diabetes therapy and problems for the cardiologist. quali difficolta pone la terapia diabetologica...
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Diabetes Therapy and Problems for the Cardiologist.
Quali difficolta pone la terapia diabetologica al cardiologo
Mariell Jessup MD, FAHA, FACC, FESCProfessor of Medicine
University of PennsylvaniaPhiladelphia, Pennsylvania
Disclosure: I have no conflicts with respect to this lecture
ADA/EASD 2012 position statementThe American Diabetes Association (ADA) and
the European Association of the Study of Diabetes (EASD)
Metforminmechanism of action
*effective only in the presence of insulin
*major effect is to decrease hepatic glucose output, increases insulin-mediated glucose utilization in peripheral tissues (such as muscle and liver)
*an anti-lipolytic effect that lowers serum free fatty acid concentrations, reducing substrate availability for gluconeogenesis
Metformin advantages
• Promotes weight loss or stabilization of weight
• Lipid lowering activity, decreased triglycerides and free fatty acids
• Less likely to cause hypoglycemia• Works well in combination
Metforminadverse effects
• Gastrointestinal: metallic taste in the mouth, mild anorexia, nausea, abdominal discomfort, and soft bowel movements or diarrhea
• Reduces intestinal absorption of vitamin B12 in up to 30% of patients, and lowers serum vitamin B12 concentrations in 5 to 10%
• Lactic acidosis: most important in renal failure, but heart failure and shock are always cited.– GFR < 60mL/min– Iodinated contrast
ADA/EASD 2012 position statementThe American Diabetes Association (ADA) and
the European Association of the Study of Diabetes (EASD)
Sulfonylureasmechanism of action
• increased responsiveness of beta cells to both glucose and non-glucose secretagogues (such as amino acids), resulting in more insulin being released at all blood glucose concentrations.
• useful only in patients with some beta cell function.
• Drugs in this class: Glipizide, glyburide (glibenclamide), gliclazide, and glimepiride
Sulfonylureasadverse effects: hypoglycemia
■After exercise or a missed meal■When the drug dose is too high■With the use of longer-acting drugs (glyburide, chlorpropamide)■In patients who are undernourished or abuse alcohol■In patients with impaired renal or cardiac function or gastrointestinal disease■With concurrent therapy with salicylates, sulfonamides, fibric acid derivatives (such as gemfibrozil), and warfarin ■After being in the hospital
Increased risk after MI????
ADA/EASD 2012 position statementThe American Diabetes Association (ADA) and
the European Association of the Study of Diabetes (EASD)
Thiazolidinedionesmechanism of action
• bind to and activate peroxisome proliferator-activated receptors (PPARs), which regulate gene expression in response to ligand binding
• increase insulin sensitivity by acting on adipose, muscle, and liver to increase glucose utilization and decrease glucose production
• drugs in this class: troglitazone, pioglitazone, and rosiglitazone.
Thiazolidinedioneseffects and adverse events
• Beneficial effects on :dyslipidemia, markers of inflammation, vascular smooth muscle proliferation, vascular reactivity, endothelial function, carotid intima media thickness, and progression of atherosclerosis on coronary intravascular ultrasound.
• But…weight gain, fluid retention, heart failure, myocardial infarction, and fractures occur
• RECORD trial (3.75 years follow-up) increased risk of HF (HR 2.24)in rosiglitazone combinations compared with metformin plus sulfonylurea.
DPP-4 inhibitorsmechanism of action
• Drugs in this class: sitagliptin, saxagliptin, linagliptin, alogliptin, vildagliptin
• Dipeptidyl peptidase 4 (DPP-4) is a ubiquitous enzyme expressed on the surface of most cell types that deactivates a variety of other bioactive peptides, including GIP and GLP-1; therefore, its inhibition could potentially affect glucose regulation through multiple effects
DPP-4 inhibitorsadverse events
• well tolerated in short-term studies. • no effects on body weight or risk of
hypoglycemia (in the absence of concomitant treatment with insulin or sulfonylureas
• common side effects include: headache, nasopharyngitis, and upper respiratory tract infection
• long-term safety with DPP-4 inhibitors has not been established.
GLP-1 receptor agonistsmechanism of actions
• GLP-1-based therapies affect glucose control through several mechanisms: enhancement of glucose-dependent insulin secretion, slowed gastric emptying, regulation of postprandial glucagon, and reduction of food intake
• Drugs in this class: xenatide, liraglutide, albiglutide, taspoglutide, lixisenatide
GLP-1 receptor agonistseffects and adverse events
• potential benefit: weight loss
• most common adverse events: –nausea, vomiting, and diarrhea–pancreatitis is serious
Diabetes Therapy and Problems for the Cardiologist.
• Since so many of our patients have diabetes, we must learn these new drugs
• Huge controversy over the long-term cardiovascular effects of diabetic drugs
• Edema is common with TZDs; lactic acidosis with metformin is probably not common
• The GLP-1 agonists are potentially useful in HF.
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