Nuevas perspectivas terapéuticas para la Diabetes Mellitus


1: Drugs  2002;62(9):1357-64; discussion 1365-6

Gliclazide modified release.

McGavin JK, Perry CM, Goa KL.

Adis International Limited, Auckland, New Zealand.

Gliclazide modified release (MR) is a new formulation of the drug gliclazide and is given once daily. The hydrophilic matrix of hypromellose-based polymer in the new formulation effects a progressive release of the drug which parallels the 24-hour glycaemic profile in untreated patients with type 2 diabetes mellitus. The formulation shows high bioavailability and its absorption profile is unaffected by coadministration with food. Mean plasma glucose levels are significantly reduced over a 24-hour period in patients with type 2 diabetes mellitus treated with gliclazide MR once daily, in both fasting and postprandial states. No cardiovascular ATP-sensitive potassium channel interaction has been observed at therapeutic concentrations of gliclazide MR. Gliclazide MR has also demonstrated antioxidant properties that are independent of glycaemic control. In a randomised, double-blind, multicentre study, gliclazide MR 30 to 120 mg once daily showed similar efficacy to gliclazide immediate release (IR) 80 to 320 mg/day (in divided doses for doses >80 mg) in patients with type 2 diabetes mellitus over a 10-month period, reducing glycosylated haemoglobin (HbA(1c)) and fasting plasma glucose (FPG) to a similar extent. The drug appeared most efficacious in patients who had previously been treated by diet alone, where significant reductions in HbA(1c) from baseline of 0.9% and 0.95% were seen at 10 and 24 months. Similarly, a sustained effect of gliclazide MR was observed in a subgroup of elderly patients defined a priori; HbA(1c) was decreased to a similar degree to that observed in the general study population. Gliclazide MR showed similar tolerability to gliclazide IR after 10 months' treatment in the randomised trial. The most commonly observed adverse events were arthralgia, arthritis, back pain and bronchitis (each <5%). Bodyweight remained stable. In this study no episodes of nocturnal hypoglycaemia or hypoglycaemia requiring third party assistance were observed during treatment with gliclazide MR. Episodes of symptomatic hypoglycaemia were infrequent, occurring in approximately 5% of patients.

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2: Diabetes Care  2002 Feb;25(2):390-4

Treatment issues in type 2 diabetes.

Bloomgarden ZT.

Diabetes Center, Mount Sinai School of Medicine, New York, NY, USA.

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3: Lancet  2001 Nov 17;358(9294):1709-16

Insulinotropic meglitinide analogues.

Dornhorst A.

Department of Metabolic Medicine, Faculty of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, W12 0NN, London, UK.

The loss of early-phase insulin secretion is an important and early event in the natural history of type 2 diabetes. Because a normal pattern of insulin secretion is essential for the effective control of postprandial metabolism, a rational basis for the development of agents that target early-phase insulin release exists. Conventional oral hypoglycaemic agents do not target, or adequately control, postprandial glycaemia. The emergence of new classes of oral agent with a more specific mode of action provides, for the first time, an opportunity to restore early-phase insulin release. One such drug class is the meglitinide analogues (repaglinide, nateglinide, and mitiglinide). These drugs are ideally suited for combination use with metformin. They could also prove effective in combination with a thiazolidinedione, a drug class that targets insulin resistance. Exogenous insulin is frequently required in the late management of type 2 diabetes. However, one hope for newer combinations of diabetic drugs is that the functional life of the beta cell can be extended, thereby delaying the need for insulin injections.

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4: Endocrinol Metab Clin North Am  2001 Dec;30(4):909-33

Oral therapies for diabetic hyperglycemia.

Lebovitz HE.

Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, New York, USA.

Many classes of oral antihyperglycemic agents are available for the treatment of type 2 diabetic patients. These classes improve glucose metabolism by different mechanisms, and their effects are additive. Therapy with lifestyle modification and a single oral antihyperglycemic agent infrequently achieves target glycemic goals, and, if it does, the effect is usually not sustained. A more rational approach would seem to be therapy with combinations of drugs with different mechanisms of action. Initial therapy might be with submaximal concentrations of two drugs. As the diabetic abnormalities progress, maximal concentrations of the drugs and addition of other classes of oral agents or insulin may be needed to maintain the target glycemic goal. In choosing combinations of oral antihyperglycemic agents, their effects on the components treatment of type 2 diabetic patients. These classes improve glucose considered, as must the specific effects of the agents on glucose metabolism.

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5: Hosp Pract (Off Ed)  2001 Sep 15;36(9):29-36 [Texto completo]

Type 2 diabetes: new drugs, new perspectives.

Goldfine AB.

Joslin Diabetes Center, Boston, USA.

