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Post-prandial glycaemic reduction by an α-glucosidase inhibitor in type 2 diabetic patients with therapeutically attained basal normoglycaemia
Abstract
Post-prandial glucose excursions remain elevated in most patients with diabetes even when normal fasting plasma glucose levels have been achieved. In 39 patients with type 2 diabetes who had attained basal normoglycaemia by therapy with diet alone, a sulphonylurea, a basal insulin supplement or basal plus prandial insulin the mean glycosylated haemoglobin (HbA1) values were at the upper end (mean +/- 1SD, 8.1 +/- 1.1%) of the normal range (5.0-8.2%). Miglitol, an alpha-glucosidase inhibitor, given in a dose of 50 mg three times a day was studied in a double blind randomized crossover study. In diet and sulphonylurea treated patients, a mean 25% reduction of the post-prandial plasma glucose excursions was obtained whereas in ultralente treated patients miglitol appeared to reduce basal plasma glucose levels (p < 0.006). Side effects were limited to minor gastrointestinal disturbances, usually ameliorating after the first week of therapy. Alpha-glucosidase inhibition to prevent post-prandial glycaemia may have a role in patients in whom sulphonylurea or diet therapy has been used to obtain normal basal glucose concentrations.
... 1,2 a-Glucosidase inhibitors can decrease postprandial plasma blood glucose levels by blocking oligosaccharide catabolism. 3,4 Miglitol (MGL) is an a-glucosidase inhibitor used as oral antihyperglycaemic agent, and it is indicated for the treatment of patients with type-2 diabetes mellitus. 5 Chemically, it is (2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl) piperidine-3,4,5-triol. ...
Objectives: To formulate and characterize miglitol (MGL)-loaded microspheres as a drug delivery system for oral administration to prolong the duration of action for achieving reductions of multiple doses. MGL, an oral antihyperglycaemic agent, possesses a short elimination half-life of 2 h, so it must be administered in multiple doses. Methods: A 32 full factorial design was employed for microsphere formulation using the solvent evaporation technique. The influences of two independent variables, the polymer and surfactant concentrations, on dependent variables, such as drug loading (DL) and the encapsulation efficiency (EE), were statistically investigated using Design Expert Software. Microspheres were characterized using field emission scanning electron microscopy (FE-SEM), Fourier transform infrared spectrophotometry (FTIR), and X-ray diffraction (XRD) and were evaluated for their in vitro drug release and stability at accelerated conditions. Results: The statistical evaluation of the design showed quadratic and linear models as significant models for DL (R2: 0.9932) and EE (R2 0.9696). The sizes of particles ranged from 54.7 μm to 140 μm, and the particles were spherical in shape with coarse surfaces. The most significant factor was the polymer amount. FTIR and XRD studies confirmed the drug-polymer compatibility. In vitro release of MGL from polymeric microspheres was found to occur a slower rate of up to 10 h. Conclusion: The developed poly-e-caprolactone-loaded MGL microspheres can be successfully formulated. These microspheres can provide a promising sustained release drug delivery system for the treatment of hyperglycaemia associated with type-2 diabetes mellitus.
... Eleven studies investigated the use of AGIs in addition to other antidiabetic therapy, and there was no clear report of a diet-only subgroup [68][69][70][71][72][73][74][75][76][77][78] . Two studies had a duration less than 12 weeks [79,80] , one study was not randomized [81] , and one study included patients with impaired glucose tolerance [82] . ...
