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Home , Insulin lispro, Liraglutide, Regular insulin

20 AUGUST 2011 • CLINICAL ENDOCRINOLOGY NEWS Improves Liraglutide Risks Control in Revisited in Letter

BY KERRI WACHTER treatment period, for a total of 24 weeks. From Drug Maker During treatment, patients were instructed to in- FROM THE ANNUAL MEETING OF THE ENDOCRINE SOCIETY ject 0.6 mg of liraglutide subcutaneously every day. At the onset of treatment, patients were advised to BY ELIZABETH MECHCATIE BOSTON – Use of the type 2 medication liraglutide reduce their basal by a quarter and bolus by helped control glycemic oscillations in type 1 diabetes, a third. “This was to avoid ,” explained FROM THE FOOD AND DRUG ADMINISTRATION significantly lowered hemoglobin A1c levels, and was Dr. Varanasi, the lead author, who is with the divi- he manufacturer of liraglutide has issued a letter associated with weight loss, a small study has shown. sion of endocrinology and at the State Tto health care professionals reminding them about The net effect is not only an improvement in University of New York at Buffalo. The eight patients the increased risk of associated with treat- mean fasting and weekly glucose concentrations, but treated for 24 weeks were advised to increase the dai- ment in patients as well as informing them about the also “you have a remarkable effect on the oscillations ly dose of liraglutide to 1.2 mg after the first week development of thyroid tumors in rodents exposed to of glucose,” seen among type 1 diabetic patients, Dr. and again to 1.8 mg after 2 weeks. clinically relevant doses of liraglutide, the Food and Paresh Dandona said at the meeting. At baseline, the mean patient age was 40 years and Drug Administration announced. the mean BMI was 24 kg/m2. Patients had type 1 di- The information is not new, but the letter is being Major Finding: Eight patients who continued abetes for an average of 24 years. The mean basal in- sent to clinicians because “a recent assessment of liraglutide treatment for 24 weeks lost a sig- sulin was 24.5 U, the mean bolus was 22.5 U/day, and healthcare providers showed that some primary care nificant amount of weight, down from a mean the mean HbA1c level was 6.6%. All but one of the providers are not fully aware of the serious risks as- of 68 kg to 63.5 kg. Mean hemoglobin A1c patients used insulin pumps, and the remaining pa- sociated with the use of Victoza,” according to the

VITALS also dropped significantly from 6.5% to tient was on four or more insulin injections per day. FDA statement. Victoza is the trade name for li- 6.1%. Mean basal insulin dropped by 48%, All patients used continuous glucose monitoring. raglutide (rDNA origin) injection, which was ap- and mean bolus dropped by 42% as well. During the first week of treatment, despite the re- proved by the FDA in 2010 as an adjunct to diet and Data Source: A prospective study of 14 pa- duction in insulin, there was a significant reduction in exercise to improve glycemic control in adults with tients with type 1 diabetes; eight patients mean fasting glucose and mean weekly blood glucose. . were treated for a total of 24 weeks. Most interestingly, said Dr. Varanasi, the mean The letter describes the “potential risk” of thyroid Disclosures: Two of the authors have signifi- weekly standard deviations in insulin concentrations C-cell tumors, including medullary carcinoma, which cant financial relationships with several phar- were significantly reduced with treatment. may be associated with liraglutide. In rats and mice, maceutical companies, but not with Novo “Even in a reasonably well-controlled [type 1] di- liraglutide causes thyroid C-cell tumors at clinically rel- Nordisk, the makers of liraglutide. The re- abetic with an HbA1c of around 7% or less, there is evant exposures, but the relevance to humans cannot maining authors, including Dr. Varanasi, re- [usually] a massive vacillation in insulin concentra- be ruled out by clinical or nonclinical studies, accord- ported that they have no relevant financial tions,” observed Dr. Dandona, the principal investi- ing to the letter. In addition, pancreatitis was more disclosures. gator, who is chief of the division of endocrinology common in patients treated with liraglutide, compared at the State University of New York at Buffalo. with comparators in clinical trials, so the drug may in- Liraglutide (Vitoza), made by , is a The eight patients on longer-term therapy lost a crease the risk of acute pancreatitis. glucagonlike -1 (GLP-1) receptor agonist that significant amount of weight – down from a mean Because of these risks, liraglutide is not recom- is currently approved for use as an adjunct to diet and of 68 kg to 63.5 kg. The mean HbA1c level dropped mended as first-line therapy, and patients should be ob- exercise to improve glycemic control in adults with from 6.5% to 6.1%, which also was significant. Mean served closely for signs and symptoms of pancreatitis type 2 diabetes mellitus. As a GLP-1 analogue, li- basal insulin dropped by 48%, and mean bolus after starting treatment and after dose increases. The raglutide stimulates the release of insulin in response dropped by 42%. The decrease in mean blood glu- company is monitoring cases of medullary thyroid to elevated levels of blood sugar. It also inhibits the re- cose was significantly reduced within the 24-48 cancer registry cases to determine whether there was lease of following meals, slowing the rate of hours. “This tells us that the response is pretty quick. an increase in cases associated with the availability of food absorption from the gut into the bloodstream. And the mean standard deviation values were re- liraglutide in the United States. At the meeting, Dr. Ajay Varanasi reported the re- duced within 48 hours,” Dr. Varanasi noted. sults of a prospective study in which 14 patients (9 Regarding the mechanism of action, Dr. Varanasi More information including a link to the letter is male) with type 1 diabetes all used liraglutide. hypothesized that liraglutide may decrease the con- available in the FDA statement at www.fda.gov/Safety/ Treatment for six of the patients involved a 1- centration of glucagon secreted after meals. Anoth- MedWatch/SafetyInformation/SafetyAlertsforHuman week pretreatment period to optimize glycemic er theory is that the decrease in postprandial glucose MedicalProducts/ucm258826.htm. Serious adverse events control, 1 week of liraglutide therapy, and 1 week excursion may be the result of slower gastric emp- associated with liraglutide should be reported to post treatment. Eight additional patients also had a tying, which is known to occur with liraglutide. The MedWatch at 800-332-1088 or www.fda.gov/medwatch, 1-week pretreatment period, followed by a 22-week weight loss seen in patients on liraglutide may have or to Novo Nordisk at 877-484-2869. period of liraglutide therapy, and a 1-week post- also contributed to improved glycemic control. ■ Recombinant Hyaluronidase Speeds Insulin Absorption