Detection at younger ages is rapidly increasing. Although diet and exercise remain the mainstays of therapy, physicians can now choose from among a variety of medications targeting different pathophysiologic facets of the disease. The newest drugs are the thiazolidinediones, a totally novel class of insulin sensitizers.


6: An Med Interna  2001 Jul;18(7):381-8

Objectives and therapeutic strategy in type 2 diabetes mellitus

Calvo Romero JM, Lima Rodriguez EM.

Servicio de Medicina Interna, Hospital Regional Universitario Infanta Cristina, Badajoz.

United Kingdom Prospective Diabetes Study (UKPDS) has demonstrated definitively that patients with type 2 diabetes mellitus (DM) benefit from intensive blood glucose control, because it diminishes the risk to develop microvascular complications. The therapeutic targets in the type 2 DM have been modified in order to reduce the risk of these complications. However, aggressive treatment may be disastrous for patients with microvascular complications and/or an increased risk of hypoglycemic unawareness, and neither it would be advised in older patients or with short life expectancy. The available drugs for treatment of type 2 DM offer many options for achieving these therapeutic targets, based on the need of the individual patient. In this job we review the targets in the metabolic control of type 2 DM and their backgrounds, and we describe briefly the therapeutic strategy recommended for reaching these targets, with special attention to the new oral antidiabetic agents (repaglinide and thiazolidinediones).

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7: Am Fam Physician  2001 May 1;63(9):1687-8, 1691-2, 1694

Treatment of type 2 diabetes mellitus: a rational approach based on its pathophysiology.

Reasner CA, Defronzo RA.

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8: Diabetes Metab  2001 Apr;27(2 Pt 2):287-93

Type 2 diabetes mellitus: Which place for thiazolidinediones in the therapeutic strategy?

Halimi S.

Service Endocrinologie, Diabetologie, Nutrition CHU de Grenoble, Grenoble, France.

Several new pharmacological agents have recently been developed to optimise the management of type 2 diabetes mellitus. The aim of this article is to briefly review the new therapeutic class: thiazolidinediones (TZD), acting as these insulin sensitizer and to suggest a logical use of these drugs in the guidelines proposed by the french recommendations for the treatment of type 2 diabetic subjects. These agents are now introduced in Europe, only in combination with metformin or sulfonylureas (or glinides). Moreover, some preliminary data indicate that these agents could delay the decrease of insulin secretion by the beta pancreatic cells and could reduce other cardiovascular risk factors often associated with type 2 diabetes: hypertension and lipid abnormalities, by reducing blood pressure, triglycerides and increasing HDL cholesterol. These new drugs bring some hope in the treatment of type 2 diabetic patients in combination with the previous oral anti-diabetic drugs which have recently demonstrated (UKPDS) their ability to prevent or to reduce complications due to diabetes. However the frequency of adverse events must be evaluated in a large use, beyond phase II and III, after the withdrawal of the first TZD introduced on the market (troglitazone).

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9: Geriatrics  2001 Jun;56(6):20-4, 32-3

Type 2 diabetes. How new insights, new drugs are changing clinical practice.

Drexler AJ, Robertson C.

Mount Sinai School of Medicine, Diabetes Center, Mount Sinai Medical Center, New York, NY, USA.

In 1997, the American Diabetes Association recommended a normal fasting blood glucose of < 126 mg/dL as the criteria for diagnosis of type 2 diabetes. Since then, new data have suggested that post-prandial glucose may have a stronger correlation with cardiovascular disease than fasting blood glucose. Two trials, the DCCT and UKPDS, provided evidence of the relationship between hyperglycemia and long-term diabetic complications. Preventing short-term complications, such as cognitive decline, is a more immediate goal and less well-studied. Type 2 diabetes is understood to result most often from insulin resistance and insulin deficiency. New classes of drugs offer expanded therapeutic options for managing this dual metabolic defect. These drugs have invalidated the former therapeutic paradigm of diet, sulfonylureas, and then insulin therapy.

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10: Rev Esp Cardiol  2001 Jun;54(6):751-63 [Texto completo]

Diabetes mellitus, inflammation and coronary atherosclerosis: current and future perspectives

Sanchez-Recalde A, Carlos Kaski J.

Coronary Artery Disease Research Unit, Department of Cardiological Sciences, St. George's Hospital Medical School, London.

