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.     

Miglitol: a review of its therapeutic potential in type 2 diabetes mellitus

Miglitol, the first pseudomonosaccharide alpha-glucosidase inhibitor, smooths postprandial peak plasma glucose levels and thus improves glycaemic control, which is reflected in a reduced glycosylated haemoglobin (HbA1c) level. This oral antihyperglycaemic agent is indicated for the treatment of patients with type 2 diabetes mellitus. Miglitol is generally well tolerated and, unlike the sulphonylurea agents, is not associated with bodyweight gain or hypoglycaemia when administered as monotherapy. The drug is systemically absorbed but is not metabolised and is rapidly excreted via the kidneys. Clinical trials with miglitol (usually 50 or 100 mg 3 times daily) in patients with type 2 diabetes mellitus consistently demonstrated a significant improvement in glycaemic control for periods of 6 to 12 months. There were also marked reductions in postprandial serum insulin levels, although miglitol generally had no effect on fasting insulin levels. In comparative studies miglitol had similar efficacy to acarbose, but at lower therapeutic doses (50 and 100 mg 3 times daily, respectively). In addition, although sulphonylurea agents provided superior reductions in HbA1c levels, miglitol provided similar or superior reductions in fasting and postprandial plasma glucose levels. In combination with other oral antidiabetic agents or insulin, miglitol improved glycaemic control in patients in whom metabolic control was suboptimal despite dietary and pharmacological intervention. Most adverse events associated with miglitol treatment involve disturbances of the gastrointestinal tract (most common effects are flatulence, abdominal pain and diarrhoea). These symptoms are usually dose dependent, mild to moderate in severity, occur at the onset of treatment, decline with time and resolve promptly on discontinuation of the drug or with dosage adjustment. As monotherapy, miglitol is not associated with hypoglycaemia, but concomitant use with other oral antidiabetic agents may necessitate dosage adjustment of the other agents. Miglitol had no significant effects on renal, cardiovascular, respiratory or haematological parameters in long term studies. No dosage adjustments are required in elderly patients, in those with hepatic impairment or in those with mild to moderate renal insufficiency. Conclusions: In long term, well designed trials miglitol reduces fasting and postprandial plasma glucose levels, thus improving glycaemic control, which is reflected in a reduced HbA1c level in patients with type 2 diabetes mellitus. Most adverse events associated with miglitol involve disturbances of the gastrointestinal tract. This agent is a useful first-line therapy in patients with type 2 diabetes mellitus insufficiently controlled by diet alone and as second-line or as adjuvant therapy in those insufficiently controlled with diet and sulphonylurea agents. Miglitol may prove particularly beneficial in elderly patients and those with hepatic impairment or mild to moderate renal impairment, in whom other oral antidiabetic agents are contraindicated or need to be used with caution.     

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.     

Clinical pharmacokinetics and pharmacodynamics of repaglinide

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.     

Pioglitazone and rosiglitazone for diabetes

Pioglitazone (Actos-Takeda) and rosiglitazone (Avandia-GlaxoSmithKline) belong to a new class of oral antidiabetic medicines (the glitazones or thiazolidinediones). Both are licensed in the UK for "oral combination treatment of type 2 diabetes mellitus in [narrowly defined groups of] patients with insufficient glycaemic control despite maximal tolerated dose of oral monotherapy with either metformin or a sulphonylurea". They are not licensed for use as monotherapy, in combination with insulin, or as part of triple therapy with metformin or a sulphonylurea. What can pioglitazone and rosiglitazone offer in the management of patients with type 2 diabetes?     

Cost-effectiveness of oral hypoglycaemic agents for the treatment of type 2 diabetes mellitus

Diabetes is a public health problem worldwide. Its treatment includes controlling hyperglycaemia, initially through changes in lifestyle such as diet, exercise and weight loss. UK Prospective Diabetes Study results showed that intensive treatment to achieve glycaemic control in patients with type 2 diabetes reduces the risk of diabetes-related complications. Typically, patients initially receive monotherapy with oral hypoglycaemic agents but usually progress to combination therapy or insulin. In the short term, the cost of achieving glycaemic control can be substantial, particularly when combination therapy is required. However, additional treatment costs of achieving recommended glycaemic control levels are predicted to be at least partially offset in the long term by the reduction of diabetes-related complications and their related management costs.     

