Diabetes Therapy and Problems
for the Cardiologist.
Quali difficolta pone la terapia
diabetologica al cardiologo
Mariell Jessup MD, FAHA, FACC, FESC
Professor of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Disclosure: I have no conflicts with respect to this lecture
ADA/EASD 2012 position statement
The American Diabetes Association (ADA) and
the European Association of the Study of Diabetes (EASD)
Metformin
mechanism 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
Metformin
adverse 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 statement
The American Diabetes Association (ADA) and
the European Association of the Study of Diabetes (EASD)
Sulfonylureas
mechanism 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
Sulfonylureas
adverse 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 statement
The American Diabetes Association (ADA) and
the European Association of the Study of Diabetes (EASD)
Thiazolidinediones
mechanism of action
• bind to and activate peroxisome proliferatoractivated 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.
Thiazolidinediones
effects 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 inhibitors
mechanism 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 inhibitors
adverse 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 agonists
mechanism 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 agonists
effects 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.