Good Tidings for Obesity Treatment?

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Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue with a 97% structural homology to human GLP-1, a gut hormone that plays a key role in the regulation of glucose homeostasis, gut motility and possibly hunger and appetite. Liraglutide is available in Europe under the brand name Victoza for the treatment of type 2 diabetes, and previous studies have shown that treatment with liraglutide in diabetic patients is also associated with modest, but clinically significant weight loss. (Readers of these pages may recall an earlier posting on similar effects reported for another GLP-1 analogue). A study by Arne Astrup (University of Copenhagen) and colleagues, published online today in The Lancet, now shows that liraglutide also induces significant weight loss in “non-diabetic” obese patients. In this double-blind, placebo-controlled 20-week trial, with open-label orlistat comparator, conducted in 19 sites in Europe, 564 individuals (BMI 30–40) were randomly assigned to one of four liraglutide doses (1·2 mg, 1·8 mg, 2·4 mg, or 3·0 mg), to placebo, or to orlistat (120 mg TID). Liraglutide and placebo were administered by once-daily subcutaneous injections. In addition, all individuals had a 500 kcal per day energy-deficit diet and increased their physical activity throughout the trial, including the 2-week run-in. Weight change analysed by intention to treat was the primary endpoint. Participants on liraglutide showed a dose-related weight loss ranging from 4·8 to 7.2 kg compared with a 2·8 kg weight loss with placebo and a 4·1 kg weight loss with orlistat. More individuals lost more than 5% weight with liraglutide 3·0 mg (76%) than with placebo (30%) or orlistat (44%). Liraglutide also reduced blood pressure at all doses and reduced the prevalence of prediabetes by around 90%. The main adverse effects of liraglutide were nausea and vomiting, occurring in upto one-third of patients at the highest dose, but adverse events were mainly transient and rarely led to discontinuation of treatment. The authors conclude that liraglutide treatment over 20 weeks is well tolerated, induces clinically meaningful weight loss, and  improves certain obesity related risk factors in non-diabetic obese patients. While the degree of weight loss is not substantially different from that seen with current anti-obesity drugs, the results of this study are certainly exciting because they possibly open a whole new avenue of anti-obesity treatments targeting gut hormones (incretins). Although liraglutide has to be delivered by once-daily injections (its circulating half-life is 13 h), I am confident that there will… Read More »

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GLP-1 Analog Taspoglutide for Weight Loss?

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GLP-1 is a gut hormone released from intestinal L-cells in response to food intake. Natural GLP-1 has a half-life of about 2 mins and is degraded primarily through the action of dipeptidyl peptidase-4 (DPP-IV). Beneficial physiological effects of GLP-1 include: – increased glucose-dependent insulin secretion. – decreased glucagon secretion. – increased beta cells mass. – delayed gastric emptying. – decreased food intake by increasing satiety. Currently available treatments that target GLP-1 for the treatment of diabetes, have demonstrated less weight gain (DPP-IV inhibitors (gliptins), e.g. sitagliptin, vildagliptin) or modest weight loss (GLP-1 analogue, e.g. exanatide, liraglutide). As a result, drugs targeting GLP-1 may be better treatments for obesity-related type 2 diabetes than other antidiabetic agents, whch often tend to promote weight gain. A study, by Michael Nauck and colleagues from Bad Lauterberg im Harz, Germany, suggests that taspoglutide (R1583), a long-acting (once-weekly) human glucagon-like peptide-1 (GLP-1) analogue, currently under investigation by Roche for the treatment of type 2 diabetes mellitus, may likewise promote modest weight loss (Diabetes Care). In this study, 306 patients with type 2 diabetes inadequately controlled with metformin (1500 mg) alone were randomly assigned to 8 weeks of double-blind subcutaneous treatment with placebo or taspoglutide, either 5, 10, or 20 mg once weekly or 10 or 20 mg once every 2 weeks, and followed for 4 additional weeks. All patients received their previously established dose of metformin throughout the study. Subjects on all doses of taspoglutide had significantly greater reductions in A1C (by ~1%) but also lost ~2 kg body weight (or ~ half a lb/week). The most common adverse event was dose-dependent, transient, mild-to-moderate nausea. This study further confirms that targeting GLP-1, in addition to improving glycemic control, can have beneficial effects on body weight – clearly a significant and potentially important advantage over conventional diabetes treatments. It will be of interest to see how taspoglutide performs in studies specifically designed for weight loss (i.e. including behavioural interventions like energy restriction and exercise) not only in type 2 diabetes but also in non-diabetic obese patients. AMS Montreal, Quebec

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