New Treatments on the Way for Diabetes-Part 1

The significant increase in theprevalence of diabetes, particularlyin younger populations,makes the need for new, more effectivetherapies crucial. Several new medicationscurrently undergoing clinicalstudies may have significant impactfor the treatment of diabetes. This articleis the first of a 2-part series thatlooks at some of the potential therapiesfor patients with diabetes.

One new class of drugs that showsearly promising results is the incretinmimetics. Incretins are endogenoushormones that are secreted from thegastrointestinal tract during foodintake. They stimulate insulin secretionin response to glucose absorption. Twoincretin hormones, glucose-dependentinsulinotropic peptide and glucagonlikepeptide-1 (GLP-1), have been identified.In addition to increasing insulinlevels, GLP-1 also is thought to suppressglucagon production.

Exenatide is the first incretinmimetic to undergo phase 3 clinicaltrials. The compound was originallyisolated from the salivary venom of aSouth American lizard. Three studies,both 30 weeks in length, show a significantreduction in hemoglobin A_1C (HbA_1C ) in patients unable to obtainadequate blood glucose control withmetformin therapy alone or with theaddition of sulfonylureas. One studyincluded 336 patients who had notachieved control on a minimum of1500 mg/day of metformin for at least3 months. Patients received either 5or 10 &#956;g of exenatide or placeboinjected subcutaneously twice daily.The average baseline A_1C level was8.2%. Of the patients who received 10&#956;g twice daily, 46% who completedthe study achieved an A_1C of<7%.Additionally, the 10-&#956;g-treatmentgroup experienced an average weightloss of 2.8 kg (6.2 lb).

Another study included 773 patientswho had not obtained adequatecontrol on combination metformin/sulfonylurea therapy. Thirty-four percentof the patients who completedthe study in the 10-&#956;g-treatmentgroup achieved an A_1C reading of<7%.The average reduction in HbA_1C overplacebo was 1%. The most commonadverse effect reported in all studieswas nausea.

Combining results from the studies,the incidence of nausea was 45% to49% in the 10-&#956;g-treatment group, comparedwith 21% to 23% in the placebogroup. The overall dropout rate due tonausea was 3% in the 10-&#956;g group, 1%in the 5-&#956;g group, and 0% in the placebogroup. In the exenatide-plus-metformin/sulfonylurea study, mild-to-moderatehypoglycemia occurred in27.8% and 19.2% of patients in the 10-and 5-&#956;g treatment groups, respectively,compared with 12.6% of patientsreceiving placebo.

One potential clinical advantage toconsider with exenatide is weight loss.With several current therapies available—including sulfonylureas, meglitinides,insulin, and thiazolidinediones—patients with diabetes oftenexperience the frustration of weight gain. With exenatide, the combinationof dose-dependent reductions in A_1C and dose-dependent weight loss maybe a motivating factor for patients towant to gain better control of their diabetes.

Another advantage seen with exenatidewas improvement in pancreaticbeta cell function. Beta cell functionimprovement was assessed using HomeostaticModel Assessment andreductions in the proinsulin/insulinratio. The major disadvantage is thatthe drug is administered by injectiononly. Development is under way toproduce a longer-acting form of thedrug that could be injected once weeklyor once monthly. Other incretinmimetics, such as liraglutide, also arein development and show early promisingresults.

Diabetes affects approximately 18million people in the United States.Disease-related complications—suchas kidney failure, retinopathy, andneuropathy—occur more frequently indiabetics who do not achieve adequatereductions in their A_1C level. Incretinmimetics are likely to be an importantnew therapeutic category to improvediabetic outcomes.

Other new therapies that can helppatients achieve these goals will be awelcome addition to the currentlyavailable modalities. The second partof this series will focus on otheradvances in diabetic therapy, includinginhaled insulin.

Dr. Brian is a clinical specialist with Cornerstone Health Care, High Point, NC.