Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rimonabant (Acomplia) is the first selective CB1 receptor blocker of the endocannabinoid system. Clinical trials showed that, compared to placebo, rimonabant 20 mg/ day consistently increases weight loss, reduces waist circumference, improves atherogenic dyslipidaemia (low HDL cholesterol, high triglycerides, high small dense LDL), diminishes insulin resistance, reduces HbA1c levels, and contributes to lower blood pressure and C-reactive protein levels. Almost half of the most important metabolic effects occur beyond weight loss, suggesting direct peripheral effects of rimonabant, especially in visceral adipose tissue as suggested by the increase in adiponectin levels. Rimonabant at a daily dose of 20 mg is indicated as an adjunct to diet and exercise for the treatment of obese patients, or overweight patients with associated risk factor(s) such as type 2 diabetes or dyslipidaemia. Adverse effects concern digestive tract (nausea, mostly transient) and psychological disorders (depressed mood, anxiety), in relation to the mechanism of action of the drug. Therefore, rimonabant is contra-indicated in case of depression and/or in patients receiving antidepressants.
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PMID:[Medication of the month. Rimonabant (Acomplia): first CB1 receptor antagonist of the endocannabinoid system]. 1830 86

(1) Many drugs are available for the treatment of type 2 diabetes, but only metformin and glibenclamide have a proven impact on morbidity and mortality outcomes (only morbidity in the case of glibenclamide). If monotherapy with one of these drugs is inadequately effective, there is a choice of abandoning strict glycaemic control, combining the two drugs, or adding insulin. (2) Sitagliptin, a glucose-lowering inhibitor of DPP-4 (dipeptidyl dipeptidase 4), the enzyme responsible for catabolising physiological incretins, is the latest addition to the list of oral glucose-lowering drugs. (3) Sitagliptin has not been tested for its effect on morbidity or mortality endpoints. (4) Five placebo-controlled trials lasting from 18 to 24 weeks have evaluated sitagliptin monotherapy (3 trials), sitagliptin combined with metformin, or sitagliptin combined with pioglitazone. These trials showed that sitagliptin induced a limited reduction in glycated haemoglobin levels, which usually remained above the cutoff point (7%) generally used to define proper glycaemic controlled. (5) A trial comparing sitagliptin + metformin versus glipizide + metformin, and a direct comparison of sitagliptin versus glipizide, provided a too low level of evidence to convincingly demonstrate the non-inferiority of the sitagliptin combination. (6) In one trial the sitagliptin + metformin combination was significantly more effective on glycated haemoglobin levels than either drug used alone. (7) In the short term, the main adverse effects of sitagliptin are nausea and constipation. In the long term, there is a risk of infections, especially upper respiratory tract infections. Cases of depression have also been reported. Sitagliptin sometimes increases creatinine levels. Pharmacological data suggest there might be an increased risk of cancer and muscular and neurological disorders. (8) In summary, whether used alone or in combination, the antidiabetic effects of sitagliptin, so far studied on surrogate endpoints, are too modest, given the outstanding safety issues, to recommend its use in patients with type 2 diabetes.
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PMID:Sitagliptin: new drug. Type 2 diabetes: limited efficacy, too many unknown risks. 1835 61

Pramlintide is a synthetic version of the naturally occurring pancreatic peptide called amylin. Amylin and pramlintide have similar effects on lowering postprandial glucose, lowering postprandial glucagon and delaying gastric emptying. Pramlintide use in type 1 and insulin requiring type 2 diabetes mellitus (DM) is associated with modest reductions in HbAlc often accompanied by weight loss. Limited data show a neutral effect on blood pressure. Small studies suggest small reductions in LDL-cholesterol in type 2 DM and modest reductions in triglycerides in type 1 DM. Markers of oxidation are also reduced in conjunction with reductions in postprandial glucose. Nausea is the most common side effect. These data indicate that pramlintide has a role in glycemic control of both type 1 and type 2 DM. Pramlintide use is associated with favorable effects on weight, lipids and other biomarkers for atherosclerotic disease.
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PMID:Pramlintide, the synthetic analogue of amylin: physiology, pathophysiology, and effects on glycemic control, body weight, and selected biomarkers of vascular risk. 1856 11

