Treatment of the patient with diabetes: importance of maintaining target HbA(1c) levels

OBJECTIVE: To review clinical trial evidence supporting treatment of patients to a near-normal HbA(1c) target level and outline therapeutic strategies that optimize glycemic control. RESEARCH DESIGN AND METHODS: The current MEDLINE database and bibliographies were searched for literature relevant to diabetic complications, glycemic control, and the intensive management of diabetes mellitus. RESULTS: Two randomized trials, the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study (UKPDS), provided evidence that intensive glycemic control obtained with either intensive insulin or oral therapy effectively slowed the onset and progression of diabetic retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. An epidemiologic analysis of the UKPDS results showed a significant correlation between glycemic control and microvascular and cardiovascular disease risk and mortality rates. CONCLUSIONS: The results of clinical trials confirm that stringent levels of glycemic control can be attained through the use of intensive multiple-injection insulin regimens (administration of insulin 3 or more times daily by injection or an external pump with dosage adjustments as needed), oral monotherapy or combination therapy, or a combination of insulin and oral therapy. The expanded choices for oral agents and the availability of insulin analogs now provide physicians with the tools to tailor therapy to prevent or delay the devastating complications of diabetes. Indeed, newer insulin analogs, both short-acting (insulin lispro, insulin aspart) and long-acting (insulin glargine), are an important part of a treatment strategy to circumvent diabetes complications and overcome the shortcomings of conventional insulin preparations.     

The therapeutic potential of islet cell transplant in the treatment of diabetes

Diabetic patients requiring insulin treatment are at an increased risk of developing chronic complications affecting the eye, kidney and heart as well as other disabilities, such as neurological and vascular disease. The Diabetes Control and Complications Trial (DCCT) showed that the development of these complications can be profoundly reduced or even prevented by strict glycaemic control through intensive insulin therapy. The DCCT study, which was concluded in 1993, administered intensive insulin treatment either by multiple (three or four per day) insulin injections or by an external insulin pump. However, it is both stressful and difficult to achieve effective glycaemic control by these methods. Furthermore, intensive insulin administration imposes a significant danger of hypoglycaemia to patients receiving this treatment. Biological replacement of the destroyed insulin-producing B-cells of pancreatic islets, with normal functioning islet transplants, remains the best option with which to achieve strict glycaemic control in diabetic patients requiring insulin treatment. The ultimate goal in transplantation is the unlimited availability of organs/tissues to be transplanted in a simple procedure that requires little or no immunosuppression. Other obstacles have also contributed to the delay in islet transplantation becoming a clinical reality. There are now good methods for isolating long-term functional islets, and it has been proposed that these islets can be immunoisolated by microencapsulation to prevent transplant rejection, an approach that could easily lead to the use of islet xenografts in human diabetic patients. Therefore, the development of microencapsulated islets promises to solve the two major obstacles to clinical islet transplantation, transplant rejection and shortage of human islets. This technique has enormous potential as a viable treatment for diabetic patients requiring insulin therapy to achieve glycaemic control.     

The therapeutic potential of islet cell transplant in the treatment of diabetes

Diabetic patients requiring insulin treatment are at an increased risk of developing chronic complications affecting the eye, kidney and heart as well as other disabilities, such as neurological and vascular disease. The Diabetes Control and Complications Trial (DCCT) showed that the development of these complications can be profoundly reduced or even prevented by strict glycaemic control through intensive insulin therapy. The DCCT study, which was concluded in 1993, administered intensive insulin treatment either by multiple (three or four per day) insulin injections or by an external insulin pump. However, it is both stressful and difficult to achieve effective glycaemic control by these methods. Furthermore, intensive insulin administration imposes a significant danger of hypoglycaemia to patients receiving this treatment. Biological replacement of the destroyed insulin-producing B-cells of pancreatic islets, with normal functioning islet transplants, remains the best option with which to achieve strict glycaemic control in diabetic patients requiring insulin treatment. The ultimate goal in transplantation is the unlimited availability of organs/tissues to be transplanted in a simple procedure that requires little or no immunosuppression. Other obstacles have also contributed to the delay in islet transplantation becoming a clinical reality. There are now good methods for isolating long-term functional islets, and it has been proposed that these islets can be immunoisolated by microencapsulation to prevent transplant rejection, an approach that could easily lead to the use of islet xenografts in human diabetic patients. Therefore, the development of microencapsulated islets promises to solve the two major obstacles to clinical islet transplantation, transplant rejection and shortage of human islets. This technique has enormous potential as a viable treatment for diabetic patients requiring insulin therapy to achieve glycaemic control.     

