Anti-diabetic Agents in Type 2 Diabetes: A Review of New Data Presented and Discussed on the EASD meeting in Rome, 2008

The results of a number of large trials and the arrival of new glucose-lowering drugs are changing the scene of diabetes care in patients with type 2 diabetes. The results of the ADVANCE and ACCORD trials have shown that strict glycemic control does not improve macrovascular outcome. Consequently, the importance of duration of disease, presence of cardiovascular disease and risk of hypoglycemia, have been brought again into focus as considerations in designing individual treatment plans. New drugs related to the incretin system have emerged in the past year, and these may decrease certain risks of classic glucose-lowering drugs. However, we have to be aware of the possibility of yet unknown longer-term risks from newly developed drugs. The new insights from the trials presented on the EASD meeting 2008 and the emerging information on the new drugs are used in this paper to start defining the contours of prospective new treatment strategies.     

Myocardial Protection from Either Ischaemic Preconditioning or Nicorandil Is Not Blocked by Gliclazide

OBJECTIVE: We compared the effects of two sulphonylureas, glibenclamide and gliclazide, on ischaemic preconditioning (IPC) and nicorandil-induced protection in the in-vivo rat. We also studied the effects of these agents on the membrane potential of isolated rat mitochondria. METHODS: Anaesthetised male Sprague-Dawley rats were used in an open chest model of myocardial infarction. Animals were randomly assigned to receive one of the following drugs: (1) saline control, (2) glibenclamide, 0.3 mg/kg, or (3) gliclazide, 1 mg/kg i.v. bolus. Each was then further randomised to one of the following treatments: (a) control, (b) IPC (consisting of 2 x 5 mins of regional ischaemia and 5 minutes reperfusion) or (c) nicorandil (50 ug/kg/min i.v). infusion. Each group then underwent 25 mins regional ischaemia and 2 hrs reperfusion. Infarct to risk zone ratio (%) was calculated by computerised planimetry of tetrazolium stained heart slices. The membrane potential of mitochondria isolated from rat ventricles was measured using flow cytometry. Comparisons were made between groups in control medium, nicorandil alone, and nicorandil with either glibenclamide or gliclazide. RESULTS: Infarct size was significantly reduced with IPC (15.0 +/- 1.1%,) and nicorandil (25.5 +/- 4.2%), versus control (44.1 +/- 3.2%), p < 0.005. Glibenclamide abolished IPC (40.8 +/- 4.6%) and nicorandil-induced protection completely (39.5 +/- 5.1%). Gliclazide had no adverse effect on IPC (20.4 +/- 1.9%) or nicorandil-induced protection (23.6 +/- 2.2%), p < 0.005. Nicorandil caused a partial depolarisation of the mitochondrial membrane potential (-14.92 +/- 2.34%), which was abolished by glibenclamide (+2.03 +/- 0.53%), but not gliclazide (-16.47 +/- 3.36%), p < 0.01. CONCLUSION: Both IPC and nicorandil-induced protection are abolished by glibenclamide but not gliclazide in-vivo. These results may have important clinical implications in type II diabetic patients at risk of acute coronary syndromes.     

Comparison of nateglinide and gliclazide in combination with metformin,for treatment of patients with Type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone

Aims To compare the effects of nateglinide plus metformin with gliclazide plus metformin on glycaemic control in patients with Type 2 diabetes. Methods Double‐blind, double‐dummy, parallel group, randomized, multicentre study over 24 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to additionally receive nateglinide (n = 133) or gliclazide (n = 129). Changes from baseline in HbA_1c, fasting plasma glucose (FPG) and mealtime glucose and insulin excursions were examined. Results HbA_1c was significantly (P < 0.001) decreased from baseline in both treatment groups (mean changes: nateglinide ?0.41%, gliclazide ?0.57%), but with no significant difference between treatments. Proportions of patients achieving a reduction of HbA_1c ≥ 0.5% or an end point HbA_1c < 7% were also similar (nateglinide 58.1%, gliclazide 60.2%). Changes from baseline in FPG were similarly significant in both treatment groups (nateglinide ?0.63, gliclazide ?0.82 mmol/l). Reduction from baseline in maximum postprandial glucose excursion were significant in the nateglinide group only (nateglinide ?0.71, gliclazide ?0.10 mmol/l; P = 0.037 for difference). Postprandial insulin levels were significantly higher with nateglinide compared with gliclazide. The overall rate of hypoglycaemia events was similar in the nateglinide group compared with the gliclazide group. Conclusions No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA_1c. However, the nateglinide combination demonstrated better postprandial glucose control.     

共无定形辛伐他汀-格列齐特的理化性质

制备共无定形辛伐他汀-格列齐特,对其溶出特性和物理稳定性进行了考察。结果证实产物为单相无定形态,辛伐他汀可能通过O-H与格列齐特磺酰脲基的C=O产生氢键相互作用,使通过常规方法难以制备成无定形的格列齐特实现了无定形化。共无定形物的形成显著提高了格列齐特的溶解度和溶出度,但对辛伐他汀无明显影响。与无定形辛伐他汀相比,该共无定形物的物理稳定性显著提高。     

Effects of gliclazide dose escalation on postprandial hyperglycemia in type 2 diabetes mellitus: A prospective, open-label, case-controlled, dose-escalation study