Type 2 diabetes mellitus is a condition associated with an increased risk of coronary artery disease. This condition is currently reaching epidemic proportions in the Western world. Epidemiological studies have shown that insulin resistance and the constellation of metabolic alterations associated with type 2 diabetes mellitus such as dyslipidaemia, systemic hypertension, obesity and hypercoagulability, have an effect on the premature onset and severity of atherosclerosis. Albeit direct, the link between insulin resistance and atherogenesis is rather complex. It is likely that its complexity relates to the interaction between genes that predispose to insulin resistance and genes that independently regulate lipid metabolism, coagulation processes and biological responses of the arterial wall. The rapid development of molecular biology in recent years has resulted in a better understanding of the immune and inflammatory mechanisms that underlie insulin resistance and atherosclerosis. For example, it is known that nuclear transcription factors such as nuclear factor kappa beta and peroxisome proliferator-activated receptor are involved in atherosclerosis. The former modulates gene expression which encodes pro-inflammatory proteins vital for the development of the atheromatous plaque. In the presence of insulin resistance there are multiple activating factors that could explain the early onset and severity of atherosclerosis. Glitazones, the new oral antidiabetic drugs and agonists of peroxisome proliferator-activated receptor, have been shown to improve peripheral insulin sensitivity and to also delay atherosclerosis progression in experimental models. Their beneficial effects have been linked to their anti-inflammatory effect.

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11: Drugs Aging  2000 Nov;17(5):411-25

Meglitinide analogues in the treatment of type 2 diabetes mellitus.

Landgraf R.

Diabetes Center, Department of Internal Medicine, University of Munich, Germany.

Type 2 diabetes mellitus is a complex heterogenous metabolic disorder in which peripheral insulin resistance and impaired insulin release are the main pathogenetic factors. The rapid response of the pancreatic beta-cells to glucose is already markedly disturbed in the early stages of type 2 diabetes mellitus. The consequence is often postprandial hyperglycaemia, which seems to be extremely important in the development of secondary complications, especially macrovascular disease. Therefore one of the main aims of treatment is to minimise bood glucose oscillations and attain near-normal glycosylated haemoglobin levels. Meglitinide analogues belong to a new family of insulin secretagogues which stimulate insulin release by inhibiting ATP-sensitive potassium channels of the beta-cell membrane via binding to a receptor distinct from that of sulphonylureas (SUR1/KIR 6.2). The pharmacokinetic and pharmacodynamic properties of repaglinide, the first drug of these new antihyperglycaemic agents on the market, and of nateglinide, which will be available soon, differ markedly from the currently used sulphonylureas [mainly glibenclamide (glyburide) and glimepiride]. Repaglinide and nateglinide are absorbed rapidly, stimulate insulin release within a few minutes, are rapidly metabolised in the liver and are mainly excreted in the bile. Therefore, following preprandial administration of these drugs, insulin is more readily available during and just after the meal. This leads to a significant reduction in postprandial hyperglycaemia without the danger of hypoglycaemia between meals. The short action of these compounds and biliary elimination makes repaglinide and nateglinide especially suitable for patients with type 2 diabetes mellitus who would like to have a more flexible lifestyle, need more flexibility because of unplanned eating behaviour (e.g. geriatric patients) or in whom one of the other first-line antidiabetic drugs, i.e. metformin, is strictly contraindicated (e.g. nephropathy with creatinine clearance < or = 50 ml/min). Meglitinide analogues act synergistically with metformin and thiazolidinediones (pioglitazone and rosiglitazone) and can be also combined with long-acting insulin (NPH insulin at bedtime). Therefore, these drugs enrich the palette of antidiabetic drugs and make the treatment more flexible and better tolerated, which both add to better metabolic control and support the empowerment and compliance of the patient. However, this will only be the case if the patient and the diabetes care team are trained for this new therapeutic schedule and the healthcare system is able to pay for these rather expensive drugs.

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12: Manag Care  2000 Aug;9(8 Suppl):11-7; discussion 24-8

Management of type 2 diabetes: update on new pharmacological options.

Blonde L.

Department of Medicine, Ochsner Clinic, New Orleans, USA.

The value of intensive control of blood glucose levels has been clearly established. Data from the UKPDS demonstrated that improving glycemic control will reduce the risk of microvascular complications of type 2 diabetes, such as diabetic retinopathy, nephropathy, and peripheral neuropathy. Further, the metformin study in overweight patients and the epidemiological analysis of the study both demonstrated a reduction in macrovascular complications and mortality related to improved glycemic control. These findings should enhance awareness among both patients and physicians of the dangers of uncontrolled hyperglycemia and the need for early diagnosis and aggressive treatment for patients with type 2 diabetes. Optimal management of type 2 diabetes most often requires a combination of glucose-lowering medications to achieve glycemic control. Current guidelines for combination therapy advise the use of agents with differing and complementary mechanisms of action in order to maximize therapeutic activity and reduce toxicity. Earlier introduction of combination therapy is increasingly being recommended. The new glyburide/metformin combination medication may facilitate earlier, more appropriate and more effective treatment for patients with type 2 diabetes.

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13: Diabetes Care  1999 Jul;22(7):1209-15

The European Association for the Study of Diabetes Annual Meeting, 1998. Treatment of type 2 diabetes and the pathogenesis of complications.

Bloomgarden ZT.

Division of Endocrinology, Mount Sinai School of Medicine, New York, New York, USA.

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