Treatment of the patient with diabetes: importance of maintaining target HbA1c levels

SUMMARY

Objective: To review clinical trial evidence supporting treatment of patients to a near-normal HbA_1c target level and outline therapeutic strategies that optimize glycemic control.

Research design and methods: The current MEDLINE database and bibliographies were searched for literature relevant to diabetic complications, glycemic control, and the intensive management of diabetes mellitus.

Results: Two randomized trials, the Diabetes Control and Complications Trial and the UK Prospective Diabetes Study (UKPDS), provided evidence that intensive glycemic control obtained with either intensive insulin or oral therapy effectively slowed the onset and progression of diabetic retinopathy, nephropathy, and neuropathy in patients with type 1 and type 2 diabetes. An epidemiologic analysis of the UKPDS results showed a significant correlation between glycemic control and microvascular and cardiovascular disease risk and mortality rates.

Conclusions: The results of clinical trials confirm that stringent levels of glycemic control can be attained through the use of intensive multiple-injection insulin regimens (administration of insulin 3 or more times daily by injection or an external pump with dosage adjustments as needed), oral monotherapy or combination therapy, or a combination of insulin and oral therapy. The expanded choices for oral agents and the availability of insulin analogs now provide physicians with the tools to tailor therapy to prevent or delay the devastating complications of diabetes. Indeed, newer insulin analogs, both short-acting (insulin lispro, insulin aspart) and long-acting (insulin glargine), are an important part of a treatment strategy to circumvent diabetes complications and overcome the shortcomings of conventional insulin preparations.     

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.     

Transitioning pharmacologic therapy from oral agents to insulin for type 2 diabetes

Prospective intervention trials using an intensive therapy approach in patients with either type 1 or type 2 diabetes have provided evidence that achieving tight glycemic control can impede the development and progression of microvascular complications. Treatment of type 2 diabetic patients has revolved around the use of oral agents to improve insulin secretion or tissue sensitization. As therapy turns to the inclusion of insulin - most often in combination with oral agents - the physician and patient must both be prepared for the issues regarding management of an injectable agent. The objective of this article is to review current evidence supporting the benefits of adding insulin therapy to existing oral hypoglycemic regimens of patients for whom these therapies are no longer providing adequate glycemic control. Approaches to initiating insulin therapy and adjusting treatment regimens are discussed, with a view towards making the addition or switch to insulin a simple and achievable next step in treatment.     

Clinical evaluation of inhaled insulin

Diabetes affects over 18.2 million individuals in the United States alone. Current therapy to treat type 1 diabetes relies on subcutaneous insulin administration either by injection or continuous infusion. In addition, patients with type 2 diabetes who fail lifestyle intervention and oral therapy require subcutaneous insulin. Optimal injection protocols to achieve tight metabolic control often prove burdensome to patients. Thus, development of pulmonary insulin delivery to supplement and/or replace subcutaneous insulin injections may be an effective alternative, allowing patients to achieve intensive diabetes management. This review will discuss the devices in development for the delivery of inhaled insulin. In addition, the efficacy of inhaled insulin in both type 1 and type 2 diabetic populations will be discussed. Finally, the available safety data with respect to the unique pulmonary effects of inhaled insulin will be covered.     

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.     

