�Disappointing results of modish treatments of blood glucose which get not convincingly reduced problems, apart from sub-clinical micro-vascular disease
Current drugs offer little evidence that treatment of moderate hyperglycaemia is of benefit to patients.
Concerns about side effect of drugs treating hyperglycaemia associated with obesity
A major barrier to obtaining evidence that long-term treatments are good is the short and often insecure drug patent-life offered by regulatory agencies. Short-termism forces regulators to accept surrogates instead of real clinical benefits
Long-term studies are required to establish the best means of treating diabetes
The need for long full term studies to establish the best means of treating Diabetes, was underlined by Prof John Cleland from the University of Hull at the ESC Congress in Munich. Prof Cleland listed the latest discourse available for patients and voiced his concern about the side-effects and efficacy of available anti-diabetic drugs.
Treating Patients with Diabetes Mellitus
Treatment should be based, wheresoever possible, on the results of studies of substantial size and duration that measure outcomes that are meaningful to patients. We know that treatment of hypertension and hyperlipidaemia reduce progression of micro-vascular disease, reduce vascular events associated with expectant vessel disease and improve the prospect of patients with diabetes.
In contrast, treatment of rip glucose has not convincingly reduced any of these problems, apart from subclinical micro-vascular disease. A major barrier to obtaining evidence that semipermanent treatments ar beneficial is the short and ofttimes insecure drug patent-life offered by regulative agencies.
Short-termism forces regulators to accept surrogates instead of real clinical benefits. This deceives manufacturers, scientists, clinicians and patients into believing that blood glucose control is an important goal of treatment rather than a mere surrogate for real success. Longer patent-life is a pre-requisite for obtaining ripe evidence that any treatment (for diabetes, blood press or lipids) designed to reduce long-term morbidity and mortality is safe and effective. Another alternative is to trammel such studies only to patients with established cardiovascular disease and thus senior high school event rates.
Type 1 Diabetes
Originally, diabetes mellitus was conceived as a syndrome of insulin deficiency, mainly affecting jr. people and often associated with weight loss, glycosuria, ketoacidosis and often rapidly fatal. This syndrome requires insulin replacing therapy, which is still predominantly granted by intermittent subcutaneous injections. The evidence that stringent insulin control is superior to a lax regime is weak.
The largest study, DCCT (n = 1,441), reported no reduction in diabetic keto-acidosis or mortality and only humble reductions in vascular events (21 patients difference afterwards 17 days follow-up) with clear benefits only on subclinical micro-vascular disease. This study was not blinded and we know that unblinded studies tend to over-estimate benefit. More intense insulin therapy was associated with substantive weight reach which may obviate whatsoever cardiovascular benefit of improved diabetes control. Insulin pumps, inhaled insulin and pancreatic islet mobile phone transplants ar potential, only mainly theoretical alternatives. Potentially, very long-run studies are required to establish the best means of treating this disease.
Type II Diabetes
Subsequently, a new population of patients with high insulin levels and hyperglycaemia (insulin-resistance) was identified. These were more than commonly senior patients, weighty and had evidence of other cardiovascular diseases including hypertension and hyperlipidaemia. This population has increased markedly over the last 20 years, partly due to the growing proportion of the population who ar elderly, partially because of the increase in fleshiness and partly because of the diminution in glucose thresholds required for diagnosing. Diabetes of this type does not really represent a distinct disease merely rather just now one end of the spectrum of the population. Blood glucose is continuously distributed in a similar way to blood pressure or spunk rate. For each, thither is an ideal natural range. Levels below this range or markedly to a higher place it causal agency acute malady and moderately elevated levels are associated with worse long-term outcome.
It is a giant effrontery to hint that victimisation drugs to get patients back into the normal range is helpful or safe. We know from experience with other diseases that this assumption is no thirster tenable. Unfortunately, there is remarkably little evidence that treatment of moderate hyperglycemia is of benefit to patients and concerns that treating hyperglycaemia associated with obesity, other perhaps than by treating obesity itself, is safe.
