The influence of glipizide on early insulin release and glucose disposal before and after dietary regulation in diabetic patients with different degrees of hyperglycaemia

Summary An early defect in subjects with non-insulin-dependent diabetes mellitus (NIDDM) and the preceding phase of impaired glucose tolerance (IGT) is a reduction in early insulin release and hence a prolonged elevation of postprandial blood glucose. We therefore assessed whether a rapidly acting sulphonylurea (glipizide 5 mg 0.5 h before a test meal) could correct these disturbances in 38 IGT/NIDDM subjects, whose early insulin release and postprandial blood glucose elevations remained unimproved after 10 weeks of dietary regulation.We also assessed whether the efficacy of glipizide was dependent upon the ambient blood glucose concentration, and if early systemic availability of the drug was important for the blood glucose lowering effect.A single dose of glipizide normalized early insulin release and hence reduced the postprandial blood glucose increase that was not lowered by dietary regulation.The efficacy of glipizide was dependent upon the early systemic availability of the drug, but early systemic availability and efficacy were independent of the extent of blood glucose elevation, at least within a range of 6–12 mmol·l^–1 of fasting blood glucose.     

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

The sulphonylureas act by triggering insulin release from the pancreatic beta 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 beta 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.     

The use of sulphonylureas in the elderly

Type 2 diabetes mellitus is a heterogeneous disorder characterised by defects in insulin secretion as well as reduced insulin action. During aging, glucose intolerance will gradually develop, and this is manifested primarily by an increase in the postprandial blood glucose response while fasting blood glucose levels are often less elevated. Abnormal beta-cell secretion of insulin is a main feature of this. Treatment of elderly patients with type 2 diabetes mellitus focuses on reduction of (hyperglycaemic) complaints and prevention of the development or progression of secondary complications. Although regular physical activity and dietary measures, aiming at bodyweight normalisation, are the cornerstones of therapy, pharmacological treatment with oral blood glucose lowering-agents often proves necessary to control the hyperglycaemia. In the United Kingdom Prospective Diabetes Study (UKPDS) it was clearly shown that patients with type 2 diabetes mellitus who were intensively treated with oral blood glucose-lowering agents or insulin developed less microvascular complications. The question whether achievement of strict metabolic control is also of benefit in elderly patients, is still unanswered. Sulphonylureas are drugs which stimulate insulin secretion by enhancing the release of insulin from the pancreatic beta-cells without an effect on insulin synthesis. They are frequently used in the treatment of type 2 diabetes mellitus, and several preparations are available. In general, there are no major differences in effectiveness between the various sulphonylureas. Long term treatment with sulphonylureas will decrease fasting and postprandial plasma glucose levels by 3 to 5 mmol/L, and glycosylated haemoglobin by 20%. However, after its initial decline, plasma glucose level will often go up slightly during the following months to years. Sulphonylureas are usually well tolerated. Hypoglycaemia is the most frequently occurring adverse effect, which may be very serious and damaging in the elderly. It has been associated primarily with long-acting sulphonylureas, like chlorpropamide and glibenclamide (glyburide). Hypoglycaemic episodes may trigger serious events like myocardial infarction or stroke. Therefore, shorter-acting compounds like tolbutamide and gliclazide have been relatively well tolerated and appear to be the best choice to treat elderly patients. It is advisable to start with a low dose and increase the dose, when needed, in small steps. The efficacy of sulphonylureas is much greater when they are taken before a meal. Because of the fact that type 2 diabetes mellitus is a progressive disease, and residual beta-cell function decreases with time, insulin therapy may ultimately be warranted in a significant number of patients.     

Pharmacokinetic optimisation of oral hypoglycaemic therapy.