Defining the role of insulin lispro in the management of postprandial hyperglycaemia in patients with type 2 diabetes mellitus

The role of postprandial hyperglycaemia in contributing to the risk of both micro- and macrovascular complications in patients with diabetes mellitus is being increasingly recognized. In type 2 diabetes, there is a progressive shift in the relative contributions of postprandial and fasting hyperglycaemia to the overall glycaemic control as the disease progresses. For patients with fairly good glycaemic control (glycosylated haemoglobin [HbA(1c)] <8.5%), postprandial hyperglycaemia makes a relatively greater contribution to the overall glycaemic load than fasting hyperglycaemia, but in patients with poorer control, the relative contribution of the two states to the overall glycaemic load is reversed. This finding, coupled with epidemiological evidence that elevated postprandial glucose concentration is an independent risk factor for cardiovascular disease (CVD), and is associated with a greater CVD risk than elevated fasting glucose, points to the need to monitor and target postprandial glucose, as well as fasting glucose and HbA(1c) levels, when optimizing insulin therapy for patients with type 2 diabetes. When insulin therapy becomes necessary in patients with type 2 diabetes who can no longer be controlled with oral antihyperglycaemic therapy, use of short-acting insulin analogues with a rapid onset of action and capable of controlling postprandial glycaemic excursions when injected immediately before a meal, has advantages over regular human insulin in that they provide a more favourable time-action profile that mimics normal physiological insulin secretion. Among the available rapid-acting insulin analogues, insulin lispro has been shown to reduce postprandial glucose concentrations to a significantly greater degree than regular human insulin in patients with type 2 diabetes. Moreover, premixed combinations of insulin lispro with the longer acting analogue neutral insulin lispro protamine suspension in 25% : 75% or 50% : 50% combinations are significantly more effective in lowering postprandial blood glucose concentrations than premixed regular human insulin plus neutral protamine Hagedorn (NPH) 30% : 70%. The premixed insulin lispro combinations offer the advantage of fewer daily injections than intensive insulin therapy, and the convenience of not having to mix insulin preparations manually. Although it has yet to be conclusively established that targeting postprandial hyperglycaemia reduces CVD risk, the potential benefits of improved postprandial and interprandial hyperglycaemia favour the use of newer insulin analogues, such as insulin lispro and insulin lispro mixes, over conventional insulin therapy, whenever insulin therapy becomes necessary in patients with type 2 diabetes.     

Feasibility and outcomes of insulin therapy in elderly patients with diabetes mellitus.

