high glucose levels and cellular damage."
In the eyes, PKC-ß has been associated with changes in muscle contraction, basement membrane protein synthesis, endothelial cell permeability, and angiogenesis. An early study by the Protein Kinase C-ß Inhibitor Diabetic Retinopathy Study group suggests that ruboxistaurin may reduce the risk of vision loss but does not prevent progression altogether.3
"The results showed that those taking ruboxistaurin once a day for 3 years had a 48% reduction in sustained vision loss, more people had vision improve, and there were fewer laser procedures needed in those who got the drug compared to those receiving placebo," says Lloyd Paul Aiello, MD, director of the Beetham Eye Institute and head of eye research at the Joslin Diabetes Center in Boston. "What all this adds up to is a reduction in the risk for further vision loss, although the actual progression of the retinopathy was not changed."
Similarly encouraging results have been seen in early human studies in nephropathy and neuropathy. For example, one group found that ruboxistaurin reduced albuminuria by 24% from baseline in 1 year compared with 9% in the placebo group.4 Another study found significant improvement in the Neuropathy Impairment Score—a score reflecting muscle weakness and reflex and sensory abnormalities based on a neurological exam—and Clinical Global Impression—a scale to assess treatment response—when compared with placebo in patients with diabetic neuropathy.5
STRONG SCIENTIFIC EVIDENCE
"The science behind this treatment is very strong, and the clinical studies to date have supported results from the experimental models," says Katherine Tuttle, MD, medical and scientific director at Providence Medical Research Center in Spokane, Wash. "In my opinion we don't have other things in the pipeline that are as strong as ruboxistaurin in treating diabetic kidney disease."
Another asset of this medication is a benign side-effect profile. "This drug has no effect on blood glucose and does not appear to interact with any of the diabetes medications, although the evidence examining drug interactions is not robust," says Ann Scates, PharmD, clinical pharmacist and drug information specialist at Duke University Hospital in Durham, N.C. "The side effects found most often in the clinical trials were gastrointestinal distress, diarrhea, vomiting, and dyspepsia. So far, there do not appear to be any glaring safety issues, although the number of patients studied is not very high."
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Although it may be a promising medication in the treatment of diabetes-related microvascular complications, none of the experts interviewed says ruboxistaurin would markedly change the need for good blood glucose control. This is borne out by the results of studies showing that ruboxistaurin can have an impact on the progression of the complications but does not stop them altogether.
"Diabetic microvascular complications are thought to have both glycemic and nonglycemic mechanisms," Myers notes. "While activation of PKC is one putative mechanism by which hyperglycemia damages the kidney, other mechanisms may still play a role. Therefore, in my mind there is no substitute for the central role of tight glycemic control to prevent end-organ damage."
WHICH PATIENTS MAY BENEFIT?
The subset of patients who will most likely be candidates for this drug is yet to be fully elucidated. Sources for this article agree that patients showing signs of microvascular complications, such as albuminuria or retinal changes, would be good candidates. Ruboxistaurin's usefulness as a preventive medication for patients who are still asymptomatic, however, is unproven at this point.
"The best patients for this treatment remain to be determined," Tuttle says. "We are currently looking at those with kidney disease, but we also want to intervene before kidney disease becomes advanced. The open question is, do we need to treat the 50% of diabetes patients who do not get kidney disease?
"My sense is that it will be a long-term treatment," continues Tuttle. "Despite our best efforts in glycemic and risk-factor control, we still have an escalating incidence of kidney failure. Understanding the science behind this, I think we will use [ruboxistaurin] more like a statin or hypertension medication—as an indefinite therapy."
Aiello agrees, noting that in the studies completed so far, ruboxistaurin did not change the progression of vision loss. He also points out that although changing the course of microvascular disease is "certainly an exciting potential" of ruboxistaurin, the long-term studies to answer questions on who should be treated and whether the drug should be used preventively have not started.
"Teamwork" is a term often used to explain how ruboxistaurin may fit into primary care practice. The side-effect profile, once-daily dosing, and lack of interactions with other diabetic drugs suggest that medication management will be straightforward. The teamwork will come, at least initially, from the need to establish the presence and staging of the microvascular complications.
"The primary care physician will have to work closely with other colleagues to monitor target-organ response to the medication," Scates says. "The primary care doctor will also still have to continue regular diabetic teaching because good control of blood glucose is an imperative to success."
Specialists also will be critical team members.
"An ophthalmologist will clearly be required to assess whether the level of retinopathy is appropriate for treatment and to monitor eye status," Aiello says. "The role of the [primary care physician] will be to make sure the patient is getting [his or her] medicine, is using it appropriately, has required follow-ups with specialists, and is managing the other clinical aspects of diabetes."
DRUG'S FUTURE IN QUESTION
FDA officials threw the future of ruboxistaurin into confusion in August 2006 when they issued an "approvable letter" for the medication and then asked Eli Lilly and Company for additional clinical efficacy evidence (DOC News, October 2006, page 5). According to reports from the company, the FDA requested another 3-year, late-stage clinical trial. When patient recruitment and statistical analysis is included, Lilly representatives say, this could delay approval for as long as 5 years.6
"The importance of objectivity and waiting until a study is finished has been emphasized to me many times during my career," says Karen Gehrs, MD, associate professor of ophthalmology at University of Iowa School of Medicine in Iowa City. "There have been two other very promising drugs that everyone thought would work because of the results of animal models or smaller pilot trials. The larger studies did not show enough benefit to merit approval."
One example she cites involved the aldose reductase inhibitor tolrestat. The controversial drug was the subject of a press exposé several years ago, alleging that the FDA acted inappropriately in keeping the drug off the market. In longer pivotal trials, tolrestat ultimately failed to delay progression of diabetic retinopathy, and along with two other drugs in its class, it eventually was pulled from the market worldwide.
The future of ruboxistaurin may be unknown, but proponents argue that the
drug's potential benefit for patients with microvascular complications
outweighs the risks. FDA has held off on approval of the drug, citing the need
for a larger study. In a November 13, 2006, press release, Lilly stated that
it had "decided to appeal the FDA's decision and recently began
discussions with officials at the FDA." 
References
2. American Diabetes Association. All about diabetes: Diabetes and retinopathy (eye complications). Available online at www.diabetes.org/diabetes-statistics/eyecomplications.jsp. Accessed December 19, 2006.
3. The PKC-DRS Study Group: The effect of ruboxistaurin on visual loss
in patients with moderately severe to very severe nonproliferative diabetic
retinopathy: Initial results of the Protein Kinase C-ß Inhibitor Diabetic
Retinopathy Study (PKC-DRS) multicenter randomized clinical trial.
Diabetes 54:2188–2197, 2005.
4. Tuttle KT, Bakris GL, Toto RD, et al.: Effect of ruboxistaurin on albuminuria and GFR in persons with type 2 diabetes and nephropathy (Abstract). Diabetes 54 (Suppl. 1): K223, 2005.
5. Litchy W, Dyck P, Tesfaye S, et al., for the MBBQ Study Group: Diabetic peripheral neuropathy assessed by neurological examination and composite scores is improved with L333531 treatment (Abstract). Diabetes 51 (Suppl. 2): A197, 2002.
6. Eli Lilly and Company: Lilly announces FDA requirement of additional clinical trial data before ruboxistaurin could be approved for treatment of diabetic retinopathy (Press release). September 29, 2006. Available online at www.prnewswire.com/cgi-bin/micro_stories.pl?ACCT=916306&TICK=LLY&STORY=/www/story/09-29-2006/0004442237&EDATE=Sep+
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