Objectives: To assess the effects of alpha-glucosidase inhibitors in patients with type 2 diabetes mellitus. Method: We searched The Cochrane Library, MEDLINE, EMBASE, Current Contents, LILACS, databases of ongoing trials, reference lists of reviews on the topic of alpha-glucosidase inhibitors and we contacted experts and manufacturers for additional trials. Date of most recent search: December 2003 (Current Contents) and April 2003 (other databases). Randomised controlled trials of at least 12 weeks duration comparing alpha-glucosidase inhibitor monotherapy in patients with type 2 diabetes with any other intervention and that included at least one of the following outcomes: mortality, morbidity, quality of life, glycemic control, lipids, insulin levels, body weight, adverse events. Two reviewers read all abstracts, assessed quality and extracted data independently. Discrepancies were resolved by consensus or by the judgement of a third reviewer. A statistician checked all extracted data entrance in the database. We attempted to contact all authors for data clarification. Results: We included 41 trials (8 130 participants), 30 investigated acarbose, seven miglitol, one trial voglibose and three trials compared different alpha-glucosidase inhibitors. Study duration was 24 weeks in most cases and only two studies lasted amply longer than one year. We found only few data on mortality, morbidity and quality of life. Acarbose had a clear effect on glycemic control compared to placebo: glycated haemoglobin -0.77% (95% confidence interval -0.90 to -0.64), fasting blood glucose -1.1 mmol/L (95% confidence interval -1.4 to -0.9), post-load blood glucose -2.32 mmol/L (95% confidence interval -2.73 to -1.92). The effect on glycated haemoglobin by acarbose was not dose-dependent. We found a decreasing effect on post-load insulin and no clinically relevant effects on lipids or body weight. Adverse effects were mostly of gastro-intestinal origin and dose dependent. Compared to sulphonylurea, acarbose decreased fasting and post-load insulin levels by -24.8 pmol/L (95% confidence interval -43.3 to -6.3) and -133.2 pmol/L (95% confidence interval -184.5 to -81.8) respectively and acarbose caused more adverse effects. Conclusions: It remains unclear whether alpha-glucosidase inhibitors influence mortality or morbidity in patients with type 2 diabetes. Conversely, they have a significant effect on glycemic control and insulin levels, but no statistically significant effect on lipids and body weight. These effects are less sure when alpha-glucosidase inhibitors are used for a longer duration. Acarbose dosages higher than 50 mg TID offer no additional effect on glycated haemoglobin but more adverse effects instead. Compared to sulphonylurea, alpha-glucosidase inhibitors lower fasting and post-load insulin levels and have an inferior profile regarding glycemic control and adverse effects.
... The class of a-glucosidase inhibitors has a unique mode of action. These drugs block oligosaccharide catabolism, delay carbohydrate digestion and absorption, and smooth and lower postprandial plasma glucose (PPG) peaks [13, 14] . Miglitol is the first pseudomonosaccharide a-glucosidase inhibitor derived from 1-deoxynojirimycin and is structurally a glucose analogue [15]. ...
The objective of this study is to examine the efficacy and tolerability of miglitol with respect to improving glycemic control in Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylurea treatment. This was a randomized, double-blinded, placebo-controlled, multicenter study. A total of 105 patients were randomized to receive 24 weeks of treatment with miglitol (n = 52; titrated from 50 mg to 100 mg 3 times daily) or placebo (n = 53). Concomitant sulfonylurea treatment and diet remained unchanged. The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline at 24 weeks. Secondary endpoints were changes in fasting plasma glucose (FPG), postprandial plasma glucose (PPG), and postprandial serum insulin (PSI). The miglitol treatment group showed significantly greater reductions in HbA1c and PPG levels compared with the placebo group. With respect to adverse events, abdominal discomfort, diarrhea, and hypoglycemia occurred with similar frequency in both groups. Results of this study indicate that miglitol significantly improves metabolic control in Chinese patients with type 2 diabetes mellitus. Miglitol is safe and well tolerated, with the exception of abdominal discomfort. Therefore, miglitol may be a useful adjuvant therapy for Chinese patients with type 2 diabetes mellitus inadequately controlled by diet and sulfonylurea treatment.
... A pharmacologically induced decrease in the rate of gastric emptying in the diabetic or prediabetic patient with rapid gastric emptying may be a new approach to slowing postprandial carbohydrate absorption in addition to methods DIABETES CARE, VOLUME 17, NUMBER 4, APRIL 1994 described previously, such as soluble fiber supplements (9,10), low glycemic index diets (11,12), a-glucosidase inhibitors (13,14), or nibbling (15,16). ...
To determine whether an oral trypsin/chymotrypsin inhibitor, POT II, will delay the rate of gastric emptying in recently diagnosed type II diabetic patients and improve their postprandial metabolic parameters.
Two gastric emptying studies were performed on each of six type II diabetic patients. During one study, the patient ingested a glucose/protein solution, and during the other study, the patient ingested the same glucose/protein solution with the addition of 1.5 g of POT II, a putative stimulant of cholecystokinin (CCK) release. Each patient served as their own control subject. Each of the two oral solutions were administered to the patients in a counter-balanced order separated by at least 1 week.