Management of diabetes mellitus medications in the nursing home

Nursing home staff are well aware of the increasing number of residents who experience diabetes mellitus. These residents consume an inordinate amount of resources and often have major disabilities and co-morbidities. Although nonpharmacological therapies, such as consistent carbohydrate intake and increased activity levels, are always indicated in diabetes management, pharmacological therapies are often necessary to prevent the acute complications of diabetes and delay some of the long-term complications. Residents with type 2 diabetes may be managed with oral antidiabetic agents and insulin, whereas residents with type 1 diabetes will always require insulin. Oral antidiabetic agents include insulin secretagogues, which stimulate endogenous insulin secretion and are most effective in leaner persons with type 2 diabetes. Metformin is another oral antidiabetic agent; this decreases inappropriate hepatic glucose release and is most effective in obese residents with high fasting blood glucose levels. The thiazolidinediones, also called glitazones, are insulin sensitisers that enable peripheral tissues to utilise insulin more effectively. The alpha-glucosidase inhibitors delay intestinal absorption of ingested carbohydrates. In addition to oral antidiabetic agents, insulin is frequently used in diabetes management. Insulin is always indicated in type 1 diabetes and is often necessary for residents with type 2 diabetes to optimise glycaemic control. Insulin can be rapid, fast, intermediate or long acting. In addition, basal insulin is now available. These insulins can be combined with each other and, in type 2 diabetes, with oral antidiabetic agents. In order to use pharmacological therapies appropriately, the glycaemic patterns of nursing home residents should be identified, using capillary blood glucose monitoring. Once these patterns have been identified, nonpharmacological therapies can be used, usually in conjunction with the many oral antidiabetic agents and various insulins available, to optimise glycaemic control in each resident.     

Antidiabetic drugs present and future: will improving insulin resistance benefit cardiovascular risk in type 2 diabetes mellitus?

Results from the United Kingdom Prospective Diabetes Study showed that intensive treatment of type 2 (non-insulin-dependent) diabetes mellitus, with sulphonylureas or insulin, significantly reduced microvascular complications but did not have a significant effect on macrovascular complications after 10 years. Insulin resistance plays a key role in type 2 diabetes mellitus and is linked to a cluster of cardiovascular risk factors. Optimal treatment for type 2 diabetes mellitus should aim to improve insulin resistance and the associated cardiovascular risk factors in addition to achieving glycaemic control. Treatment with sulphonylureas or exogenous insulin improves glycaemic control by increasing insulin supplies rather than reducing insulin resistance. Metformin and the recently introduced thiazolidinediones have beneficial effects on reducing insulin resistance as well as providing glycaemic control. There is evidence that, like metformin, thiazolidinediones also improve cardiovascular risk factors such as dyslipidaemia and fibrinolysis. Whether these differences will translate into clinical benefit remains to be seen. The thiazolidinediones rosiglitazone and pioglitazone have been available in the US since 1999 (with pioglitazone also being available in Japan). Both products are now available to physicians in Europe.     

Inhaled human insulin (Exubera): a review of its use in adult patients with diabetes mellitus

Inhaled human insulin (Exubera) (insulin human [rDNA origin]) Inhalation Powder) has recently been approved in the European Union and the US for preprandial use in adult patients with diabetes mellitus. This formulation of insulin has a more rapid onset, but similar duration, of glucose-lowering activity compared with subcutaneously administered regular human insulin.Preprandial inhaled human insulin provided glycaemic control that was comparable to preprandial subcutaneous regular insulin when added to long- or intermediate-acting subcutaneous basal insulin in patients with type 1 diabetes mellitus. Inhaled human insulin is also effective when administered alone, when combined with oral antihyperglycaemic therapy, or when combined with basal subcutaneous insulin in patients with type 2 diabetes mellitus. Comparable rates of hypoglycaemia occurred in patients treated with inhaled human insulin and in those treated with subcutaneous regular human insulin. Patients treated with inhaled human insulin demonstrated a greater decline in pulmonary function (forced expiratory volume in 1 second [FEV(1)], carbon monoxide diffusing capacity [DL(CO)]) than patients treated with comparator antihyperglycaemic agents; the mean difference between the treatment groups that favoured the comparators was noted within the first several weeks of treatment, and did not change over a 2-year treatment period. This agent has also been associated with significant improvements in some quality-of-life and treatment satisfaction scores, especially when compared with subcutaneous mealtime insulin regimens. Inhaled human insulin is an effective and well tolerated formulation suitable for preprandial use in combination with basal subcutaneous insulin in patients with type 1 diabetes. It is also well tolerated and effective in patients with type 2 diabetes when administered alone, when combined with oral antihyperglycaemic therapy, or when combined with basal subcutaneous insulin.     