Although the micro-vascular complications of diabetes mellitus are of great fear, few older patients with diabetes subsist long enough to train them. For instance, over 10 years follow-up in the 411 patients of UKPDS-34 managed with low-pitched intensity regimen (to maintain fasting blood glucose
Oral Drugs for Treating Hyperglycaemia
Two major drug classes that have been in use for some decades are biguanides (metformin) and sulphonylureas (eg:- chlorpropamide, gliclazide and glyburide). Metformin reduces hepatic synthesis of glucose (considered its main effect) and increases glucose uptake (insulin sensitivity) of peripheral tissues. There is more evidence for a therapeutic benefit with this agent than any other but even that grounds is not strong. Sulphonylureas increase pancreatic insulin secretion. There is little evidence that these agents thin micro- or macro-vascular complications but they do cause obesity.
Newer Agents
Thiazolidinediones (eg:- Pioglitazone, Rosiglitazone)
These agents increase glucose uptake (insulin sensitivity) in peripheral tissues. They typically reduce HbA1c by 0.5-2% compared to placebo. Two solid trials ingest been reported and several meta-analyses. Overall, these suggest little or no force on clinically relevant outcomes in patients with diabetes mellitus. However, these agents can cause fluid holding that may cause peripheral and/or pulmonic oedema. A trial of pioglitazone (PROACTIVE) did hint some clinical benefit only after undermentioned more than 5,000 patients for 3 years there was only 9 deaths difference between active and control groups.
Alpha-Glucosidase Inhibitors (Precose and Miglitol)
These agents slow the digestion of composite carbohydrates and reduce HbA1c by 0.5 to 1.0%. No adequate trial has been conducted to show that they improve outcome.
Glinides (Repaglinide, Nateglinide)
These agents enhance the release of insulin in response to glucose and therefore mimic normal human physiology. This reduces HbA1c by 0.5-2% compared to placebo. They may be combined with glucophage but are not recommended with sulponylureas, which likewise stimulate insulin release. These are short-acting agents and should be taken ahead meals.
Peptidyl peptidase-IV (DDP-IV) Inhibitors (Sitagliptan, Vildagliptin)
These agents block the degradation of incretins (such as GLP-1 see below). This increases insulin release in response to glucose, may better islet-cell mass and function and better peripheral glucose uptake. They reduce HbA1c by virtually 1% and may shrink weight by 1-2kg. There is no evidence yet that these effects translate into clinical benefits.
New Subcutaneous Agents
Glucagonlike Peptide-I (Incretin) Analogues (GLP-1) (Exenatide, Liraglutide)
In healthy citizenry GLP-1 rises along with insulin in response to food intake. Analogues can be exploited to enhance secretion of endogenous insulin in patients with type II diabetes mellitus. They also retard gastric voidance, may increase beta-cell (insulin producing) mass and enhance uptake glucose in the periphery. Treatment is associated with weight unit loss of up to 4-5kg over 2 old age. HbA1c drops by more or less 1%. There is no evidence that these effects translate into clinical benefits for patients.
Amylin Analogues
Insulin is co-secreted with a peptide called amylin, which delays the surge in blood glucose by slowing gastric voidance and reducing glucose production by the liver. Unlike insulin it suppresses appetency and causes weight passing. Unfortunately, it can make a toxic substance called amyloid in animal models. Accordingly, pramlintide, a synthetical analogue of amylin that should non cause this problem, has been developed which may be co-injected with insulin. Studies intimate a 0.5-1.0% reduction in HbA1c associated with a 1-2kg system of weights loss. There is no evidence that this treatment is efficient, or so safe, for long-term use in patients.
EUROPEAN SOCIETY OF CARDIOLOGY (ESC)
The European Heart House
2035 Route diethylstilbesterol Colles
B.P. 179 - Les Templiers
FR-06903 Sophia Antipolis
http://www.escardio.org
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Friday 5 September 2008
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