The use of insulin in elderly patients raises special considerations. Most people who develop diabetes mellitus late in life have type 2 diabetes mellitus, in which there is some residual endogenous insulin secretion. This pancreatic insulin secretion, when present, stabilises their metabolic status. However, some elderly people lose virtually all their endogenous insulin secretory capacity over time, or may even have type 1 (autoimmune) diabetes mellitus with no endogenous insulin. Generally, older patients with diabetes mellitus can be managed for years, often decades, with nutritional therapy and oral agents. More options exist now than did previously. In addition to a variety of sulfonylureas, there is metformin, troglitazone, and/or alpha-glucosidase inhibitors, that are viable options to be used before turning to insulin. The goals of insulin therapy in the elderly must be considered. When hyperglycaemia causes symptoms (polyuria, polydypsia and bodyweight loss) blood glucose levels are generally >200 mg/dl, and insulin is needed if maximal doses of oral agents have been used. Insulin is also indicated when hyperglycaemia puts patients at risk of hyperosmolar states, for example, when blood glucose is >300 mg/dl during a normal day. Clinical judgement dictates whether to use insulin to control glycaemia in the attempt to avoid long term complications such as neuropathy, retinopathy or nephropathy. In people with relatively short life expectancy, major comorbities and no sign of diabetic complications, the risk may be small. On the other hand, in patients for whom neuropathy, in particular, is a major risk, controlling glycaemia (with insulin if necessary) does reduce that risk. Most patients with type 2 diabetes mellitus can be managed with relatively simple insulin regimens thanks to their endogenous insulin secretion. A single bedtime dose of neutral protamine Hagedorn (NPH) insulin, with or without continuation of daytime oral agents, may control fasting blood glucose. A pre-mix combination of NPH and Regular insulin such as 70/30 or 50/50 may be used pre-meal. More customised, 'intensive' insulin regimens are needed when the glycaemia is unstable. Hypoglycaemia is clearly the most significant risk of insulin therapy. If mild and easily treated, it is of no real concern. On the other hand, nocturnal hypoglycaemia, and, in particular, hypoglycaemia unawareness, are clear signs that the insulin regimen should be modified. In summary, insulin therapy may be necessary, and can be used effectively, in elderly patients. However, risk:benefit considerations must be taken into account when deciding which patients to treat with insulin and what insulin regimen to use.     

Troglitazone: a review of its use in the management of type 2 diabetes mellitus

Troglitazone is the first of a new group of oral antidiabetic drugs, the thiazolidinediones, and is indicated for the treatment of patients with type 2 (non-insulin-dependent) diabetes mellitus. Troglitazone acts by enhancing the effects of insulin at peripheral target sites and, unlike the sulphonylurea drugs, is not associated with hypoglycaemia when administered as monotherapy. Clinical trials with troglitazone (usually 200 to 600 mg/day) in patients with type 2 diabetes mellitus consistently showed marked improvement in glycaemic control, as well as reductions in fasting serum insulin, C-peptide and triglyceride levels. Comparative studies with either glibenclamide (glyburide) or metformin indicated similar glycaemic control with troglitazone or these agents. Serum insulin levels were lower with troglitazone than with glibenclamide. Clinical trials of up to approximately 2 years' duration showed that glycaemic control is maintained with troglitazone on a long term basis. In general, troglitazone is well tolerated by the majority of patients. However, discontinuation of troglitazone because of elevated liver enzyme levels occurs in approximately 2% of patients receiving the drug, and frequent monitoring of liver enzymes is required (e.g. at least 11 times during the first year of therapy). Among patients who started troglitazone therapy in 1998 (after the incorporation of a boxed warning and increased monitoring requirements in the product labelling), the estimated risk of liver-related death is approximately 1 in 100,000. CONCLUSIONS: Troglitazone improves the ability of target cells to respond to insulin. The drug has been shown to improve glycaemic control in patients with type 2 diabetes mellitus when used as monotherapy or in combination with other oral antidiabetic drugs or insulin, and its efficacy is similar to that of glibenclamide or metformin. Although troglitazone is generally well tolerated, close monitoring of liver enzyme function is required to minimise the rare occurrence of serious hepatic dysfunction. Drug acquisition and liver function monitoring costs, as well as potential adverse effects, are important factors that may ultimately determine the precise place of troglitazone in the management of type 2 diabetes mellitus. Nevertheless, as the first member of a new class of oral antidiabetic agents, the thiazolidinediones, troglitazone offers an effective treatment option in patients with type 2 diabetes mellitus through its action of improving insulin sensitivity.     

Treatment of type 2 diabetes: inadequate assessment of oral antidiabetic combinations

(1) Metformin and glibenclamide are the only oral antidiabetics with a proven impact on the complications of type 2 diabetes. (2) Treatment with one of these drugs often fails to achieve the recommended target in HbA1c level (below 7%). (3) Only one randomised trial has assessed the preventive efficacy of a combination of oral antidiabetics when hyperglycaemia persists despite treatment with a glucose-lowering sulphonylurea. The trial showed that combining metformin and a glucose-lowering sulphonylurea is associated with a higher mortality than therapy with a sulphonylurea alone. (4) Despite this result, most clinical guidelines recommend the metformin + glucose-lowering sulphonylurea combination when oral antidiabetic monotherapy fails. (5) In the absence of convincing data supporting any particular strategy, all options should be discussed with patients including continuing with oral antidiabetic monotherapy, or starting insulin.     

