LEAD-3試驗的兩年更新資料 確認Liraglutide的效果耐久性
作者：Alison Palkhivala
出處：WebMD醫學新聞
October 23, 2009 (蒙特婁) — 一項比較liraglutide和磺醯尿素類藥物用於第2型糖尿病患研究的兩年更新資料顯示，liraglutide對於血糖的持續控制優於磺醯尿素類藥物，且不會增加低血糖風險。這項資料發表於國際糖尿病聯盟(International Diabetes Federation，IDF)第20屆世界糖尿病研討會。
發表人、第一作者、Alan J. Garber博士向Medscape Diabetes and Endocrinology表示，Liraglutide (Novo Nordisk藥廠)是一種人類「類升糖素第1型胜肽(glucagon-like peptide-1)」類似物，當有葡萄糖時，會有胰島素刺激效果，當血糖低、減緩胃排空、食慾降低時會有升糖素抑制效果。
Garber博士表示，它聽起來似乎是過重第2型糖尿病患的理想併用方法，它的確是。它可以降低體重、不會引起低血糖、血糖值會下降。Garber博士曾任職於德州休士頓Baylor醫學院教師發展中心，也是美國臨床內分泌醫師協會秘書。
【LEAD-3試驗顯示Liraglutide用於第2型糖尿病的效果耐久性】
在「Liraglutide Effect and Action in Diabetes-3 (LEAD-3)」研究中，有746名身體質量指數小於等於45 kg/m2的第2型糖尿病患，隨機分派接受每天一次的liraglutide (1.2 mg或1.8 mg)或磺醯尿素類藥物glimepiride 8 mg，為期52週。主要終點為糖化血色素(HbA1c)的改變比率。試驗開始時，所有病患都是用飲食和運動，或者口服最大劑量一半以下的糖尿病藥物，來控制他們的糖尿病。
Garber博士表示，原本的一年隨機試驗登載於今年初的The Lancet [2009;373(9662):473-481]，顯示liraglutide的效果幾乎是傳統刺激胰島素分泌之磺醯尿素類藥物的兩倍，且在一整年的隨機試驗中，反應看似可以持續。
【兩年的更新資料顯示一致結論】
在IDF會議中，Garber博士發表兩年的追蹤資料，研究對象是完成LEAD-3試驗的473名病患中的440人。
整體而言，有321名病患完成兩年的治療。與glimepiride相比，使用liraglutide治療可以明顯降低更多的HbA1c，且最後的HbA1c更低(liraglutide 1.2 mg 結果為6.9%、liraglutide 1.6 mg結果為7.1%、glimepiride結果為7.5%)。Liraglutide治療也與較多病患達到HbA1c值小於7%或小於6.5%有關，且較不會低血糖或體重增加，空腹血糖(FPG)降低更多、最後的FPG值更低(分別是7.45和7.58與8.54 mmol/L)、平均每日飯後血糖和體重也降低較多。使用glimepiride的病患體重實際上平均增加1.0公斤。
Garber博士表示，我們報告的第二年資料中，對於A1c的持續控制和在一年時所見一樣；所以，它看來是相當相當穩定且持久的效果。使用藥物時體重不會增加，且耐受良好。
儘管liraglutide獲得較低的HbA1c 值，此治療實際引起的低血糖事件比glimepiride少。liraglutide 1.2 mg 組中，每病患-年有0.21件低血糖事件，liraglutide 1.8 mg組為0.22件，glimepiride組為1.75 件。liraglutide最常發生的副作用為噁心與腹瀉。
【關鍵在保護Beta細胞】
IDF代表、I. George Fantus醫師、多倫多Mount Sinai醫院醫學教授、多倫多大學研究副院長向Medscape Diabetes and Endocrinology表示，增泌素為基礎的治療，如liraglutide之關鍵，在於是否可實際保護beta細胞。
他表示，那是增泌素的關鍵：使用這些不同於磺醯尿素類的藥物時，長久以往，是否可以比較成功且比較不需要胰島素。體重減輕是意料中的事，以前也曾經報導過。較少低血糖事件也是意料中的事，因為它降低葡萄糖與促進胰島素分泌的作用是與葡萄糖有關。至於磺醯尿素類藥物，大家都知道，並非與葡萄糖有關，所以會有低血糖。
Fantus醫師表示，另外一個問題是和併發症風險有關，有少許的、可能嚴重的胰臟炎或甲狀腺問題。現在還不能下定論。我認為這些上市後出現的問題，和實際運用的人越來越多有關。
Novo Nordisk藥廠贊助本研究，研究作者中有Novo Nordisk藥廠的員工。其他作者接受Novo Nordisk藥廠的顧問費、演講費與其他資助。Fantus博士宣告沒有相關財務關係。
國際糖尿病聯盟(IDF)第20屆世界糖尿病研討會：摘要P-1397。發表於2009年10月21日。
Two-Year Update of LEAD-3 Trial Confirms Durability of Liraglutide's Effects
By Alison Palkhivala
Medscape Medical News
October 23, 2009 (Montreal, Quebec) — A 2-year update of a trial comparing liraglutide with a sulfonylurea in patients with type 2 diabetes demonstrates that liraglutide continues to control hyperglycemia better than a sulfonylurea without increasing the risk for hypoglycemia. Results of 2 years of data were presented here at the International Diabetes Federation (IDF) 20th World Diabetes Congress.
