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    <recommendedItem id="20090101_19_3166"
                     title="EASD: New Drug Classes Entering Type 2 Pipeline"
                     score="-0.005"
                     href="http://www.medpagetoday.com/MeetingCoverage/EASD/tb/16316?impressionId=1265729823069"
                     
      &lt;p&gt;VIENNA  --  Farnesoid X receptor agonists, 11-&amp;#946;-HSD1 inhibitors, and glucokinase activators are some of the new approaches to treating type 2 diabetes described in research presented here, but some senior researchers expressed doubts about the clinical need for them.&lt;/p&gt;
&lt;p&gt;Early-stage clinical data were reported at the European Association for the Study of Diabetes annual meeting.&lt;/p&gt;
&lt;p&gt;For example, Reid Huber, PhD, of Incyte Corp., said that glycated hemoglobin levels dropped about 0.5% after 12 weeks of treatment with an 11-&amp;#946;-HSD1 inhibitor called INCB13739 in a placebo-controlled, 159-patient phase II trial.&lt;/p&gt;
&lt;p&gt;Insulin resistance, as measured by the HOMA-IR scale, was reduced by a full point at the highest dosage of the drug, whereas it increased 0.25 points in the placebo group.&lt;/p&gt;
&lt;p&gt;Blood lipid levels  --  particularly low-density lipoprotein cholesterol  --  also declined by a clinically significant degree, Huber said.&lt;/p&gt;
&lt;p&gt;The 11-&amp;#946;-HSD1 target is an enzyme that catalyzes the conversion of cortisone to cortisol in vivo. Huber explained that that attracted drug-development interest in type 2 diabetes because of evidence that it is upregulated in obese patients and those with insulin resistance.&lt;/p&gt;
&lt;p&gt;Also, Cushing syndrome, which results from defective cortisol metabolism, shares features with type 2 diabetes, including insulin insensitivity, obesity, and hypertension.&lt;/p&gt;
&lt;p&gt;Clinical results for a drug with a very different target were also presented here.&lt;/p&gt;
&lt;p&gt;David Shapiro, MD, of Intercept Pharmaceuticals, said an agent that activates farnesoid X receptors showed promising signs of activity in patients with type 2 diabetes and nonacloholic fatty liver disease (NAFLD) in a brief, placebo-controlled pilot study.&lt;/p&gt;
&lt;p&gt;Farnesoid X intracellular receptors regulate lipid metabolism and also appear to control insulin sensitivity and body fat mass, Shapiro said.&lt;/p&gt;
&lt;p&gt;The company&apos;s drug, INT-747, is an analogue of the receptors&apos; natural ligand, chenodeoxycholic acid.&lt;/p&gt;
&lt;p&gt;Two doses were tested against placebo in 64 patients in a six-week, double-blind trial. Duration was too short to use HbA1c as an endpoint, so Shapiro and colleagues instead measured glucose disposal rates under euglycemic clamp conditions.&lt;/p&gt;
&lt;p&gt;Both with low- and high-dose insulin, glucose disposal rates increased from baseline to the end of treatment, whereas they declined in patients receiving placebo.&lt;/p&gt;
&lt;p&gt;Patients taking a 25-mg daily dose of INT-747 had a mean 1% loss of body weight, while a 50-mg dose was associated with a 2% loss, Shapiro reported. No change was seen in the placebo group (not significant).&lt;/p&gt;
&lt;p&gt;Adverse events that appeared more common with the drug included constipation and headache.&lt;/p&gt;
&lt;p&gt;Both Huber and Shapiro said their drugs were slated for more clinical testing.&lt;/p&gt;
&lt;p&gt;Data on two glucokinase activators were presented as well.&lt;/p&gt;
&lt;p&gt;Glucokinase is a glucose-sensing enzyme that is critical in the homeostatic system by which insulin secretion is matched to blood glucose levels. Activating this pathway is expected to lead to increased insulin secretion whenever blood glucose is elevated, such as after meals.&lt;/p&gt;