Evolving strategies for insulin delivery and therapy

It has now been conclusively proven that adequate control of blood glucose delays or prevents the progression of diabetic complications. In order to achieve the suggested targets for glycaemic control necessary to reduce the incidence of diabetic complications, it has been established that a more intensive insulin regimen requiring multiple insulin injections is required for patients with type 1 diabetes mellitus. For patients with type 2 diabetes, oral antidiabetic therapy is generally used initially, but given the natural history of type 2 diabetes and the need to achieve improved glycaemic control, earlier use of insulin has been promoted. However, the use of insulin in more intensive regimens for the patient with type 1 diabetes or for earlier treatment of the patient with type 2 diabetes is not routine. Many factors are responsible for this observation. Nevertheless, available device options such as insulin pens or insulin pumps are routinely available for implementation of intensive insulin therapy. However, a major limitation for advancing to intensive insulin therapy is that the only viable way to administer insulin is through injection. Delivery options that use dermal, nasal and oral approaches have been explored. The oral approach may include gastrointestinal, buccal or pulmonary uptake. Recent evidence shows that delivery of insulin via the oral cavity with uptake occurring in the pulmonary alveoli may be the most viable clinical option in the future.     

Insulin in type 2 diabetes: a useful alternative despite limited assessment based on surrogate endpoints

(1) There are few clinical trials comparing combination therapy with a sulphonylurea and metformin after oral antidiabetic monotherapy fails to provide adequate glycaemic control. The UKPDS study suggested that this combination had a negative impact on mortality. (2) The assessment of insulin therapy in patients in whom oral antidiabetic therapy fails is based solely on surrogate endpoints: mainly HbA1c (glycated haemoglobin), bodyweight, and the frequency of hypoglycaemia. (3) In a comparative randomised trial involving patients whose glucose levels were no longer controlled by a sulphonylurea, the addition of metformin or a daily injection of insulin isophane (NPH) was similarly effective in reducing HbA1c levels. However, metformin caused less weight gain. (4) There are no randomised controlled trials comparing the addition of insulin versus a sulphonylurea when ongoing metformin monotherapy is inadequate. (5) Randomised comparative trials show that, when glycaemia is no longer controlled by a sulphonylurea plus metformin, adding a daily insulin injection is more effective in lowering HbA1c levels than the addition of acarbose and as effective as adding a glitazone. The adjunction of insulin appears to have a better risk-benefit balance than an oral three-drug regimen. (6) Several randomised controlled trials have shown that the addition of an oral antidiabetic to ongoing insulin therapy reduces HbA1c levels in patients with type 2 diabetes. The addition of metformin is also beneficial in terms of body weight changes. (7) Nine randomised controlled trials involving patients whose glycaemia was inadequately controlled by a sulphonylurea, alone or in combination with metformin, have compared the addition of a bedtime injection of insulin isophane versus replacement of the oral antidiabetics by several daily insulin injections. The two strategies had a similar impact on HbA1c (-1.5% to -2.5%), but patients experienced less weight gain when the oral antidiabetics were continued and a single insulin injection was added. (8) The few available comparative trials fail to show which oral treatment (a sulphonylurea, metformin, or a combination of the two) has the best risk-benefit balance when combined with a bedtime injection of insulin isophane. (9) Insulin isophane is the first-choice insulin for combination therapy with an oral antidiabetic. In comparative trials, when combined with an oral antidiabetic, insulin glargine was no more effective than insulin isophane in terms of HbA1c levels or weight gain. Insulin glargine seems to provoke less hypoglycaemia but, in the absence of adequate follow-up, its long-term adverse effects are not known. (10) When a bedtime insulin injection plus an oral antidiabetic fail to control hyperglycaemia, indirect comparisons support the use of several daily insulin injections plus metformin, or three injections of an ultrarapid insulin analogue plus a sulphonylurea.     