Two main classes of oral hypoglycaemic drugs, the sulphonylureas and the biguanides, are currently used in the therapy of type II, non-insulin-dependent diabetes mellitus (NIDDM). The basic pharmacokinetic properties of these agents are discussed with a view to efficient and safe treatment. Both first- and second-generation sulphonylureas are rapidly absorbed from the gastrointestinal tract. In the plasma compartment, these drugs are strongly bound to serum proteins. All sulphonylureas are metabolised in the liver, and the metabolites and the parent drugs are eliminated mainly in the urine, but also (second-generation derivatives) in the faces. Rapid- and short-acting sulphonylureas may improve early insulin release and promote better postprandial glucose control. Long-acting derivatives may ensure better control of overnight glycaemia. The elderly are at risk of developing severe sulphonylurea-induced hypoglycaemia, and in this population the agent chosen should have a short or intermediate duration of action and no active metabolites. Caution is needed when prescribing any sulphonylurea in patients receiving drugs known to affect sulphonylurea action, and in those with impaired liver and/or kidney function. The bioavailability of the biguanides ranges from 40 to 60%. Binding to plasma proteins is absent or very low. Metformin and buformin are not metabolised and are excreted in the urine; phenformin undergoes hepatic hydroxylation and is excreted in both urine and faeces. Metformin is the only agent of this class currently recommended for clinical use. The main indications of metformin treatment are NIDDM associated with obesity and/or hyperlipidaemia, and in combination with sulphonylurea both as primary treatment and when secondary failure occurs with sulphonylurea alone. Lactic acidosis may develop in patients receiving therapy with biguanides, especially in the presence of a preexisting contraindication to their use.     

Block of Ca(2+)-channels by alpha-endosulphine inhibits insulin release

1. alpha-Endosulphine, isolated as an endogenous equivalent for sulphonylureas, is a 121-amino acids protein of 19 kDa apparent molecular mass, member of a cyclic AMP-regulated phosphoprotein family. We have previously shown that alpha-endosulphine inhibits sulphonylurea binding and K(ATP) channel activity, thereby stimulating basal insulin secretion. 2. We now describe that in the perfused rat pancreas, no stimulation was detected and that alpha-endosulphine inhibited glucose stimulated insulin release. This inhibition was dose-dependent and affected both phases of insulin secretion. 3. This inhibitory effect of alpha-endosulphine also occurred on MIN6 beta-cells when insulin release was stimulated either by glucose, sulphonylureas or a high K(+) depolarization. Inhibition was concentration-dependent with a half-maximal inhibition at 0.5 microM and was mirrored by inhibition of calcium influx. 4. Electrophysiological experiments demonstrated, in comparison to the effects of the sulphonylurea tolbutamide, that these inhibitory effects were linked to a direct inhibition of L-type Ca(2+)-channels and were independent from a regulation of K(ATP) channels. 5. Although alpha-endosulphine is able to stimulate insulin release under specific conditions acting via modulation of K(ATP) channel activity, the present study suggests that, under physiological conditions, the peptide mainly acts to block voltage-gated Ca(2+)-channels. This block leads to the inhibition of calcium influx and triggers inhibition of insulin release. 6. We conclude that alpha-endosulphine is not exclusively an endogenous equivalent for sulphonylureas and not solely a K(ATP) channel regulator.     

Mechanisms and clinical effects of thiazolidinediones

Studies of pioglitazone, troglitazone, BRL 49653 and other thiazolidinediones in preclinical animal models of non-insulin dependent diabetes mellitus (NIDDM) and obesity led to the observation that these compounds were effective in reducing hyperglycaemia and hyperlipidaemia. In these models, animals treated with thiazolidinediones had notable improvements in blood glucose levels, hepatic glucose output, peripheral insulin resistance, and serum lipid levels. Mechanistic studies indicate that thiazolidinediones act at many intracellular sites and can influence several processes to increase cell sensitivity to insulin. These include influence on insulin receptor kinase activity, control of insulin receptor phosphorylation, change in number of insulin receptors, quantity and activity of GLUT-4, modulation of tumour necrosis factor (TNF) activity, activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and alteration of hepatic glucose metabolism. Available data on pioglitazone and troglitazone from clinical studies support the efficacy and safety of this class of compounds in reducing hyperglycaemia, hypertriglyceridaemia and insulin resistance associated with NIDDM. Currently, only troglitazone is approved for use in the United States and only in combination with insulin. This new pharmacological class of drugs has great promise for the treatment of NIDDM and also as a valuable research tool to further the understanding of the mechanisms that underlie NIDDM and insulin resistance syndrome.     

