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Vildagliptin有助糖尿病患者的二甲双胍治疗

——Vildagliptin有助糖尿病患者的二甲双胍治疗

2005-08-16 11:27:07 作者：新特药房来源：中国新特药网浏览次数：98 文字大小：【大】【中】【小】

最新研究表明，在Ⅱ型糖尿病患者的二甲双胍治疗中增加vildagliptin，可改善进食相关的β细胞功能和胰岛素敏感性。

  研究负责人、瑞典Lund大学的Bo Ahren 博士说，这具临床意义，因为Ⅱ型糖尿病是一种β细胞功能减退的疾病。Vildagliptin 似乎具有改善疾病基本因子的作用。二肽基肽酶IV (DPP-4)可灭活胰高血糖素样肽-1，后者具有抗糖尿病的作用。DPP-4抑制剂已在糖尿病患者和动物模型试验成功。

  为了检查DPP-4抑制剂vildagliptin的作用，研究人员随机指定糖尿病患者除了进行二甲双胍治疗外，接受vildagliptin或安慰剂。

  在52周中完成了所有进食试验的57例受试者中，vildagliptin 治疗组的患者HbA1c降低(1%)(p < 0.001)，安慰剂组则升高。治疗组空腹血糖水平也显著降低。Vildagliptin组胰岛素分泌增加，安慰剂组降低。前组胰岛素敏感性也增高，安慰剂组无改变。此外，vildagliptin组适应指数（根据β细胞使胰岛素分泌适应周围胰岛素敏感性的能力）增高，安慰剂组降低。此改变与HbA1c 变化相关。

   研究人员总结，对接受二甲双胍治疗的患者加用DPP-4抑制剂vildagliptin可改善β细胞功能以及餐后胰岛素敏感性。

Inhibition of Dipeptidyl Peptidase-4 with Vildagliptin: Vildagliptin: a Potent and Specific Inhibitor of DPP-4

Vildagliptin: a Potent and Specific Inhibitor of DPP-4

Vildagliptin is an N-substituted glycyl-2-cyanopyrrolidine (figure 2). It is a potent competitive and reversible inhibitor of human and rodent DPP-4 in vitro, with a median inhibitory concentration (IC50) ~2-3 nmol/L.^[33] Importantly, vildagliptin inhibits DPP-4 with high specificity relative to other similar peptidases where its IC50 exceeds 200 µmol/L.^[33] This specificity is of potential clinical importance as inhibition of DPP-8 and DPP-9 has been associated with immune, histopathological and gastrointestinal toxicity in various animal models.^[34]

Figure 2.
Vildagliptin (chemical structure is based on the common design for DPP-4 inhibitors: a L-amino acid with a protonable N-terminal primary amine in the P-2 site) exhibits high-affinity, reversible, DPP-4 inhibition resulting in increased levels of active GLP-1

In healthy humans, vildagliptin is rapidly and almost completely absorbed (~85% of administered dose) after oral administration with a tmax of 1-2-hours.^[33,35,36] Plasma levels were linearly related to dose and the plasma half-life ranged from 1.5-4.5 hours with doses from 25 to 200 mg. The drug does not appear to accumulate with multiple dosing and the pharmacokinetics are not affected by food. Most of the drug is metabolised with hydrolysis of the cyano moiety dominating (55%), but a fraction (22%) is also excreted unchanged by the kidneys.^[33,35,36] The drug is minimally metabolised by the major cytochrome P450 enzymes that metabolise many other drugs and is neither an inhibitor nor an inducer of these enzymes. In the circulation, vildagliptin is not extensively protein bound (4-17%). No adjustment of dose is necessary in either hepatic or renal insufficiency.^[37]

Single doses of vildagliptin (25-200 mg) rapidly inhibit plasma DPP-4, achieving > 90% inhibition within 30-60 minutes.^[33,35] The duration of inhibition is dose dependent; with the anticipated therapeutic doses of 50 mg and 100 mg, DPP-4 activity is inhibited by ~70 and 90% at 12 hours and remains inhibited by ~40% at 24 hours with the higher dose.

In drug naïve patients with type 2 diabetes, four weeks of treatment with vildagliptin at a dose of 100 mg per day reduced both fasting and postprandial plasma glucose levels, resulting in significant decreases in HbA_1C.^[38] Vildagliptin treatment also improved insulin secretion, as assessed by the insulin responses relative to the glucose responses to a standard mixed meal, increased both basal and postprandial GLP-1 levels, and decreased glucagon levels. The drug appeared well tolerated.

The results of additional phase 2 and phase 3 studies of vildagliptin in patients with type 2 diabetes have recently been made available and are summarised below.