Sulphonylurea antidiabetic drugs. An update of their clinical pharmacology and rational therapeutic use

Apart from the amelioration of symptoms, a major aim of the treatment of non-insulin-dependent diabetes mellitus (NIDDM, type 2 diabetes) should be the prevention of cardiovascular complications. These are associated with the chronic hyperglycaemia that is characteristic of NIDDM, and the risk of complications is already increased in subjects with impaired glucose tolerance (IGT). For these reasons, and because hyperglycaemia appears to be a self-perpetuating condition, treatment should be introduced as early as possible and should be aimed at normalisation of blood glucose. To enable early detection and intervention, screening is necessary. As diet regulation alone rarely suffices to normalise blood glucose, addition of sulphonylurea drugs is indicated in many cases. If introduced in the IGT phase, sulphonylureas drugs combined with diet regulation may postpone the development of IGT to manifest NIDDM, and may reduce the increased risk of cardiovascular morbidity and mortality. Sulphonylureas stimulate insulin release, possibly via interaction with receptors in the pancreatic B cells. In addition, such treatment enhances the reduced insulin action. This might be a primary effect but is also a consequence of the increased access to insulin and the subsequent reduction of hyperglycaemia. Sulphonylureas may enhance insulin availability by reducing insulin clearance. Effects on blood lipids are probably secondary phenomena. Fast and short acting sulphonylureas may improve the impaired meal-induced acute insulin release. If combined with weight-reducing diet regulation and introduced early, such treatment can maintain (near) normal blood glucose levels and an improved insulin action for several years without increasing basal insulin secretion, without chronic hyperinsulinaemia, and without weight increase. If not combined with diet regulation, sulphonylurea therapy is likely to fail. If introduced when NIDDM is advanced, the efficacy of these drugs is limited, with secondary failures developing at a rate of 5 to 10% per year. Continuous (24-hour-a-day) exposure to drug treatment could possibly desensitise the B cell to sulphonylurea stimulation. 'Second-generation' sulphonylurea drugs have a higher potency than 'first-generation' drugs, but this need not signify a greater clinical efficacy. The effect of several of these drugs may be increased if they are ingested half an hour before meal(s). Short acting sulphonylureas may be safer than long acting ones, which seem more likely to cause long lasting and fatal hypoglycaemia, at least in elderly patients.(ABSTRACT TRUNCATED AT 400 WORDS)     

Increasing awareness of hypoglycaemia in patients with Type 2 diabetes treated with oral agents

Abstract

Hypoglycaemia is the most common acute complication of type 2 diabetes and can limit therapeutic efforts to improve glycaemic control in order to protect against long-term complications. It is a potential side effect of the drugs used to treat diabetes, specifically exogenous insulin or insulin secretagogues. As many people are prescribed these agents, hypoglycaemia is frequent in clinical practice, although patients commonly do not inform their healthcare professional of the problems spontaneously. The impact of hypoglycaemia on the patient and to the healthcare system is significant through reduced treatment satisfaction and adherence, reduced quality of life and serious health consequences. This has financial implications and costs for the patient, the public and the economy at large.

The single most important risk factor for hypoglycaemia is previous hypoglycaemia. Prevention depends on appropriate education regarding diabetes management and selfcare, self-monitoring of blood glucose, awareness of factors that may precipitate hypoglycaemia, and an individualized approach to therapy and glycaemic control targets.

The purpose of this review is to increase understanding of the impact and consequences of hypoglycaemia, in particular that associated with sulphonylurea therapy, and to highlight areas requiring more attention in order to improve the overall management of people with type 2 diabetes.     