BY MIRIAM E. TUCKER (Halozyme Therapeutics’ 6.9%. They were randomized to either the the last 2 weeks of each treatment peri- investigational Insulin-PH20) could pro- Insulin-PH20 or for 2 con- od showed similar mean glucose values FROM THE ANNUAL SCIENTIFIC SESSIONS OF THE AMERICAN duce glycemic control comparable to secutive 12-week periods, with twice-dai- (153 vs. 143 mg/dL), with similar DIABETES ASSOCIATION that of the currently available rapid-act- ly glargine as basal insulin in both groups. amounts of time spent in the target ing analogues. The ultimate aim is to Forty-one of the 46 completed the trial. range of 70-130 mg/dL (39% vs. 44%). SAN DIEGO – Recombinant human combine it with those to make an even The prespecified primary end point There were no significant differences hyaluronidase combined with human faster-acting analogue, Dr. Satish K. Garg was a noninferiority margin of post- in overall hypoglycemia, defined as blood regular insulin yielded comparable said at the meeting. prandial glucose values not exceeding glucose value of 70 mg/dL or below. glycemic responses to lispro insulin in a “If we really want to achieve eug- 21.6 mg/dL for three meals over 3 days. Dr. Garg has received grants and hon- study of 46 patients with well-controlled lycemia in the postprandial phase, espe- The difference in glycemic excursions oraria from Halozyme Therapeutics, type 1 diabetes. cially 1 and 2 hours after meals, we need between the two insulin formulations Sanofi-Aventis, Novo-Nordisk, Dexcom, Recombinant human hyaluronidase an ultra–fast-acting insulin, and we don’t was 2.4 mg/dL, clearly meeting the end and Eli Lilly. ■ (rHuPH20) is approved by the Food and have that,” said Dr. Garg, professor of point, Dr. Garg said. Drug Administration to increase the dis- medicine and pediatrics at the Universi- HbA1c was maintained for both groups To view an interview persion and absorption of other injected ty of Colorado, Denver. in the trial, 7.0% for Insulin-PH20 and with Dr. Garg, drugs. This randomized, open-label, The 46 patients had a mean age of 42 6.9% for lispro, meeting the commonly simply scan this QR crossover study investigated whether a years, a mean of 26 applied noninferiority margin of 0.4%. code using your 2 combination of rHuPH20 with human kg/m , and a mean hemoglobin A1c of Continuous glucose monitoring during smartphone.