Insulin therapy in type 2 diabetes

OBJECTIVE: To review the increasingly common use of insulin therapy in patients with type 2 diabetes and the practical aspects of initiating insulin therapy in these patients. DATA SOURCES: Recent scientific and clinical literature identified through MEDLINE searches for the years 1995-2001 using the terms oral agents, type 2 diabetes, insulin therapy, glycemic control and diabetic complications, glucose toxicity, insulin lispro, insulin aspart, and insulin glargine. STUDY SECTION: Reports of key large (1,000 patients or more) and significant smaller, randomized, controlled clinical trials were reviewed. For studies comparing insulin analogs, the authors reviewed a sampling of the identified trials for their characteristics and clinical importance. DATA SYNTHESIS: Tight blood glucose control can help reduce the risk of diabetes complications. Evidence suggests that early insulin therapy can help correct the underlying pathogenetic abnormalities in type 2 diabetes and improve long-term glycemic control. For these reasons, some diabetes experts advocate the initiation of insulin therapy earlier in the course of type 2 diabetes than has been common in the past. Insulin regimens should be designed to mimic the body's natural physiologic secretion of insulin, including the basal amounts released continuously by the pancreas and the insulin surges produced in response to glucose loads. Using new insulin analogs is a useful approach to achieving this ideal. Insulin glargine provides a nearly constant, peakless release of insulin when injected subcutaneously once daily. Two new rapid-acting insulin analogs, insulin lispro (Humalog--Lilly) and insulin aspart (NovoLog--Novo Nordisk), enhance patients' flexibility in terms of meals by permitting injection immediately before meals, rather than 30 minutes before meals, as with regular insulin. CONCLUSION: Patients should be reassured that early initiation of insulin therapy is a positive event that should improve their long-term health and does not represent a decline in the course of their disease.     

Role of antioxidants, essential fatty acids, carnitine, vitamins, phytochemicals and trace elements in the treatment of diabetes mellitus and its chronic complications

Nowadays, the treatment of diabetes mellitus is based on the variable use and combination of diet, antidiabetic oral agents (metformin, sulphanylureas, glynides, acarbose and thiazolidinediones) and insulin or its analogs, depending on the type of diabetes and the needs of the patient. The prevention and treatment of chronic micro- and macrovascular complications, on the other hand, is based on the achievement and maintenance of an optimal glycaemic control and requires the combined use of adjunctive therapy such as antihypertensive drugs and cholesterol-lowering medications. Furthermore, several herbal preparations and dietary supplements, such as antioxidants, essential fatty acids, lipid metabolism activators, vitamins and trace elements, are advertised and prescribed to patients as a useful adjuvant to a diabetic diet and conventional medications in order to improve glycaemic control and reduce the impact of chronic complications. In this regard, we have attempted to review the current concepts dealing with the usefulness of these complementary therapies in treating diabetic patients.     

Inhaled human insulin: new drug. No short-term advantages, too many unknowns in the long term