Pioglitazone, rosiglitazone, and rosiglitazone + metformin: new drugs. Glitazone + oral antidiabetic combination: inadequately evaluated

(1) When single-agent therapy provides inadequate glycaemic control for patients with type 2 diabetes, most guidelines recommend metformin in combination with a glucose-lowering sulphonylurea as standard treatment, despite the lack of any proven impact on morbidity or mortality. Other options include switching to insulin or abandoning the target of strict glycaemic control. (2) Pioglitazone and rosiglitazone are approved for use in combination with a glucose-lowering sulphonylurea when metformin is poorly tolerated or contraindicated, and in combination with metformin in overweight patients. (3) A fixed-dose combination containing 1 or 2 mg of rosiglitazone plus 500 mg of metformin (hydrochloride) was launched onto the French market in October 2004. (4) The indication for rosiglitazone was extended to include its use as triple-agent therapy in combination with metformin and a glucose-lowering sulphonylurea. (5) No clinical trials assessing effects on mortality or morbidity have evaluated rosiglitazone or pioglitazone in combination with other oral antidiabetic drugs. (6) Several trials have compared the glucose-lowering effects of dual-agent therapy using rosiglitazone or pioglitazone plus a glucose-lowering sulphonylurea or metformin versus dual-agent therapy with metformin and a glucose-lowering sulphonylurea. (7) These clinical trials indicate that in terms of HbA1c level, dual-agent therapy based on rosiglitazone or pioglitazone is about as effective as combination therapy with metformin plus a glucose-lowering sulphonylurea. (8) The main known adverse effect of pioglitazone and rosiglitazone is water-sodium retention, which can provoke oedema and haemodilution anaemia, and can aggravate or reveal heart failure. (9) Pioglitazone has a positive effect on the lipid profile, whereas rosiglitazone increases the LDL-cholesterol level. (10) Dual-agent therapy with pioglitazone and a sulphonylurea causes more weight gain than metformin plus a sulphonylurea. (11) Several trials have assessed triple-agent regimens containing a glitazone. Three placebo-controlled double-blind trials have tested pioglitazone (one trial, nearly 300 patients) or rosiglitazone (two trials, about 1200 patients) for 12 to 26 weeks in patients whose glycaemia was poorly controlled by dual-agent therapy with a sulphonylurea plus metformin. The glycated haemoglobin level fell by 0.3% to 1.1% (in absolute values), depending on the trial and the dosage, but at a cost of the usual adverse effects such as weight gain, anaemia and oedema. Three unblinded trials have compared oral triple-agent regimens containing glitazone versus insulin plus metformin, alone or in combination with a glucose-lowering sulphonylurea; the treatment including glitazone was no more effective in terms of the glycated haemoglobin level, but was associated with an increase in adverse effects and dropouts. (12) Given the limited clinical data available in early 2005, pioglitazone and rosiglitazone have no place in the management of type 2 diabetes.     

Bodyweight changes associated with antihyperglycaemic agents in type 2 diabetes mellitus.

The majority of patients with type 2 diabetes mellitus are overweight or obese at the time of diagnosis, and obesity is a recognised risk factor for type 2 diabetes and coronary heart disease (CHD). Conversely, weight loss has been shown to improve glycaemic control in patients with type 2 diabetes, as well as to lower the risk of CHD. The traditional pharmacotherapies for type 2 diabetes can further increase weight and this may undermine the benefits of improved glycaemic control. Furthermore, patients' desire to avoid weight gain may jeopardise compliance with treatment, thereby limiting treatment success and indirectly increasing the risk of long-term complications. This review evaluates the influences of established and emerging therapies on bodyweight in type 2 diabetes.Improvement in glycaemic control with insulin secretagogues has been associated with weight gain. On the other hand, biguanides such as metformin have been consistently shown to have a beneficial effect on weight; metformin appears to modestly reduce weight when used as a monotherapy. alpha-Glucosidase inhibitors are considered weight neutral; in fact, the results of some studies show that they cause reductions in weight.Thiazolidinediones (TZDs) are typically associated with weight gain and increased risk of oedema, while the impact of some TZDs, such as pioglitazone, on lipid homeostasis could be beneficial. Insulin, the most effective therapy when oral agents are ineffective, has always been linked to significant weight gain. Newly developed insulin analogues can lower the risk of hypoglycaemia compared with human insulin, but most have no advantage in terms of weight gain. The basal analogue insulin detemir, however, has been demonstrated to cause weight gain to a lesser extent than human insulin. The emerging treatments, such as glucagon-like peptide-1 agonists and the amylin analogue, pramlintide, seem able to decrease weight in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 inhibitors seem to be weight neutral.In summary, while reduction of hyperglycaemia remains the foremost goal in the treatment of patients with type 2 diabetes, the avoidance of weight gain may be a clinically important secondary goal. This is already possible with careful selection of available therapies, while several emerging therapies promise to further extend the options available.     