Mechanisms and clinical effects of thiazolidinediones

Studies of pioglitazone, troglitazone, BRL 49653 and other thiazolidinediones in preclinical animal models of non-insulin dependent diabetes mellitus (NIDDM) and obesity led to the observation that these compounds were effective in reducing hyperglycaemia and hyperlipidaemia. In these models, animals treated with thiazolidinediones had notable improvements in blood glucose levels, hepatic glucose output, peripheral insulin resistance, and serum lipid levels. Mechanistic studies indicate that thiazolidinediones act at many intracellular sites and can influence several processes to increase cell sensitivity to insulin. These include influence on insulin receptor kinase activity, control of insulin receptor phosphorylation, change in number of insulin receptors, quantity and activity of GLUT-4, modulation of tumour necrosis factor (TNF) activity, activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and alteration of hepatic glucose metabolism. Available data on pioglitazone and troglitazone from clinical studies support the efficacy and safety of this class of compounds in reducing hyperglycaemia, hypertriglyceridaemia and insulin resistance associated with NIDDM. Currently, only troglitazone is approved for use in the United States and only in combination with insulin. This new pharmacological class of drugs has great promise for the treatment of NIDDM and also as a valuable research tool to further the understanding of the mechanisms that underlie NIDDM and insulin resistance syndrome.     

Effect of nifedipine on glucose potentiation of the acute insulin response to arginine in non-insulin-dependent diabetics

Summary The effect of 7-days of nifedipine treatment on insulin secretion has been analyzed in hypertensive patients with non-insulin-dependent mellitus (NIDDM). Pancreatic -cell function was assessed as insulin release following stimulation with arginine after potentiation by hyperglycaemia. Two groups of 5 patients with NIDDM (fasting blood glucose 139.2 mg·dl^–1), on the same controlled diet, were compared; one was treated with nifedipine 30 mg per d and the other was the control.The mean blood pressure in the nifedipine group decreased (110 vs 102 mm Hg). Fasting blood glucose and basal plasma insulin were not affected by nifedipine. The acute insulin response (AIR) to 5 g arginine after potentiation by hyperglycaemia (clamped at 240 and 350 mg/dl for 30 min) was significantly (P<0.05) decreased, as well as the potentiation slope (line relating AIR and plasma glucose level) in those patients, and were unchanged in the control group.Thus, nifedipine may impair insulin secretion at high glucose levels in patients with NiDDM.     

Oral antidiabetic agents: current role in type 2 diabetes mellitus

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance. Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis--beyond expected effects on glycaemic control--is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA1c), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.     

Alterations of insulin secretion from mouse islets treated with sulphonylureas: perturbations of Ca2+ regulation prevail over changes in insulin content.

1. To determine how pretreatment with sulphonylureas alters the beta cell function, mouse islets were cultured (18 - 20 h) without (controls) or with (test) 0.01 microM glibenclamide. Acute responses to glucose were then determined in the absence of glibenclamide. 2. Test islets were insensitive to drugs (sulphonylureas and diazoxide) acting on K+-ATP channels, and their [Ca2+]i was already elevated in the absence of stimulation. 3. Insulin secretion was increased in the absence of glucose, and mainly stimulated between 0 - 10 instead of 7 - 20 mM glucose in controls. The maximum response was halved, but this difference disappeared after correction for the 45% decrease in the islet insulin content. 4. The first phase of glucose-induced insulin secretion was abrogated because of a paradoxical decrease of the high basal [Ca2+]i in beta cells. The second phase was preserved but occurred with little rise of [Ca2+]i. These abnormalities did not result from alterations of glucose metabolism (NADPH fluorescence). 5. In islets cultured with 50 microM tolbutamide, glucose induced biphasic increases in [Ca2+]i and insulin secretion. The decrease in the secretory response was matched by the decrease in insulin content (45%) except at maximal glucose concentrations. Islets pretreated with tolbutamide, however, behaved like those cultured with glibenclamide if tolbutamide was also present during the acute functional tests. 6. In conclusion, treatment with a low glibenclamide concentration causes long-lasting blockade of K+-ATP channels and rise of [Ca2+]i in beta cells. Glucose-induced insulin secretion occurs at lower concentrations, is delayed and is largely mediated by a modulation of Ca2+ action on exocytosis. It is suggested that glucose regulation of insulin secretion mainly depends on a K+-ATP channel-independent pathway during in vivo sulphonylurea treatment.     