Serum insulin, plasma glucose, plasma gastric inhibitory polypeptide (GIP) values, and the rate of gastric emptying were all significantly (P < 0.05) decreased over the 2-h testing period when POT II was added to the oral glucose/protein meal. The area under the curve above baseline for glucose with POT II was 75% of the glucose value without POT II. The area under the curve above baseline for insulin with POT II was 68% of the value without POT II. Plasma CCK was significantly increased by POT II 15 min postprandially.
A trypsin/chymotrypsin inhibitor, POT II, can delay the rate of gastric emptying, and decrease postprandial plasma glucose levels, GIP levels, and serum insulin levels in type II diabetic patients diagnosed recently. Delay of gastric emptying in diabetic patients may provide a unique or adjunctive approach to the treatment of type II diabetes.
... Among the agents available for management of type 2 diabetes, only ␣-glycosidase inhibitors (19) and short-acting insulinotropic agents such as repaglinide (20) and nateglinide (21) have definitely been shown to impact the postprandial glucose levels. ...
To compare the effects of repaglinide, glipizide, and glibenclamide on insulin secretion and postprandial glucose after a single standard 500-kcal test meal.
A total of 12 type 2 diabetic patients with early diabetes (mean HbA(1c) of 6.1%) and 12 matched control subjects were enrolled in this randomized, double-blind, crossover trial. Subjects received placebo, 2 mg repaglinide, 5 mg glipizide, and 5 mg glibenclamide in a random fashion during the trial. Administration of each drug was followed by a single standard 500-kcal test meal. A washout period of 7-12 days existed between the four study visits.
All three drugs were equally effective on the total prandial insulin secretion (area under the curve [AUC] -15 to 240 min). However, clear differences were noted in the early insulin secretion (AUC -15 to 30 min); both repaglinide and glipizide increased secretion in nondiabetic subjects by approximately 61 and 34%, respectively, compared with placebo. In the diabetic patients, the difference versus placebo was 37 and 47%, respectively. The difference between glipizide and glibenclamide reached significance in both groups of subjects, whereas repaglinide was more effective than glibenclamide only in the healthy nondiabetic subject group. All three drugs were effective in decreasing total glucose AUC in the nondiabetic and diabetic population. In the nondiabetic subjects, however, repaglinide was significantly more effective than glibenclamide. The differences disappeared in the diabetic subjects, probably as a result of increased prevalence of insulin resistance in this group.
Repaglinide and glipizide but not glibenclamide significantly enhanced the early insulin secretion in both nondiabetic and diabetic subjects with preserved beta-cell function after a single standard meal.
Objectives
The primary objective was to assess tolerability of the onset of treatment with miglitol according to a progressive posological regime. The secondary objective was to assess therapeutic compliance.
Methods
Prospective, observational and multicenter study that includes 1,795 patients with type 2 diabetes mellitus, treated with miglitol in progressive posological regime for 3 months.
Results
The incidence of adverse reactions decreased during the study from 19% (341/1,745) at one month of treatment to 9.1% (155/1,708) after completing 3 months. The side effects were mostly of mild intensity and occasional appearance and related with the drug action mechanism. Only 1.8% of the patients dropped out of the treatment for this reason. Regime compliance was at about 90%.
Conclusions
Miglitol is a drug which, like other alpha- glucosidase inhibitors, presents an adverse reaction profile related with its action mechanism.
The incidence of adverse reactions of miglitol can decrease if the treatment is initiated with low doses and the regime progressively increased, improving tolerability during the weeks of treatment.
Compliance by the patients of the progressive regime of miglitol prescribed by the physician is at about 90%.
A series of tetrahydroquinoline-linked thiazolidinediones was designed and synthesized and their peroxisome proliferator activated receptor-gamma (PPAR gamma) agonistic activities were evaluated. A number of analogs were revealed to have significant PPAR gamma agonistic activity. Among these compounds, compound 1h possessing N-heptyl moiety was found to be the most active in PPAR gamma transactivation assay. Molecular modeling suggested that the heptyl group of 1h appropriately interacts with hydrophobic amino acid residues in the active site of PPAR gamma.