Vildagliptin as Monotherapy

Several phase 2 and phase 3 studies have examined the use of vildagliptin as monotherapy for patients with type 2 diabetes inadequately controlled with diet and exercise alone. A 12-week dose-ranging study in 279 patients compared dosing regimens of 25, 50 and 100 mg once daily and 25 mg twice daily.^[39] From a mean baseline HbA_1C of ~7.7%, vildagliptin at doses of 50 and 100 mg a day produced significant reductions in HbA_1C of ~0.5%. Another 12-week study in 98 patients demonstrated that vildagliptin at a dose of 25 mg twice daily decreased HbA_1C by 0.6% (p=0.0012) relative to placebo from a baseline of 8.0%.^[40] In a subset of subjects with a higher initial baseline ranging between 8.0-9.5%, a 1.2% reduction in HbA_1C was observed. In this study, fasting and prandial glucose levels were reduced by 1.1+0.4 (p=0.0043) and 1.9+0.5 mmol/L (p<0.0001), respectively. In a 24-week phase 3 study in 380 patients managed with diet and exercise (baseline HbA_1C 7.5-11%), vildagliptin at doses of 50 and 100 mg per day and 50 mg twice daily (these are the predominant doses used in the published phase 2/3 studies) reduced HbA_1C by 0.8-0.9% from baseline. The reduction in HbA_1C was highly significant for all doses of vildagliptin relative to placebo (which reduced HbA_1C by 0.3% in this study), but none of the dosing regimens was significantly different from one another. Two additional phase 3 studies of vildagliptin monotherapy have recently been reported. In the first, a 52-week head-to-head study versus metformin, vildagliptin 50 mg twice daily (n=526) reduced HbA_1C by 1.0% from a starting HbA_1C of 8.7%, whereas metformin at a dose of 2,000 mg per day (n=254) reduced HbA_1C by 1.4% (p<0.05 compared to vildagliptin in the intention-to-treat analyses).^[41] The reductions in HbA_1C were sustained for the entire 52 weeks with both vildagliptin and metformin. In the second study, vildagliptin 50 mg twice daily for 24 weeks was similar to rosiglitazone 8 mg per day.^[42] In a subset of subjects with higher HbA_1C levels at baseline (mean 10%), vildagliptin (n=166) reduced HbA_1C by 1.82% while rosiglitazone (n=88) reduced HbA_1C by 1.86%.^[42]

Vildagliptin in Combination

Two studies have examined the glucose lowering effects of vildagliptin when added-on to metformin monotherapy. The first, a 12-week phase 2 study in 107 patients on metformin demonstrated that vildagliptin at a dose of 50 mg per day reduced HbA_1C by 0.6% from a mean baseline of 7.7%, whereas HbA_1C was unchanged in the group randomised to placebo.^[43] Patients in this study were followed during a 40-week extension for a total of 52 weeks. The reductions in HbA_1C were sustained in the group receiving metformin plus vildagliptin, whereas HbA_1C increased over the course of the year in subjects treated with metformin plus placebo. At the end of the extension, HbA_1C was 1.1% lower in those who received vildagliptin in addition to metformin compared to those who received metformin alone. Notably, fasting and prandial glucose concentrations were significantly lower, whereas insulin responses to a standard meal challenge were significantly higher after 52 weeks of treatment with vildagliptin. A 3-arm 24-week phase 3 study in 416 patients on metformin monotherapy (baseline HbA_1C 7.5-11%) compared the effects of vildagliptin at doses of 50 mg per day (n=143) and 50 mg twice a day (n=143) to placebo (n=130).^[44] Starting from a mean HbA_1C of ~8.5%, both the 50 mg per day and 50 mg twice daily doses of vildagliptin significantly decreased HbA_1C relative to placebo by 0.7% and 1.1%, respectively, although the difference between doses was not statistically significant.

A similar phase 3 study examined the effects of vildagliptin added to sulphonylurea monotherapy. This study compared vildagliptin 50 mg per day (n=132) and 50 mg twice a day (n=132) to placebo (n=144) added-on to glimepiride 4 mg per day. Starting from a mean HbA_1C ~8.7%, the 50 mg per day and 50 mg twice daily doses of vildagliptin significantly decreased HbA_1C relative to placebo by 0.8 and 0.9%, respectively.

Finally, a phase 3 study of vildagliptin 50 mg twice a day (n=144) or placebo (n=152) in insulin-treated type 2 diabetic patients demonstrated significant reductions in HbA_1C in the group treated with vildagliptin (-0.5%) compared to those receiving placebo.^[45] Of note, the improvements in HbA_1C with vildagliptin occurred in association with a lower total daily insulin dose and no episodes of significant (defined as blood glucose levels < 3.1 mmol/L with symptoms of hypoglycaemia and patient unable to initiate self-treatment) hypoglycaemia (compared with six episodes in those treated with insulin plus placebo).

Collectively, the results to date indicate that vildagliptin monotherapy at daily doses of 50-100 mg produces clinically significant reductions in HbA_1C, comparable to those observed with rosiglitazone, although possibly less than those observed with metformin at one year. Vildagliptin also produces clinically significant reductions in HbA_1C in patients already treated with metformin, glimepiride or insulin who are not at goal. The reductions in HbA_1C with vildagliptin are attributable to improvements in both fasting and postprandial glucose levels and are associated with higher active GLP-1 levels, lower glucagon levels and improvements in insulin secretion. Improvements in insulin sensitivity have also been demonstrated in some studies, however, whether these changes are direct or indirect remains to be determined. Vildagliptin appears to work well in patients with higher baseline HbA_1C levels and effects are durable for up to one year. Interestingly, small, but statistically significant reductions in blood pressure have been noted with vildagliptin therapy.^[46] Finally, a study in 31 drug naïve patients with type 2 diabetes suggests that vildagliptin reduces post-prandial lipemia.^[47]

Safety and Tolerability of Vildagliptin

In general, vildagliptin as monotherapy and in combination with other antidiabetic treatments has proved to be well tolerated for periods up to 52 weeks.^[35,41,43] The incidence of hypoglycaemia is low and similar to that with metformin or rosiglitazone.^[39,41,42] Even with treatment of up to 52 weeks, there is no apparent weight gain or oedema.^[41,43] The incidence of GI side effects is comparable to placebo and is much less than in metformin-treated patients.^[39,41] In addition, the incidence of cardiac adverse events (including arrhythmias and conduction abnormalities) and hypertension with vildagliptin is comparable to placebo and is also less than with metformin.^[41] Table 2 highlights some of the uncertainties regarding the safety of DPP-4 inhibitors.