Non insulin-dependent diabetes mellitus (type 2) secondary failure. Metformin-glibenclamide treatment

The goal of sulphonylurea (S) treatment in Non-Insulin-Dependent Diabetes Mellitus (NIDDM - type 2 diabetes) subjects should be to obtain a satisfactory glycemic control (fasting glycemic levels < 140 mg%). The loss of an adequate blood glucose control after an initial variable period of S is known as secondary failure (SF). The number of SF are extremely variable among different trials for many reasons, some of which are patient-related: increased food intake, weight gain, non-compliance, poor physical activity, stress, diseases and÷or impaired pancreatic beta cell function, desensitization after S chronic therapy, reduced absorption, concomitant therapies. Many therapeutic strategies have been proposed to achieve an adequate metabolic control in type 2 diabetes patients: switch to intensive insulin therapy and subsequent return to S therapy; association with insulin; association with sulphonylureas plus biguanides. The association biguanides and S, in particular glibenclamide plus metformin, is now widely used by diabetologists in SF since glibenclamide improves insulin secretion while metformin exerts its antidiabetic.     

Optimising therapy for insulin-treated type 2 diabetes mellitus

The purpose of this article is to provide a guide to the optimal use of insulin in type 2 (non-insulin-dependent) diabetes mellitus. Based on pathophysiological considerations and a knowledge of drug actions, an individualised, targeted strategy is selected for obtaining good metabolic control without compromising well-being and quality of life. The treatment should target hyperglycaemia along with other risk factors. Insulin is indicated when adequate glycaemia can no longer be obtained with diet and oral antihyperglycaemic agents. Commonly, the oral drugs are replaced by insulin, but preferably they should be used in combination with insulin. This approach can lead to improved glycaemic control, a reduced insulin dose and counteraction of insulin-associated bodyweight gain. There may also be less hypoglycaemia with combination insulin/oral therapy as compared with insulin monotherapy, as well as other benefits. Optimisation of oral drug therapy should be attempted before initiating insulin. A combination of insulin with a sulphonylurea agent is commonly used: the adjunctive effect of the sulphonylurea is dependent on pancreatic beta cell function. The combination of insulin with metformin or a thiazolidinedione is more logical as insulin resistance is targeted directly. Bedtime insulin plus metformin conferred the most benefits among several options investigated in a randomised 1-year study. The combination of insulin with acarbose is a further option when there is significant postprandial hyperglycaemia. It is recommended to start with a medium- to long-acting insulin preparation at bedtime or premixed insulin before the evening meal. Changes in insulin administration can be subsequently introduced as needed, e.g. use of twice-daily premixed insulin, multiple injections of rapid-acting insulin or insulin analogues. There are many options, but limited clinical data are available to support a number of the regimens.     

Long-term effects of glipizide on insulin secretion and blood glucose control in patients with non-insulin-dependent diabetes mellitus

Summary Of 23 patients with non-insulin-dependent diabetes mellitus (NIDDM), whose fasting blood glucose had not reached 6.0 mmol·l^–1 after 10 weeks of dietary regulation, 15, who had had a weight reduction of –2.8 kg by dietary control, did achieve a fasting blood glucose 6.0 mmol·l^–1 after addition of 20 mg glipizide daily. They had a sustained (2 years) increase in meal-induced insulin secretion (32% increase in postprandial C-peptide AUC), and a sustained reduction in postprandial hyperglycaemia (34% reduction in AUC). Ten of the patients took a mean daily dose <5mg (4.8 mg) and had a sustained increase in insulin secretion rate (increased C-peptide slope). The 15 patients had no elevation of basal insulin secretion and no impairment of weight reduction. The remaining 8 subjects, who showed little or no weight reduction on dietary control, had little or no reduction in fasting blood glucose despite long-term treatment with 20 mg glipizide daily, a less sustained increase in meal-induced insulin secretion, a smaller reduction of postprandial hyperglycaemia, and an increase in body weight. On diagnosis the 8 subjects did not differ from the other 15 subjects in age, body weight, blood glucose, HbA₁c, C-peptide or insulin, nor in their glucose and insulin responses to a test dose of glipizide; the main reason for the apparent drug failure appeared to be deficient compliance with dietary regulation rather than a primary inability to respond to sulphonylurea treatment. The findings indicate that glipizide is able to promote and maintain increased meal-induced insulin secretion and near-normal fasting and non-fasting blood glucose levels without continuous B cell stimulation. However, these improvements prevail mainly in subjects who persist with hypocaloric dietary regulation.     