The management of diabetes mellitus in older individuals.

Nearly 50% of individuals with type II diabetes mellitus are over the age of 65 years. There are numerous reasons to maintain blood glucose levels below 11.1 nmol/L (200 mg/dl) in older persons, and there are a number of changes often seen with advancing age that persons, and there are a number of changes often seen with advancing age that may interfere with the management of diabetes mellitus, e.g. hypodipsia, anorexia, visual disturbance, altered renal and hepatic function, depression, impaired basoreceptor response and multiple medications. Hyperglycaemia appears to produce cognitive impairment which may lead to poor compliance. It is often difficult to manipulate diet in older people, and in fact dietary changes can lead to severe protein energy malnutrition. High maximum voluntary oxygen intake has been correlated with increased glucose disposal, but there is little evidence that physical exercise can improve diabetic control in the elderly. Oral sulphonylurea hypoglycaemic agents are extremely useful in the treatment of diabetes in these patients, but it should be remembered that they are more liable to develop hypoglycaemia than are younger diabetics. The role of metformin in the management of older diabetic patients is poorly studied. Many older persons can cope well with insulin therapy, but those with visual disturbances often make errors when drawing up insulin and require special attention. Combination therapy of insulin with oral hypoglycaemic agents is not recommended in this group of patients, and serum fructosamine is preferred to glycated haemoglobin to monitor control. Successful management of elderly diabetic patients thus requires an interdisciplinary team approach.     

Novel drug delivery systems for insulin: clinical potential for use in the elderly

Diabetes mellitus is a very common disease in the elderly and its complications are responsible for excess morbidity/mortality, loss of independence and impaired quality of life. Recent studies, while not performed in the elderly, have outlined the importance of achieving tight glycaemic control in order to prevent complications. Eighty years after its discovery, subcutaneous insulin remains a major treatment for diabetes. It is used as a first-line agent in type 1 diabetes, and in type 2 diabetes when oral antihyperglycaemic agents combined with diet and exercise fail to achieve an appropriate metabolic control. To avoid injections, other routes of insulin administration have been studied, including oral, dermal and rectal routes but they were not found to be appropriate for clinical use. Buccal or nasal insulin combined with absorption enhancers proved to have interesting properties. Inhaled insulin appears to be suitable for use in patients with diabetes because of its better bioavailability and a pharmacokinetic profile that mimics the time kinetics of insulin secretion after a meal. Clinical studies were conducted among small numbers of patients with type 1 or type 2 diabetes who had been treated with subcutaneous insulin. Inhaled insulin was given three times daily, just before meals, and was combined with a bedtime subcutaneous injection of long-acting insulin. In patients with type 1 or type 2 diabetes the metabolic control achieved with inhaled insulin was similar to that obtained with a subcutaneous insulin regimen. Tolerance of inhaled insulin was good and treatment satisfaction was better than that with the subcutaneous regimen. Insulin inhalation appears to be an interesting way of insulin delivery for elderly patients with diabetes. However, no studies have been conducted in elderly patients with diabetes to assess this route's acceptability, convenience and ease of use in this particular population. In addition, it is necessary to conduct pharmacokinetic studies in the elderly because lung aging might reduce the bioavailability of inhaled insulin.     