Exenatide (Byetta) is a synthetic derivative of exendin-4 and an agonist of receptors of glucagon-like peptide-1 (GLP-1). It is resistant to the rapid inactivation by dipeptidylpeptidase-4 and acts as an incretin mimetic. It stimulates insulin secretion by the B cell in a glucose-dependent manner whereas it inhibits glucagon secretion. Exenatide improves mainly postprandial glucose concentrations and lowers glycated haemoglobin (HbA(1c)) levels, without being directly responsible for hypoglycaemia or requiring mandatory home blood glucose monitoring. Furthermore, it slows down gastric emptying and promotes sustained body weight reduction, even in absence of frequently reported nausea following treatment initiation. Exenatide is recommended and reimbursed in Belgium for the treatment of type 2 diabetes, in combination with metformin and a sulfonylurea, in patients not adequately controlled with maximal tolerated doses of these oral glucose-lowering agents. Exenatide is presented as pre-filled pens for subcutaneous injection. The recommended initial dose is 5 microg before morning and evening meals, to be up titrated to 10 microg twice daily. Exenatide may represent a valuable alternative to insulin therapy, especially in overweight or obese patients with type 2 diabetes and not ready to perform home blood glucose monitoring.
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PMID:[Medication of the month... Exenatide (Byetta) incretinomimetic in the treatment of type 2 diabetes after failure and as add-on therapy to oral agents]. 1856 73

The benefits and drawbacks of exenatide as an alternative to insulin in the treatment of poorly regulated type 2 diabetes are reviewed. Exenatide and insulin have equal effects on HbA1c but exenatide causes weight-loss and improved postprandial glucose control. Nausea is reported by nearly half of patients treated with exenatide. Exenatide can be considered in the overweight patient without extremely elevated HbA1c but nausea could pose a substantial hurdle for successful treatment.
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PMID:[Exenatide--an alternative to insulin in the treatment of type 2 diabetes?]. 1882 27

The incretin effect denominates the phenomenon that oral glucose elicits a higher insulin response than intravenous glucose. Glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide are the principal hormones responsible for incretin effect. In patients with type 2 diabetes the incretin effect of these hormones is impaired. Therapeutic approaches for enhancing the incretin action include degradation resistant GLP-1 receptor agonists (incretin mimetics) and inhibitors of dipeptidyl peptidase-IV (DLP-IV) activity (incretin enhancers- gliptins). These groups of medications have similar efficacy with regards to glycaemic improvement (reduction of HbA1c between 0.5 to 1.1%) and have side-effects like nausea. The incretin mimetics are injectable agents and are more likely to reduce weight or be weight neutral when compared to the oral gliptins. Long-term studies are essential to determine the real potential and role of these newer agents in the management of type 2 diabetes.
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PMID:Incretin based therapies for type 2 diabetes mellitus. 1883 49

Pramlintide, the first member of a new class of drugs for the treatment of insulin-using patients with type 2 or type 1 diabetes mellitus, is an analog of the peptide hormone amylin. Amylin is co-secreted with insulin from pancreatic beta cells and acts centrally to slow gastric emptying, suppress postprandial glucagon secretion, and decrease food intake. These actions complement those of insulin to regulate blood glucose concentrations. Amylin is relatively deficient in patients with type 2 diabetes, depending on the severity of beta-cell secretory failure, and is essentially absent in patients with type 1 diabetes. Through mechanisms similar to those of amylin, pramlintide improves overall glycemic control, reduces postprandial glucose levels, and reduces bodyweight in patients with diabetes using mealtime insulin. Reductions in postprandial glucose and bodyweight are important, since postprandial hyperglycemia is associated with an increased risk of microvascular and macrovascular complications, and increased weight is an independent risk factor for cardiovascular disease. Pramlintide is generally well tolerated, with the most frequent treatment-emergent adverse event being mild to moderate nausea, which decreases over time. Pramlintide treatment is also associated with improvements in markers of oxidative stress and cardiovascular risk and improved patient-reported treatment satisfaction. These factors make pramlintide an attractive option for the treatment of postprandial hyperglycemia in patients with diabetes using mealtime insulin.
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PMID:Pramlintide in the treatment of diabetes mellitus. 1899 55