The only new pharmaceutical therapy for Type 2 (non-insulin-dependent) diabetes that has become available for clinical use in the last 40 years is the alpha-glucosidase inhibitor, acarbose, which reduces postprandial glucose levels by retarding digestion of complex carbohydrates in the gut. It has proved difficult to find other new metabolically active drugs that lack toxicity. Agents that reduce insulin resistance include the thiazolidinediones, which are very effective in animals. Of these, the only one that has been maintained in clinical evaluation appears from preliminary data to have an effect that although still useful, is not greater than that reported for current oral agents. Agents that reduce non-esterified fatty acid levels by inhibiting lipolysis, thereby allowing increased peripheral uptake of glucose, have so far given minimal reduction in glycaemia. The development of fatty acid oxidation inhibitors to reduce gluconeogenesis in the liver has been hampered by toxicity, but additional new agents are being studied. The most promising new approach for enhancing insulin secretion has been suggested by the demonstration that pharmacological doses of GLP-1 (7-36 amide), a natural enteric incretin hormone, improves pancreatic beta-cell and alpha-cell sensitivity to glucose and can induce normal basal glucose levels in diabetic man. The future development of GLP-1 agonists will be of great interest. This is timely as other insulin secretogogues, such as alpha 2 adrenergic blockers have proved relatively ineffective. Anti-obesity agents would in theory be beneficial, but have either had limited efficacy or have been avoided because of concern about long-term safety. Until new pharmaceutical agents become available, if near-normal glycaemia is to be achieved, many more Type 2 diabetic patients will need insulin therapy. When full insulin replacement therapy is not feasible, reducing the fasting blood glucose level towards normal with a single daily basal insulin supplement, either alone or in combination with oral agents, could become a more widely used therapy.
The study compared the long-term efficacy and safety of miglitol to placebo in Type 2 diabetic outpatients inadequately controlled on combination therapy of diet, glibenclamide and metformin.
Type 2 diabetic patients (n = 154) receiving glibenclamide 7-20 mg/day and at least one 500-850 mg tablet metformin per day were randomized to receive additional miglitol or placebo for 24 weeks, titrated up stepwise from 25 to 100 mg trice daily.
Addition of miglitol to sulphonylureas and metformin (per protocol analysis) produced a statistically, significantly greater reduction in HbA1c (-0.55%, P = 0.04) and postprandial glucose (-2.6 mmol/l, P = 0.0009) from baseline to endpoint than placebo (-0.2% and -0.6 mol/l, respectively). Reduction in fasting blood glucose was greater with miglitol than placebo, and there was a possible difference in favor of miglitol for fasting and postprandial triglyceride levels, but these did not reach statistical significance. Flatulence and diarrhea were reported by statistically, significantly more patients receiving miglitol than placebo, but adverse events overall were reported by only 10% more patients in the miglitol group. No cases of hypoglycaemia were reported.
Miglitol can safely and effectively be added to long-term combination therapy in people with Type 2 diabetes inadequately controlled with glibenclamide plus metformin.
To investigate the efficacy and safety of miglitol in combination with metformin in improving glycemic control in outpatients in whom type 2 diabetes is insufficiently controlled by diet alone.
In this multicenter, double-blind, placebo-controlled study, 324 patients with type 2 diabetes were randomized, after an 8-week placebo run-in period, to treatment with either placebo, miglitol alone, metformin alone, or miglitol plus metformin for 36 weeks. The miglitol was titrated to 100 mg three times a day and metformin was administered at 500 mg three times a day. The primary efficacy criterion was change in HbA(1c) from baseline to the end of treatment. Secondary parameters included changes in fasting and postprandial plasma glucose and insulin levels, serum triglyceride levels, and responder rate.
A total of 318 patients were valid for intent-to-treat analysis. A reduction in mean placebo-subtracted HbA(1c) of -1.78% was observed with miglitol plus metformin combination therapy, which was significantly different from treatment with metformin alone (-1.25; P = 0.002). Miglitol plus metformin also resulted in better metabolic control than metformin alone for fasting plasma glucose (-44.8 vs. -20.4 mg/dl; P = 0.0025), 2-h postprandial glucose area under the curve (-59.0 vs. -18.0 mg/dl; P = 0.0001), and responder rate (70.6 vs. 45.52%; P = 0.0014). All therapies were well tolerated.
In type 2 diabetic patients, miglitol in combination with metformin gives greater glycemic improvement than metformin monotherapy.
