Aims: Progressive deterioration of glycaemic control in type 2 diabetes mellitus (T2DM) often requires treatment intensification. Dapagliflozin increases urinary glucose excretion by selective inhibition of renal sodium-glucose cotransporter 2 (SGLT2). We assessed the efficacy, safety and tolerability of dapagliflozin added to glimepiride in patients with uncontrolled T2DM.

Methods: This 24-week, randomized, double-blind, placebo-controlled, parallel-group, international, multicentre trial (ClinicalTrials.gov NCT00680745) enrolled patients with uncontrolled T2DM [haemoglobin A1c (HbA1c) 7–10%] receiving sulphonylurea monotherapy. Adult patients (n = 597) were randomly assigned to placebo or dapagliflozin (2.5, 5 or 10 mg/day) added to open-label glimepiride 4 mg/day for 24 weeks. Primary endpoint was HbA1c mean change from baseline at 24 weeks. Secondary endpoints included change in body weight and other glycaemic parameters.

Results: At 24 weeks, HbA1c adjusted mean changes from baseline for placebo versus dapagliflozin 2.5/5/10 mg groups were −0.13 versus −0.58, −0.63, −0.82%, respectively (all p < 0.0001 vs. placebo by Dunnett's procedure). Corresponding body weight and fasting plasma glucose values were −0.72, −1.18, −1.56, −2.26 kg and −0.11, −0.93, −1.18, −1.58 mmol/l, respectively. In placebo versus dapagliflozin groups, serious adverse events were 4.8 versus 6.0–7.1%; hypoglycaemic events 4.8 versus 7.1–7.9%; events suggestive of genital infection 0.7 versus 3.9–6.6%; and events suggestive of urinary tract infection 6.2 versus 3.9–6.9%. No kidney infections were reported.

Conclusions: Dapagliflozin added to glimepiride in patients with T2DM uncontrolled on sulphonylurea monotherapy significantly improved HbA1c, reduced weight and was generally well tolerated, although events suggestive of genital infections were reported more often in patients receiving dapagliflozin.

Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24‐week, double‐blind, placebo‐controlled trial

Aims 

Glimepiride is a new sulfonylurea for diabetes treatment which is supposed to impact less on extra-pancreatic ATP-dependent K+channels than the conventional drug glibenclamide. This study was performed to evaluate whether this results in a better maintenance of ATP-dependent K+channel mediated ischaemic myocardial preconditioning.

Methods and Results 

In a double-blind placebo-controlled study the period of total coronary occlusion during balloon angioplasty of high grade coronary artery stenoses was used as a model to compare the effects of both drugs. Quantification of myocardial ischaemia was achieved by recording the intracoronary ECG and the time to the occurrence of angina during vessel occlusion. All patients underwent three dilatations. The first dilatation (dilatation 1) served to determine the severity of ischaemia during vessel occlusion. During dilatation 2, baseline values were recorded. Thereafter, glimepiride (15 patients: 1·162mg), glibenclamide (15 patients: 2·54mg) or placebo (15 patients) were intravenously administered over 12min. Dilatation 3 started 10min after the beginning of the drug administration.

Mean ST segment shifts in the placebo group decreased by 35% (dilatation 2: 0·23; dilatation 3: 0·15mV; CI −0·55 to 0·00mV; P =0·049). A similar reduction also occurred in the glimepiride group, in which repetitive balloon occlusion led to a 34% reduction (dilatation 2: 0·35; dilatation 3: 0·23mV; CI −0·21 to −0·02mV; P =0·01). There was little influence however, on mean ST segment shifts in the glibenclamide group (dilatation 2 and dilatation 3: 0·24mV; CI −0·10 to 0·25mV; P =0·34). Accordingly, time to angina during balloon occlusion slightly increased (by 30%) in the placebo group (dilatation 2: 37s; dilatation 3: 48s; CI 0·0 to 15·0s; P =0·16); increased by 13% in the glimepiride group (dilatation 2: 40s; dilatation 3: 45s; CI 0·0 to 14·0s; P =0·023); and remained unchanged in the glibenclamide group (dilatation 2 and dilatation 3: 30s; CI −7·5 to 7·5s; P =0·67).

Conclusion 

These results show that glimepiride maintains myocardial preconditioning, while glibenclamide might be able to prevent it.

http://www.cmethai.org/pdf_file/vol6_14.pdf

Sulfonylureas and ischaemic preconditioning; a double-blind, placebo-controlled evaluation of glimepiride and glibenclamide.

