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.