Diabetes mellitus type 2 is a world-wide growing health problem affecting more than 150 million people at the beginning of the new millennium. It is believed that this number will double in the next 25 yr. The pathophysiological hallmarks of type 2 diabetes mellitus consist of insulin resistance, pancreatic β-cell dysfunction, and increased endogenous glucose production. To reduce the marked increase of cardiovascular mortality of type 2 diabetic subjects, optimal treatment aims at normalization of body weight, glycemia, blood pressure, and lipidemia. This review focuses on the pathophysiology and molecular pathogenesis of insulin resistance and on the capability of antihyperglycemic pharmacological agents to treat insulin resistance, i.e., α-glucosidase inhibitors, biguanides, thiazolidinediones, sulfonylureas, and insulin. Finally, a rational treatment approach is proposed based on the dynamic pathophysiological abnormalities of this highly heterogeneous and progressive disease.

Pathophysiology and pharmacological treatment of insulin resistance.

Patients with diabetes mellitus have >2× the risk for developing heart failure (HF; HF with reduced ejection fraction and HF with preserved ejection fraction). Cardiovascular outcomes, hospitalization, and prognosis are worse for patients with diabetes mellitus relative to those without. Beyond the structural and functional changes that characterize diabetic cardiomyopathy, a complex underlying, and interrelated pathophysiology exists. Despite the success of many commonly used antihyperglycemic therapies to lower hyperglycemia in type 2 diabetes mellitus the high prevalence of HF persists. This, therefore, raises the possibility that additional factors beyond glycemia might contribute to the increased HF risk in diabetes mellitus. This review summarizes the state of knowledge about the impact of existing antihyperglycemic therapies on HF and discusses potential mechanisms for beneficial or deleterious effects. Second, we review currently approved pharmacological therapies for HF and review evidence that addresses their efficacy in the context of diabetes mellitus. Dysregulation of many cellular mechanisms in multiple models of diabetic cardiomyopathy and in human hearts have been described. These include oxidative stress, inflammation, endoplasmic reticulum stress, aberrant insulin signaling, accumulation of advanced glycated end-products, altered autophagy, changes in myocardial substrate metabolism and mitochondrial bioenergetics, lipotoxicity, and altered signal transduction such as GRK (g-protein receptor kinase) signaling, renin angiotensin aldosterone signaling and β-2 adrenergic receptor signaling. These pathophysiological pathways might be amenable to pharmacological therapy to reduce the risk of HF in the context of type 2 diabetes mellitus. Successful targeting of these pathways could alter the prognosis and risk of HF beyond what is currently achieved using existing antihyperglycemic and HF therapeutics.

Heart Failure in Type 2 Diabetes Mellitus.

The sulphonylureas act by triggering insulin release from the pancreatic β cell. A specific site on the adenosine triphosphate (ATP)-sensitive potassium channels is occupied by sulphonylureas leading to closure of the potassium channels and subsequent opening of calcium channels. This results in exocytosis of insulin. The meglitinides are not sulphonylureas but also occupy the sulphonylurea receptor unit coupled to the ATP-sensitive potassium channel. Glibenclamide (glyburide), gliclazide, glipizide and glimepiride are the primary sulphonylureas in current clinical use for type 2 diabetes mellitus. Glibenclamide has a higher frequency of hypoglycaemia than the other agents. With long-term use, there is a progressive decrease in the effectiveness of sulphonylureas. This loss of effect is the result of a reduction in insulin-producing capacity by the pancreatic β cell and is also seen with other antihyperglycaemic agents. The major adverse effect of sulphonylureas is hypoglycaemia. There is a theoretical concern that sulphonylureas may affect cardiac potassium channels resulting in a diminished response to ischaemia. There are now many choices for initial therapy of type 2 diabetes in addition to sulphonylureas. Metformin and thiazolidinediones affect insulin sensitivity by independent mechanisms. Disaccharidase inhibitors reduce rapid carbohydrate absorption. No single agent appears capable of achieving target glucose levels in the majority of patients with type 2 diabetes. Combinations of agents are successful in lowering glycosylated haemoglobin levels more than with a single agent. Sulphonylureas are particularly beneficial when combined with agents such as metformin that decrease insulin resistance. Sulphonylureas can also be given with a basal insulin injection to provide enhanced endogenous insulin secretion after meals. Sulphonylureas will continue to be used both primarily and as part of combined therapy for most patients with type 2 diabetes.

https://link.springer.com/content/pdf/10.2165%2F00003495-200464120-00006.pdf

The role of sulphonylureas in the management of type 2 diabetes mellitus.

Background

Severe hypoglycaemia is a potentially life-threatening condition. The aim of the present study was to compare the frequency of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.



Methods

This prospective, population-based, 4-year study examined the incidence of severe hypoglycaemia in a region of Germany with 200 000 inhabitants. The blood glucose of all 30 768 patients who attended the emergency department of the region's central hospital was determined to detect severe hypoglycaemia, which was defined by the requirement for intravenous glucose or glucagon injection and blood glucose value of <2.8 mmol/l. Additionally, 6631/7804 patients (85%) attended to by the emergency medical services received a blood glucose test at the emergency site. The regional prescribing frequency of both sulphonylureas was determined by an independent external institute.



Results

Despite glimepiride being prescribed more frequently than glibenclamide (6976 vs 6789 person-years), glimepiride induced fewer episodes of hypoglycaemia (6 vs 38 episodes); one episode occurred with a combination of the two preparations. The incidence of severe hypoglycaemia was 0.86/1000 person-years for glimepiride and 5.6/1000 person-years for glibenclamide. The characteristics of the 45 patients who presented with sulphonylurea-associated hypoglycaemia were as follows: mean age 79 years (95% CI 75.2; 82.6); glycosylated haemoglobin 5.4% (95% CI 5.1; 5.7); impaired renal function in 62%.



Conclusions

In people with type 2 diabetes, glimepiride was associated with fewer episodes of severe hypoglycaemia than glibenclamide in routine clinical use. However, severe hypoglycaemia did occur with glimepiride and may be minimised if treatment targets are determined on an individual basis. Copyright © 2001 John Wiley & Sons, Ltd.

Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide.

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

Giinter Muller

Papers

Extrapancreatic effects of sulfonylureas — a comparison between glimepiride and conventional sulfonylureas