Cardiovascular adenosine-5′-triphosphate-sensitive potassium (KATP) channels have been reported to play an important role in endogenous cardioprotective mechanisms. Sulphonylurea derivatives can inhibit these cardioprotective mechanisms in animal models. We investigated whether therapeutic concentrations of sulphonylurea derivatives can block vascular KATP channels in humans. The forearm vasodilator responses to administration of the specific KATP channel opener diazoxide into the brachial artery of healthy male volunteers were recorded by venous occlusion plethysmography. This procedure was repeated with concomitant intraarterial infusion of: 1) the sulphonylurea derivative glibenclamide (0.33 or 3.3 Μg · min−1 · dl−1, both n=12), 2) the new sulphonylurea derivative glimepiride (2.5 Μg · min−1 · dl−1, n=12) or 3) placebo (n=12). The effects of glibenclamide on the vasodilator responses to sodium nitroprusside were also studied (n=12). Glibenclamide significantly inhibited the diazoxide-induced increase in forearm blood flow ratio (ANOVA with repeated measures: p<0.01). During the highest diazoxide dose this ratio (mean ± SEM) was lowered from 892±165 to 449±105%, and from 1044±248 to 663±114% by low- and high-dose glibenclamide, respectively. In contrast, neither glimepiride nor placebo attenuate diazoxide-induced vasodilation. Furthermore, glibenclamide did not affect nitroprusside-induced vasodilation. We conclude that therapeutic concentrations of the classical sulphonylurea derivative glibenclamide result in significant blockade of vascular KATP channels in humans. The newly developed glimepiride seems to be devoid of these properties.

/pdf/interaction-of-sulphonylurea-derivatives-with-vascular-atp-59fgho9m5v.pdf

Interaction of sulphonylurea derivatives with vascular ATP-sensitive potassium channels in humans

The hypoglycemic sulfonylurea drugs cause reduction of blood glucose predominantly via stimulation of insulin release from pancreatic β cells. In addition, during long-term treatment, an insulin-independent blood glucose-decreasing mechanism is assumed to operate. This may include insulin-sensitizing and insulin-mimetic activity in muscle and adipose tissue. This review summarizes our current knowledge about the putative modes of action of the sulfonylurea compound, Amaryl, in pancreatic β cells and, in particular, peripheral target cells that form the molecular basis for its characteristic pharmacological and clinical profile. The analysis was performed in comparison with the conventional and the “golden standard” sulfonylurea, glibenclamide. I conclude: (I) The blood glucose decrease provoked by Amaryl can be explained by a combination of stimulation of insulin release from the pancreas and direct enhancement, as well as potentiation of the insulin response of glucose utilization in peripheral tissues only. (II) The underlying molecular mechanisms seemed to rely on β cells on a sulfonylurea receptor protein, SURX, associated with the ATP-sensitive potassium channel (KATP) and different from SUR1 for glibenclamide, and in muscle and adipose cells on: (a) the increased production of diacylglycerol and activation of protein kinase C; (b) the enhanced expression of glucose transporter isoforms; and (c) the insulin receptor-independent activation of the insulin receptor substrate/phosphatidylinositol-3-kinase pathway. (III) The latter mechanism involved a nonreceptor tyrosine kinase and a number of components, such as caveolin and glycosylphosphatidylinositol structures, which are assembled in caveolae/detergent-insoluble glycolipid-enriched rafts of the target cell plasma membrane. Since hyperinsulinism and permanent KATP closure are supposed to negatively affect the pathogenesis and therapy of non-insulin-dependent diabetes mellitus, the demonstrated higher insulin-independent blood glucose-lowering activity of Amaryl may be therapeutically relevant.

/pdf/the-molecular-mechanism-of-the-insulin-mimetic-sensitizing-33dtv0yh5o.pdf

The Molecular Mechanism of the Insulin-mimetic/sensitizing Activity of the Antidiabetic Sulfonylurea Drug Amaryl

OBJECTIVE:To review the clinical pharmacology data regarding the sulfonylurea glimepiride, and to summarize the clinical trials of glimepiride efficacy and safety alone and in combination with insulin for the treatment of type 2 diabetes mellitus.DATA SOURCES:A MEDLINE database search (English language, January 1985–April 1997) was performed to identify relevant published articles, including reviews and abstracts; the manufacturer (Hoechst Marion Roussel, Kansas City, MO) provided unpublished data.STUDY SELECTION:Pharmacology information was taken from representative original research articles. Eight clinical studies were selected for analysis on the basis of large enrollment, appropriate study design, and publication of results.DATA EXTRACTION:All clinical trials, published and unpublished, were reviewed.DATA SYNTHESIS:Glimepiride is a sulfonylurea that is pharmacologically distinct from other sulfonylureas because of differences in receptor-binding properties and potentially selective effects on ATP-sen...

Eberhard Draeger

Papers

Clinical profile of glimepiride.