(1) The standard treatment for type 1 diabetes is intensive insulin therapy, with at least 3 daily subcutaneous injections. Insulin is sometimes useful in type 2 diabetes, in which case the first-line treatment is an injection of isophane insulin at bedtime, in addition to ongoing oral antidiabetic therapy. (2) Pfizer has been granted marketing authorization in the EU for a powdered insulin product for pulmonary inhalation, for the treatment of adults with type 1 or type 2 diabetes. Two dose strengths are available (1 and 3 mg). (3) When inhaled, the insulin powder acts as rapidly as subcutaneous lispro insulin and lasts as long as a standard insulin injection. (4) Inhalation of 1 mg of insulin powder has similar glucose-lowering effects as 3 units of subcutaneous insulin, but inhalation of 3 mg is comparable to 8 units rather than 9 units of injected insulin. Three inhalations of 1 mg each have more glucose-lowering potency than a single inhalation of 3 mg. (5) None of the clinical trials published thus far have assessed the effects of inhaled insulin on clinical complications of diabetes. (6) In patients with type 1 diabetes, 7 randomised trials have compared inhaled insulin plus 1 or 2 subcutaneous injections of long-acting insulin with standard or intensive insulin therapy. They failed to show that intensive insulin therapy consisting of 3 insulin inhalations plus 1 or 2 injections of long-acting insulin reduced the HbA1c concentration or the frequency of hypoglycaemia more effectively than standard insulin therapy consisting of 2 daily subcutaneous insulin injections. (7) In type 2 diabetes, the addition of inhaled insulin has not been compared with the addition of injected insulin in patients whose glycaemia is not controlled by oral antidiabetic therapy. (8) In type 2 diabetes, 3 randomised trials have compared intensive insulin therapy based on inhaled insulin to subcutaneous insulin (2 to 4 daily injections), without oral antidiabetic drugs. The results suggest that glycaemic control is similar with both treatments. (9) The adverse effects of inhaled insulin have been assessed in fewer than 4000 patients participating in clinical trials, fewer than 600 of whom were treated for more than a year. During treatment lasting a few months, the most frequent short-term adverse effects (other than hypoglycaemia) seem to be mild respiratory adverse effects (cough, upper airway infections, etc.). (10) Treatment with inhaled insulin causes a gradual reduction in the peak expiratory flow rate (not convincingly shown to be reversible after the end of treatment) as well as a high incidence of anti-insulin antibodies. The possible long-term clinical consequences of these changes are unknown. The results of planned, long-term comparative trials should be available in 2014-2016. (11) The assessment of inhaled insulin in patients with respiratory disorders is inadequate. The effect of acute respiratory tract infections on the efficacy of inhaled insulin has not been adequately assessed. (12) Smoking (active or passive) and salbutamol, to a lesser extent, have important effects on the efficacy of inhaled insulin. (13) The insulin powder is very sensitive to high humidity, which can occur under normal conditions, leading to a risk of under-dosing. (14) The inhalation device is much larger than an injector pen. It does not permit precise insulin dose adjustment and delivers a maximum of 8 units per inhalation. (15) In practice, the many unknowns concerning the adverse effects of long-term treatment with inhaled insulin powder will probably not be resolved before 2016. In the meantime, subcutaneous injection remains the standard method of insulin delivery.     

Noninjectable methods of insulin administration

Optimal glycemic control is essential for the prevention of diabetes-related complications, and the intensive insulin regimens that best resemble physiological insulin secretion are most likely to attain it. However, there are many limitations that preclude the early use of insulin by patients with type 2 diabetes or wider implementation of the intensive regimens in type 1 diabetes. More acceptable alternative routes of insulin administration and effective, noninvasive, patient-friendly delivery systems that alleviate the burden of insulin injections have been researched over the years. To date, only pulmonary inhalation of insulin has become a feasible alternative; it has proved to be as effective and well tolerated as the subcutaneously injected regular insulin and it has a pharmacodynamic profile well suited for mealtime insulin therapy. Several pulmonary insulin delivery systems are in different stages of development, and one (Exubera, Nektar Therapeutics/Pfizer Inc.-Sanofi-Aventis Group) has already become clinically available in the United States and Europe for patients with diabetes. Other noninjectable methods of insulin administration are reviewed.     

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.     

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.     

Type 1 diabetes: benefits of intensive insulin therapy. Patients should control blood glucose strictly

The DCCT randomised trial compared insulin therapy with strict glycaemic control versus less strict insulin therapy in patients with type 1 diabetes. The trial itself lasted more than 6 years, and most of the patients were subsequently followed up for another 4 years. The initial benefit of strict glycaemic control on the onset or worsening of diabetic retinopathy and nephropathy does appear to persist in the long term     

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.     

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.