Liraglutide (Novo Nordisk) is a human glucagon-like peptide-1 analogue that "has insulin stimulatory effects in the presence of glucose, has glucagon-suppressive effects in the absence of hypoglycemia, retards gastric emptying, and diminishes appetite," presenter and lead author Alan J. Garber, MD, PhD, FACE, told Medscape Diabetes and Endocrinology.
"It sounds like an ideal combination for overweight people with type 2 diabetes, and it is. They lose weight, they don't get hypoglycemic, and their sugars come down," said Dr. Garber, who is from the Baylor College of Medicine Faculty Center in Houston, Texas, and is secretary of the American Association of Clinical Endocrinologists.
LEAD-3 Shows Durability of Liraglutide's Effect in Type 2 Diabetes
In the Liraglutide Effect and Action in Diabetes-3 (LEAD-3) study, 746 patients with type 2 diabetes and a body mass index (BMI) of 45 kg/m2 or less were randomized to receive once-daily liraglutide (1.2 mg or 1.8 mg) or the sulfonylurea drug glimepiride 8 mg for 52 weeks. The primary end point was change in proportion of glycosylated hemoglobin (HbA1c). At the outset of the trial, all patients had their diabetes controlled with diet and exercise alone or by taking oral diabetic agents at half or less of the maximal dose.
"The original 1-year randomized trial that appeared in The Lancet earlier this year [2009;373(9662):473-481] showed [that liraglutide] was about twice as effective as a traditional means of stimulating insulin secretion using a sulfonylurea, and [the response] was fairly durable over the full year of the randomized trial," said Dr. Garber.
Two-Year Update Shows Consistent Results
At the IDF meeting, Dr. Garber presented data on a 2-year follow-up that was conducted in 440 of the 473 patients who completed LEAD-3.
Overall, 321 patients completed a full 2 years of treatment. Compared with glimepiride, treatment with liraglutide resulted in significantly greater reductions in HbA1c and a lower final HbA1c (6.9% with 1.2 mg of liraglutide and 7.1% with 1.6 mg of liraglutide vs 7.5% with glimepiride). Liraglutide therapy was also associated with a greater proportion of patients achieving HbA1c levels of less than 7% or of 6.5% or more without hypoglycemia or weight gain, greater reductions in fasting plasma glucose (FPG), and lower final FPG values (7.45 and 7.58 vs 8.54 mmol/L, respectively), greater reductions in mean daily postprandial glucose, and weight loss. Patients receiving glimepiride actually gained a mean of 1.0 kg.
"In the second-year extension that we're showing here, you get the same persistent A1c control at full dose as what you saw at 1 year," said Dr. Garber. "So, it appears to be a very, very stable, durable effect. There is no weight regain while on drug, and it's very well tolerated."
Despite lower HbA1c values with liraglutide, this therapy actually caused fewer hypoglycemic events than glimepiride. There were 0.21 hypoglycemic events per patient-year with 1.2 mg of liraglutide and 0.22 events with 1.8 mg of the drug, compared with 1.75 events per patient-year with glimepiride. The most frequently occurring adverse events with liraglutide were nausea and diarrhea.
Protection of Beta Cells is Key
IDF delegate I. George Fantus, MD, FRCPC, associate dean of research at the University of Toronto and professor of medicine at Mount Sinai Hospital in Toronto, Ontario, told Medscape Diabetes and Endocrinology that the key issue with incretin-based therapies, such as liraglutide, will be whether they truly protect beta cells.
"That's the key issue with the incretins: whether over the long term there is going to be more success and less progression to require insulin using these drugs as opposed to sulfonylureas," he said. "The weight loss is expected and has been demonstrated previously. Less hypoglycemia is expected because its [actions of] lowering glucose and [promoting] insulin secretion are glucose-dependent. Sulfonylureas, it's well known, are not glucose dependent, so there is hypoglycemia."
"The other question is about the [risk for] complications," said Dr. Fantus. "There's a hint of pancreatitis or thyroid problems, which [might] be significant. It's too early to say. . . . I think these things usually come out in postmarketing, with large, large numbers of people in the real world."
This research was sponsored by Novo Nordisk and the study authors included an employee of Novo Nordisk. Other authors in the study received consulting and lecture fees as well as other support from Novo Nordisk. Dr. Fantus has disclosed no relevant financial relationships.
International Diabetes Federation (IDF) 20th World Diabetes Congress: Abstract P-1397. Presented October 21, 2009.