Effects of theα-glucosidase inhibitor 1 desoxynojirimycin (BAY M 1099) on postprandial blood glucose,serum insulin and C-peptide levels in type II diabetic patients

Summary Bay m 1099 is a newly developed inhibitor of intestinal-glucosidase. Its ability to lower postprandial plasma glucose, serum insulin and C-peptide levels in Type II diabetics has been investigated. Fifteen obese Type II diabetic patients with inadequate metabolic control during sulphonylurea treatment received a standardized diet and were treated either with Bay m 1099, b.d. (100 mg before breakfast and dinner) or placebo for 3 days, according to a double-blind cross-over design. The postprandial blood glucose level was significantly lower during Bay m 1099 treatment compared to placebo after breakfast and dinner (AUC after breakfastp<0.001). The reduced postprandial hyperglycaemia was associated with a decrease in meal stimulated serum insulin and C-peptide levels. Thus, Bay m 1099 may be a useful addition in the treatment of Type II diabetic patients.     

New non-sulfonylurea insulin secretagogues

Current treatments for non-insulin dependent diabetes mellitus (NIDDM) remain far from ideal. The universal finding of islet dysfunction characterised by the absence of first phase insulin secretion, even prior to the level of hyperglycaemia diagnostic of NIDDM, challenges the rationale for treatments that only enhance insulin action. To date, however, the sulfonylureas are the only insulin secretagogues available and even the most rapid acting of these fail to restore early insulin release in response to meals. Four novel non-sulfonylurea insulin secretagogues are in advanced clinical development: A-4166, KAD-1229, BTS 67 582 and repaglinide. These promising new agents control prandial hyperglycaemia by augmenting the early insulin response to meals. Preclinical and early clinical data suggest that their potencies vary considerably, as do their pharmacokinetics and, importantly, their pharmacodynamics. The two shortest-acting compounds, A-4166 and KAD-1229, will be developed to be taken prior to each main meal, while the slower, longer duration agents, repaglinide and BTS 67 582, may be developed to be taken twice daily. With a sufficiently rapid onset and short duration of action, the new non-sulfonylurea insulin secretagogues may improve or even restore the impairment of early insulin secretion without inducing the prolonged hyperinsulinaemia characteristic of sulfonylureas. Treatment with these new agents will immediately improve prandial glucose control and with continued treatment these agents are expected to improve the overall metabolic state. Furthermore, a short-acting secretagogue will have minimal propensity to elicit prolonged or delayed hypoglycaemia and it is expected that by minimising chronic hyperinsulinaemia the weight gain that accompanies sulfonylurea treatment will be avoided. In summary, the new non-sulfonylurea insulin secretagogues will make an important contribution to the limited and inadequate armamentarium currently available for the treatment of NIDDM, and their use in combination with insulin sensitising agents may provide, for the first time, an approximation to ideal metabolic control in NIDDM.     

The potential role of valsartan + AHU377 (LCZ696) in the treatment of heart failure

Current treatments for non-insulin dependent diabetes mellitus (NIDDM) remain far from ideal. The universal finding of islet dysfunction characterised by the absence of first phase insulin secretion, even prior to the level of hyperglycaemia diagnostic of NIDDM, challenges the rationale for treatments that only enhance insulin action. To date, however, the sulfonylureas are the only insulin secretagogues available and even the most rapid acting of these fail to restore early insulin release in response to meals. Four novel non-sulfonylurea insulin secretagogues are in advanced clinical development: A-4166, KAD-1229, BTS 67 582 and repaglinide. These promising new agents control prandial hyperglycaemia by augmenting the early insulin response to meals. Preclinical and early clinical data suggest that their potencies vary considerably, as do their pharmacokinetics and, importantly, their pharmacodynamics. The two shortest-acting compounds, A-4166 and KAD-1229, will be developed to be taken prior to each main meal, while the slower, longer duration agents, repaglinide and BTS 67 582, may be developed to be taken twice daily. With a sufficiently rapid onset and short duration of action, the new non-sulfonylurea insulin secretagogues may improve or even restore the impairment of early insulin secretion without inducing the prolonged hyperinsulinaemia characteristic of sulfonylureas. Treatment with these new agents will immediately improve prandial glucose control and with continued treatment these agents are expected to improve the overall metabolic state. Furthermore, a short-acting secretagogue will have minimal propensity to elicit prolonged or delayed hypoglycaemia and it is expected that by minimising chronic hyperinsulinaemia the weight gain that accompanies sulfonylurea treatment will be avoided. In summary, the new non-sulfonylurea insulin secretagogues will make an important contribution to the limited and inadequate armamentarium currently available for the treatment of NIDDM, and their use in combination with insulin sensitising agents may provide, for the first time, an approximation to ideal metabolic control in NIDDM.     