Objectives: The aims of this study were to determine the effects of increasing doses of gliclazide on postprandial glucose excursions after a standardized breakfast and lunch, and to clarify the relationship between gliclazide dose and glucose response.Methods: This prospective, open-label, case-controlled, dose-escalation study was conducted at the Addington Hospital Diabetes Clinic, eThekwini/Durban, KwaZulu-Natal, South Africa. Male and female patients aged ≥18 years with type 2 diabetes mellitus (DM) and postprandial hyperglycemia (2-hour postprandial blood glucose [PPBG_{2 h}] level, ≥11.1 mmol/L [≥200 mg/dL]) and receiving an oral hypoglycemic agent were eligible. After a 1-week washout period during which patients were asked to discontinue treatment with all oral hypoglycemic agents, baseline glycemic measurements were performed (fasting blood glucose, PPBG_{2 h}, 6-hour postprandial blood glucose [PPBG_{6 h}], mean blood glucose [MBG], plasma insulin, fasting serum fructosamine, and glycosylated hemoglobin). All patients subsequently received 2 weeks of oral treatment with each of 3 doses of gliclazide: 40, 80, and 160 mg/d. Glycemic parameters were measured at the end of each dosing interval. Adverse-effect monitoring included direct reporting of untoward effects to the resident medical practitioner, clinical examination, monitoring of home blood glucose records, hematology, and liver and kidney function tests. Compliance was assessed using pill counts, examination of diary entries, and patient interview.Results: Thirty-three patients were screened; 14 entered the dose-escalation phase. Thirteen patients completed the study (7 women, 6 men; mean [SD] age, 52.0 [11.1] years); 1 was withdrawn because of poor compliance. Dose escalation from 40 to 80 mg/d was associated with a significant change only in MBG (mean [SD], 11.3 [4.2] vs 10.0 [3.9] mmol/L [203.6 (75.7) vs 180.1 (70.3) mg/dL]; P<0.001). Dose escalation from 80 to 160 mg/d was associated with a significant change only in PPBG_{6 h} (9.5 [4.2] vs 10.3 [4.1] mmol/L [171.1 (75.7) vs 185.6 (73.9) mg/dL]; P=0.018). No other significant changes in glycemic parameters between doses were found throughout the treatment period. No adverse effects were reported.Conclusions: In this small study of gliclazide dose escalation in patients with type 2 DM and postprandial hyperglycemia, gliclazide 80 mg/d was associated with a reduction in postprandial hyperglycemia. Dose escalation from 80 to 160 mg/d was not found to be associated with additional clinical benefit. Based on these results, we recommend that gliclazide dose escalation to the maximum dose recommended by the manufacturer be guided by measures of glycemia. All doses were well tolerated.     

HPLC法测定格列齐特缓释片的含量及有关物质

目的：建立一种适用于格列齐特缓释片有关物质及含量测定的HPLC分析方法。方法：采用Merck RP8（250mm×4.6mm,5μm）色谱柱,柱温30℃,以乙睛-水-三乙胺-三氟乙酸（45：55：0.1：0.1）为流动相,流速1.0mL/min,检测波长235nm。结果：格列齐特主峰与有关物质及降解产物均能达到有效分离。格列齐特在5.150～41.20μg/mL浓度范围内呈良好线性（r=0.9999）,检测限为0.013ng,含量测定的回收率为99.28%（n=9,RSD=1.21%）。结论：本法专属性强,结果准确可靠。     

格列齐特缓释片的制备及其释药因素考察

目的以格列齐特为模型药物,考察缓释片的处方及工艺因素对其体外释放的影响。方法以羟丙基甲基纤维素(HPMC)为骨架材料,预胶化淀粉等为填充剂,以体外释放度为判断原则考察处方及工艺因素对药物溶出度的影响。结果获得了满足设计要求的缓释片处方,通过对体内生物利用度的初步研究,发现格列齐特缓释凝胶骨架片在体内的有效血药浓度可维持24h以上。结论该制剂工艺简单,所用各种辅料成本低,制得的格列齐特缓释片释放度符合规定。     

Nateglinide or gliclazide in combination with metformin for treatment of patients with type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone: 1-year trial results

AIM: To compare long-term efficacy and safety of nateglinide plus metformin with those of gliclazide plus metformin in patients with type 2 diabetes not adequately controlled with metformin monotherapy. METHODS: Double-blind, double-dummy, multicentre study extended to a total of 52 weeks. Patients with inadequate glucose control on maximal doses of metformin were randomized to nateglinide (N = 133) or gliclazide (N = 129) add-on treatment. After the initial 6-month study, the majority of patients in the nateglinide group [n = 112 (93.3%)] and in the gliclazide group [n = 101 (92.7%)] entered a 6-month, double-blind, extension study. RESULTS: There was no significant difference between treatment regimens in haemoglobin Alc (HbA1c) change from baseline to 52 weeks (-0.14% for nateglinide vs. -0.27% for gliclazide; p = 0.396). Proportions of patients achieving an endpoint HbA1c of <7% were similar (40 vs. 47.4%) for nateglinide and gliclazide groups. There was no significant between-treatment difference in fasting plasma glucose change from baseline to 52 weeks (nateglinide: -0.2 mmol/l and gliclazide: -0.7 mmol/l; p = 0.096). The decreases in prandial plasma glucose area under the curve(0-4 h) from baseline were -3.26 and -1.86 h x mmol/l in the nateglinide and the gliclazide groups respectively, and the change was statistically significant in the nateglinide group only (p = 0.006). Initial insulin response to a meal was augmented with nateglinide treatment only, without between-treatment difference in 2-h insulin response. The overall rate of hypoglycaemic events was similar with nateglinide and gliclazide combinations with metformin. Nateglinide plus metformin treatment was not associated with weight gain. CONCLUSIONS: No significant difference was seen between nateglinide plus metformin and gliclazide plus metformin in terms of HbA1c. Treatment with nateglinide plus metformin for up to 12 months was not associated with weight gain.