To investigate the efficacy and safety of miglitol vs. placebo in type 2 diabetic outpatients insufficiently controlled (HbA1c between 7.5 and 10.5%) with diet and metformin.
Patients treated with diet and metformin (1500-2250 mg/day) were randomized to receive additional treatment with either miglitol or placebo for 32 weeks. The dosages were force-titrated: 4 weeks at 25 mg miglitol t.i.d., 12 weeks at 50 mg miglitol t.i.d., and 16 weeks at 100 mg miglitol t.i.d. or matching placebo. If the highest dosage could not be tolerated, patients could be down-titrated to 50 mg t.i.d. The primary efficacy criterion was the change in glycated haemoglobin (HbA1c). Secondary efficacy parameters included fasting and 1 h postprandial blood glucose, serum insulin, and fasting and 1 h postprandial triglyceride levels. Safety and tolerability were evaluated by the incidence of adverse events and changes in vital signs or routine biochemical and haematological parameters.
One hundred and fifty-two patients were valid for the intent-to-treat (ITT) analysis. There was a significant decrease in HbA1c on adding miglitol to metformin compared to adding placebo (miglitol treatment effect, - 0.21%; placebo treatment effect, + 0.22%; p = 0.011). Postprandial blood glucose declined in both the miglitol/metformin and placebo/metformin groups with a statistically significant difference in favour of miglitol/metformin (end of treatment adjusted means 13.8 mmol/l for miglitol vs. 15.8 mmol/l for placebo, p = 0.0007). Adverse events (AEs) were reported by only 8% more patients in the miglitol/metformin group than placebo/metformin. No cases of hypoglycaemia were reported.
Miglitol can safely and effectively be added to diet and metformin in patients whose type 2 diabetes is insufficiently controlled, and improves glycaemic control by significantly reducing HbA1c and postprandial blood glucose levels.
To review the effects of monotherapy with alpha-glucosidase inhibitors (AGIs) for patients with type 2 diabetes, with respect to mortality, morbidity, glycemic control, insulin levels, plasma lipids, body weight, and side effects.
We systematically searched the Cochrane Central register of Controlled Trials, MEDLINE, EMBASE, Current Contents, LILACS, databases of ongoing trials, and reference lists, and we contacted experts and manufacturers. Inclusion criteria were randomized controlled trials of at least 12 weeks' duration, AGI monotherapy compared with any intervention, and one of the following outcome measures: mortality, morbidity, GHb, blood glucose, lipids, insulin levels, body weight, or side effects. Two independent reviewers assessed all abstracts, extracted all data, and assessed quality. We contacted all authors for data clarification. Continuous data were expressed as weighted mean differences and analyzed with a random-effects model. Possible influences of study characteristics and quality were assessed in sensitivity and meta-regression analyses.
Forty-one studies were included in the review (30 acarbose, 7 miglitol, 1 voglibose, and 3 combined), and heterogeneity was limited. We found no evidence for an effect on mortality or morbidity. Compared with placebo, AGIs had a beneficial effect on GHb (acarbose -0.77%; miglitol -0.68%), fasting and postload blood glucose and postload insulin. With acarbose dosages higher than 50 mg t.i.d., the effect on GHb was the same, but the occurrence of side effects increased. Acarbose decreased the BMI by 0.17 kg/m2 (95% CI 0.08-0.26). None of the AGIs had an effect on plasma lipids. Compared with sulfonylurea, AGIs seemed inferior with respect to glycemic control, but they reduced fasting and postload insulin levels. For comparisons with other agents, little data were available.
We found no evidence for an effect on mortality or morbidity. AGIs have clear beneficial effects on glycemic control and postload insulin levels but not on plasma lipids. There is no need for dosages higher than 50 mg acarbose t.i.d.
Alpha-glucosidase inhibitors may be used for patients with type 2 diabetes. They delay the absorbance of carbohydrates ('complex form of sugar') in the gut. In this review we present data from meta-analyses that show (among other things) a decrease in glycated haemoglobin, fasting and post-load blood glucose and post-load insulin. But we found no evidence for an effect on mortality or morbidity. We found clues that with higher dosages the effect on glycated haemoglobin, in contrast to post-load blood glucose, remains the same. This might be because a lower compliance due to increasing side-effects.
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