This study assessed the dose-dependent efficacy and safety of exenatide over 12 weeks in Japanese patients with type 2 diabetes suboptimally controlled despite therapeutic doses of sulfonylurea (SU), SU plus biguanide, or SU plus thiazolidinedione. Patients were randomly assigned to placebo (N = 40), 2.5 microg (N = 38), 5 microg (N = 37), or 10 microg (N = 38) exenatide administered subcutaneously twice daily (BID). Patients randomly assigned to 10 microg exenatide received 5 microg BID for the first 4 weeks, with the dose escalated to 10 microg BID for the final 8 weeks. Patients were 60.3 +/- 9.7 years old, with body mass index 25.3 +/- 4.3 kg/m(2) and hemoglobin A1c (HbA1c) 8.0 +/- 0.8%. Baseline-to-endpoint HbA1c changes (%) were +0.02 +/- 0.1 (placebo), -0.9 +/- 0.1 (2.5 microg), -1.2 +/- 0.1 (5 microg), and -1.4 +/- 0.1 (10 microg) (all p < 0.001 vs. placebo). Of patients with baseline HbA1c -7%, 5.1% (placebo), 50.0% (2.5 microg), 71.4% (5 microg), and 79.4% (10 microg) achieved HbA1c <7% at endpoint (p < 0.001, trend test). Baseline-to-endpoint fasting plasma glucose changes (mg/dL) were +6.0 +/- 4.8 (placebo), -18.6 +/- 5.7 (2.5 microg), -25.0 +/- 7.0 (5 microg), and -28.9 +/- 5.9 (10 microg) (all p < or = 0.001 vs. placebo). Treatment-emergent adverse events were mostly mild; dose-dependent increases in incidence were observed for hypoglycemia, nausea, anorexia, decreased appetite, and diarrhea (all p < or = 0.044, trend test). Over 12 weeks, exenatide dose-dependently improved glycemic control in Japanese patients with type 2 diabetes.
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PMID:Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes. 1919 50

Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications. Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB(1) receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin- or sulfonylurea-treated patients with type 2 diabetes and in drug-naive or insulin-treated diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease.
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PMID:The endocannabinoid system: a promising target for the management of type 2 diabetes. 1927 73

Liraglutide is a novel glucagon-like peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence identity to native GLP-1. An amino acid substitution and fatty acid side chain enable a more protracted pharmacokinetic profile of over 24 hours. These modifications make liraglutide suitable for once-daily dosing. Liraglutide use exploits the incretin effect to glucose-dependently stimulate insulin secretion. The LEAD (Liraglutide Effect and Action Diabetes) program evaluated the safety and efficacy of liraglutide and demonstrated an improved level of glycemic control relative to currently used oral antidiabetic drugs, including other GLP-1-based therapies. In these trials, liraglutide was shown to enable many patients to achieve hemoglobin A1c (HbA1c) targets and to improve several morbidities commonly associated with type 2 diabetes; liraglutide induced weight loss, reduced systolic blood pressure and improved beta-cell function. Liraglutide was well tolerated, although an increased incidence of mild nausea was observed. Since liraglutide mimics the glucose-sensitive action of native GLP-1, it does not induce hypoglycemia. Liraglutide offers an interesting alternative therapy to control blood glucose levels in patients with type 2 diabetes, who commonly present with hypertension and overweight. It is expected to be approved by the U.S. Food and Drug Administration and the European Medicines Agency in Europe for use in 2009.
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PMID:Liraglutide: a new treatment for type 2 diabetes. 1934 30


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