&lt;p&gt;Agents developed by Merck and Array BioPharma were described in separate poster presentations.&lt;/p&gt;
&lt;p&gt;Elizabeth Migoya, PharmD, of Merck, reported that a glucokinase activator called MK-0599 reduced plasma glucose levels relative to placebo in healthy, nondiabetic volunteers.&lt;/p&gt;
&lt;p&gt;Similar phase I results were also reported for the Array product, ARRY-403, except that its study involved patients with type 2 diabetes.&lt;/p&gt;
&lt;p&gt;James Trevillyan, PhD, said that daytime glucose concentrations, both postprandial and at other times, were reduced following administration of the drug after acute dosing. Fasting plasma glucose levels were reduced as well, compared with placebo.&lt;/p&gt;
&lt;p&gt;Insulin and C-peptide levels were increased &quot;consistent with the mechanism of action,&quot; Trevillyan reported.&lt;/p&gt;
&lt;p&gt;But Edwin Gale, MD, of the University of Bristol in U.K. and editor of the EASD&apos;s official journal, &lt;em&gt;Diabetologia&lt;/em&gt;, suggested the difficulties in managing patients with type 2 diabetes were unlikely to be solved with new drugs.&lt;/p&gt;
&lt;p&gt;&quot;I&apos;m not interested in new drug classes,&quot; he said. &quot;We need to get on top of the ones we have.&quot;&lt;/p&gt;
&lt;p&gt;John Buse, MD, of the University of North Carolina, said that safety had become the paramount issue in diabetes therapy.&lt;/p&gt;
&lt;p&gt;More important than improving the potential for reducing blood glucose, he suggested, is ensuring that therapy doesn&apos;t increase patients&apos; overall risk for adverse effects, including hypoglycemia as well as cardiovascular events.&lt;/p&gt;
&lt;p&gt;Buse said the FDA had been appropriately cautious in reviewing the most recent new class of diabetes drugs, the dipeptidyl peptidase-4 inhibitors.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The studies were funded by the drugs&apos; manufacturers: Incyte, Intercept Pharmaceuticals, Array BioPharma, and Merck.&lt;/p&gt;&lt;p&gt;The presenters were employees of the respective manufacturers.&lt;/p&gt;&lt;p&gt;Gale reported no potential conflicts of interest.&lt;/p&gt;&lt;p&gt;Buse had relationships with Insulet and Novo Nordisk.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20100101_19_28"
                     title="Leptin-Linked Gene Reverses Diabetes in Mice (CME/CE)"
                     score="-0.005"
                     href="http://www.medpagetoday.com/Endocrinology/Diabetes/tb/17781?impressionId=1265729823069"
                     
      &lt;p&gt;The hunger hormone leptin can reverse diabetes  --  at least in mice  --  without causing weight loss, researchers have discovered.&lt;/p&gt;
&lt;p&gt;The effect is mediated by a gene expressed in the liver that is controlled by leptin, according to Jeffrey Friedman, MD, PhD, of Rockefeller University in New York City, and colleagues.&lt;/p&gt;
&lt;p&gt;The finding raises the possibility that the gene, called &lt;em&gt;IGFBP2, &lt;/em&gt; may have therapeutic effects in humans with the disease, Friedman and colleagues wrote in the January issue of &lt;em&gt;Cell Metabolism&lt;/em&gt;.&lt;/p&gt;
&lt;p&gt;The researchers were investigating central nervous system pathways by which leptin regulates insulin sensitivity and glucose output from the liver.&lt;/p&gt;
&lt;p&gt;Because leptin causes weight loss, which by itself can improve diabetes, they first set out to define the lowest dose that would correct insulin resistance and diabetes without affecting food intake or reducing body weight.&lt;/p&gt;