Comparative tolerability of sulphonylureas in diabetes mellitus.

The sulphonylurea drugs have been the mainstay of oral treatment for patients with diabetes mellitus since they were introduced. In general, they are well tolerated, with a low incidence of adverse effects, although there are some differences between the drugs in the incidence of hypoglycaemia. Over the years, the drugs causing the most problems with hypoglycaemia have been chlorpropamide and glibenclamide (glyburide), although this is a potential problem with all sulphonylureas because of their action on the pancreatic beta cell, stimulating insulin release. Other specific problems have been reported with chlorpropamide that occur only rarely, if at all, with other sulphonylureas. Hyponatraemia secondary to inappropriate antidiuretic hormone activity, and increased flushing following the ingestion of alcohol, have been well described. The progressive beta cell failure with time results in eventual loss of efficacy, as these agents depend on a functioning beta cell and are ineffective in the absence of insulin-producing capacity. Differences in this secondary failure rate have been reported, with chlorpropamide and gliclazide having lower failure rates than glibenclamide or glipizide. The reasons for this are unclear, but the more abnormal pattern of insulin release produced by glibenclamide may be partly responsible and, indeed, may explain the increased risk of hypoglycaemia with this agent. Previously reported increased mortality associated with tolbutamide therapy has not been substantiated, and more recent data have shown no increased mortality from sulphonylurea treatment. Indeed, benefit from glycaemic control, regardless of the agent used--insulin or sulphonylurea--was reported by the United Kingdom Prospective Diabetes Study. Nevertheless, there is still ongoing controversy in view of the experimental evidence, mainly from animal studies, of potential adverse effects on the heart from sulphonylureas, but these are difficult to extrapolate into clinical situations. Most of these studies have been carried out with glibenclamide, which makes comparison of possible risk difficult. Other cardiovascular risk factors may be modified by gliclazide, which seems unique among the sulphonylureas in this respect. Its reported haemobiological and free radical scavenging activity probably resides in the azabicyclo-octyl ring structure in the side chain. Reduced progression or improvement in retinopathy has been reported in comparative trials with other sulphonylureas, and the effect is unrelated to improvements in glycaemia. There are differences between the sulphonylureas in some adverse effects, risk of hypoglycaemia, failure rates and actions on vascular risk factors. As a group of drugs, they are very well tolerated, but differences in overall tolerability can be identified.     

α2-adrenoceptor regulation of blood glucose homeostasis

The α(2A)-adrenoceptor has been identified as an important regulator of blood glucose homeostasis. α(2A)-Adrenoceptors on pancreatic β-cells inhibit insulin secretion, and α(2A)-adrenoceptors on sympathetic nerves and on adrenomedullary chromaffin cells limit sympathoadrenal output. Recently, human α(2A)-adrenoceptor gene polymorphisms that influence α(2A)-adrenoceptor expression and function have been described. Increased α(2A)-adrenoceptor expression has been associated with impaired glucose-stimulated insulin secretion, elevated fasting blood glucose levels and an increased risk of type 2 diabetes. Accordingly, administration of α(2)-adrenoceptor agonists generally increases blood glucose levels, in spite of the ensuing sympatholysis that would be expected to lower blood glucose as a result of diminished α(1)- and β-adrenoceptor activation. α(2)-Adrenoceptor antagonists increase insulin secretion and reduce blood glucose levels by inhibiting tonically active α(2A)-adrenoceptors on pancreatic β-cells, but may also enhance sympathoadrenal output. In addition, α(2)-adrenoceptor antagonists potentiate the insulinotropic effect of sulphonylurea drugs, pointing to a potentially serious adverse drug interaction when the two classes of drugs are combined. The α(2)-adrenoceptor antagonist atipamezole is widely used in veterinary medicine, and sulphonylureas are prescribed for the treatment of type 2 diabetes in cats and dogs. Even if no dedicated α(2)-adrenoceptor antagonists are in clinical use in humans, some antipsychotic and antidepressant drugs are relatively potent α(2)-adrenoceptor antagonists. In the treatment of type 2 diabetes, α(2)-adrenoceptor agonists could possibly protect against sulphonylurea-induced hypoglycaemia, and α(2)-adrenoceptor antagonist drugs could improve insulin secretion. The potential usefulness of such drugs may vary between individuals, depending on α(2A)-adrenoceptor genetics, sympathetic tone and concomitant pathological conditions, such as cardiovascular disease and obesity.     