Management of Type 2 diabetes: the role of incretin mimetics

Type 2 diabetes is characterised by insulin resistance and progressive β-cell dysfunction (which leads to hyperglycaemia), the risk of progressive worsening of glycaemic control and an increased risk of both macrovascular and microvascular complications. Existing treatment strategies target deficient insulin secretion and insulin resistance, but do not generally address the underlying progressive β-cell dysfunction that is common to Type 2 diabetes. Traditionally, Type 2 diabetes is first treated with medical nutrition therapy (reduced food intake and increased physical activity), followed by stepwise addition of oral antidiabetes therapies and, ultimately, exogenous insulin, as required. Unfortunately, these approaches have not been shown to delay the need for additional therapies, nor do they generally prevent or delay the inexorable decline in β-cell function. Patients with Type 2 diabetes commonly experience deterioration in glycaemic control, and may have substantial weight gain due to the diabetes therapies that contribute to worsening obesity. In addition, insulin-providing therapies, such as sulfonylureas and exogenous insulin, carry the risk of hypoglycaemia, and cannot fully address the complex hormonal irregularities that characterise Type 2 diabetes, including the role of glucagon hypersecretion. New therapeutic approaches are being developed that couple durable glycaemic control with improved control of body weight. These approaches include development of the incretin mimetics, which are a novel class of agents that share several of the glucoregulatory effects of incretin hormones, such as glucagon-like hormone-1. Deficiency of glucagon-like hormone-1 secretion is known to be present in those with abnormal glucose tolerance. Agents that manipulate the physiological actions of incretin hormones, such as glucagon-like hormone-1, may significantly benefit patients with Type 2 diabetes.     

Insulin aspart: a review of its use in the management of type 1 or 2 diabetes mellitus

Insulin aspart (NovoRapid, NovoLog) is a short-acting insulin analogue, which has a faster onset and shorter duration of action than regular human insulin. Insulin aspart administered immediately before meals provided significantly greater improvements in glycosylated haemoglobin and better postprandial glycaemic control than regular human insulin administered 30 minutes before meals, when used in a basal-bolus regimen with neutral protamine Hagedorn (NPH) insulin, in randomised, nonblind studies in patients with type 1 diabetes mellitus. In patients with type 2 diabetes, insulin aspart provided similar glycaemic control to regular human insulin, administered in a basal-bolus regimen with NPH insulin. Small studies suggest that the use of insulin aspart in combination with oral hypoglycaemic agents may be beneficial. Insulin aspart, administered by continuous subcutaneous insulin infusion (CSII) provided better glycaemic control than insulin aspart multiple daily injection regimens in patients with type 1 (but not type 2) diabetes, and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Limited studies show insulin aspart to be effective in children, adolescents and young adults with type 1 diabetes. Insulin aspart had a tolerability profile similar to that of regular human insulin in clinical trials. The incidence of major or nocturnal hypoglycaemic events reported in patients receiving insulin aspart was lower than that of regular human insulin in several studies.In conclusion, insulin aspart, administered immediately before meals in a basal-bolus regimen with NPH insulin, provided better long-term glycaemic control than regular human insulin administered 30 minutes before meals in patients with type 1 diabetes, and was as effective as regular human insulin in patients with type 2 diabetes. A significantly lower risk of hypoglycaemia was seen in several trials. Insulin aspart CSII provided better glycaemic control than insulin aspart multiple daily subcutaneous injection (MDI) in patients with type 1 (but not type 2) diabetes and had similar efficacy to CSII with insulin lispro or regular human insulin in type 1 diabetes. Insulin aspart is an effective and well tolerated alternative to regular human insulin and insulin lispro for the maintenance of glycaemic control in patients with type 1 or 2 diabetes.