&lt;p&gt;In mice lacking the gene for leptin  --  so-called ob/ob mice  --  they found that an infusion of 12.5 nanograms per hour significantly lowered blood glucose without affecting weight, while 25 nanograms per hour normalized plasma glucose and insulin, again without affecting body weight.&lt;/p&gt;
&lt;p&gt;&quot;It was surprising to me how potent leptin was in treating diabetes,&quot; Friedman said in a statement. &quot;It had a highly significant impact at plasma levels that were undetectable.&quot;&lt;/p&gt;
&lt;p&gt;The researchers then conducted microarray experiments to see which genes in the liver were more active after the leptin doses than before. The gene that emerged was &lt;em&gt;IGFBP2&lt;/em&gt;  --  one of a family of genes that bind the insulin growth factor.&lt;/p&gt;
&lt;p&gt;Compared with controls given saline, they found, &lt;em&gt;IGFBP2&lt;/em&gt; was upregulated more than five-fold at 25 nanograms per hour of leptin and 1.6-fold at 12.5 nanograms per hour. Both differences were significant at &lt;em&gt;P&lt;/em&gt;&amp;lt;0.01.&lt;/p&gt;
&lt;p&gt;Friedman and colleagues cloned the gene and inserted it into an adenovirus vector. Through a tail vein, ob/ob mice were given either the combination or a control virus without the gene.&lt;/p&gt;
&lt;p&gt;Five days after the injection, mice that had received the gene showed normal plasma glucose and insulin, the researchers found.&lt;/p&gt;
&lt;p&gt;Control animals had average blood glucose levels of 320 milligrams per deciliter, while the &lt;em&gt;IGFBP2&lt;/em&gt;-treated animals had average levels of 94 milligrams per deciliter, a difference that was significant at &lt;em&gt;P&lt;/em&gt;&amp;lt;0.01.&lt;/p&gt;
&lt;p&gt;Plasma insulin levels also became normal in the&lt;em&gt; IGFBP2&lt;/em&gt;-treated mice at 85 nanograms per milliliter, compared with 5, on average, in controls. Again, the difference was significant at &lt;em&gt;P&lt;/em&gt;&amp;lt;0.01.&lt;/p&gt;
&lt;p&gt;The treated animals also had normal glucose clearance after a glucose challenge, the researchers said in the journal.&lt;/p&gt;
&lt;p&gt;The effect of &lt;em&gt;IGFBP2&lt;/em&gt; overexpression was similar in both wild-type mice and diabetic animals resistant to leptin, the researchers said.&lt;/p&gt;
&lt;p&gt;For example, they said, in mice with diet-induced diabetes, injection of the &lt;em&gt;IFGBP2&lt;/em&gt;-adenovirus combination led to a 32% drop in blood glucose, significant at &lt;em&gt;P&lt;/em&gt;&amp;lt;0.01, compared with control animals.&lt;/p&gt;
&lt;p&gt;The researchers also found lower levels of the &lt;em&gt;IGFBP2&lt;/em&gt; protein in three leptin-deficient people, compared with normal controls. In two of the three, &lt;em&gt;IGFBP2&lt;/em&gt; levels increased after leptin treatment.&lt;/p&gt;
&lt;p&gt;While that study is small  --  the three patients represent only about 10% of all such leptin-deficient cases in the world  --  the finding suggests that the &lt;em&gt;IFGBP2&lt;/em&gt; protein could have therapeutic value, Friedman and colleagues concluded.&lt;/p&gt;
&lt;p&gt;They are currently trying to produce a recombinant version of the protein, but they cautioned that more research is needed to see if the protein has clinical benefits in humans.&lt;/p&gt;
&lt;div style=&quot;float:left;border-style:solid;border-width:1px;border-color:#8dabbc;font-family:arial;font-size:12px;background-color:#DBE9F2;padding:5px;&quot;&gt;&lt;p&gt;The researchers did not report any external support for the study or any conflicts.&lt;/p&gt;&lt;/div&gt;&lt;div style=&quot;clear:both;&quot;&gt;&lt;/div&gt;
    </recommendedItem>
    <recommendedItem id="20090101_1_25"
                     title="Periodontal Disease Gets Head Start in Diabetic Children"
                     score="-0.006"
                     href="