Rosiglitazone

Type 2 diabetes mellitus is characterised by impaired insulin secretion, diminished peripheral insulin action and increased hepatic glucose production. Clinical trials have indicated that near-normal glucose control may reduce the risk for microvascular and - to a lesser extent - macrovascular complications in Type 2 diabetic patients. Thiazolidinediones improve insulin action by activating a nuclear receptor, PPARgamma. Therefore, these drugs are often referred to as 'insulin sensitisers'. Rosiglitazone is the second compound of this group. Clinical studies with rosiglitazone have shown that it is effective in lowering blood glucose levels in Type 2 diabetic patients treated with either diet alone, sulphonylurea or metformin. Preliminary studies suggest that rosiglitazone also improves glycaemic control in insulin-treated patients while even slightly decreasing insulin dose. The magnitude of the effects is, however, moderate. In diet-treated patients, the reduction of HbA1c levels amounted on average 0.5 - 1.5% and addition to existing sulphonylurea therapy decreased HbA1c by 1.0 - 1.2%. The clinical relevance of additional beneficial effects, i.e., on blood pressure and microalbuminuria, needs to be determined further. Rosiglitazone does not cause hypoglycaemia or gastrointestinal side effects. There is however some concern related to fluid retention, which seems to be an effect of all PPARgamma agonists. In patients treated with rosiglitazone, no severe hepatotoxic side effects have been noticed until now. In the treatment of our patients with Type 2 diabetes, drugs like rosiglitazone which directly reduce insulin resistance are very welcome but more data on its combined use with insulin are needed. Additional studies will also explore its long-term effects in sparing beta-cell function and reducing diabetes-related complications and atherosclerosis.     

Rosiglitazone and pioglitazone: new preparations. Two new oral antidiabetics both poorly assessed

(1) Treatment of type 2 (non insulin-dependent) diabetes is based on lifestyle measures and management of cardiovascular risk. (2) The reference first-line drug therapy for type 2 diabetes, when drug therapy is needed, is single-agent treatment with metformin (a biguanide) for overweight patients, or with glibenclamide (a glucose-lowering sulphonylurea) for other patients. (3) If monotherapy fails to control blood glucose levels adequately, most clinical guidelines then recommend a combination of metformin with a glucose-lowering sulphonylurea, although the few available comparative clinical data raise the possibility of excess mortality with this treatment. (4) Rosiglitazone and pioglitazone (glitazones that reduce insulin resistance) have been authorized in the European Union for combination with a glucose-lowering sulphonylurea (for patients in whom metformin is ineffective or poorly tolerated) or with metformin (for obese patients). (5) None of the available trials of rosiglitazone and pioglitazone include data on mortality or morbidity. (6) There are fewer data on pioglitazone than on rosiglitazone. (7) According to short-term comparative trials, rosiglitazone and pioglitazone are more effective than placebo on blood glucose levels. Combinations of rosiglitazone or pioglitazone with metformin or with glucose-lowering sulphonylureas have not been compared with the metformin + glucose-lowering sulphonylurea combination or with insulin. (8) Rosiglitazone and pioglitazone frequently cause weight gain. (9) Pioglitazone has a slightly favourable effect on lipid profiles, unlike rosiglitazone, which increases LDL-cholesterol levels. (10) The main side effect of rosiglitazone and pioglitazone is sodium and water retention, which can provoke oedema, anaemia (by haemodilution), and even heart failure. Rosiglitazone and pioglitazone are also hepatotoxic. (11) Combining rosiglitazone with insulin is contraindicated, owing to the increased risk of heart failure. The same applies to pioglitazone. (12) In practice, neither rosiglitazone nor pioglitazone has a place in the management of type 2 diabetes, except in the context of strictly controlled long-term comparative clinical trials.