Metformin

With over 40 years of use, it has a long safety record and can be taken without risk of significant hypoglycemia. It does not cause weight gain, as many other agents do, and also reduces cardiovascular risk in overweight patients.

 

mechanism

Metformin increases glucose uptake and metabolism; reduces gluconeogenesis in the liver. Accordingly, it does not depend on functioning beta cells.

 

benefits

Metformin has many benefits. These include:

• does not promote weight gain or hypoglycemia
• as montherapy, can reduce HbA1C by 1-2%
• UKDPS 3-4 trial showed dec mortaility (NNT=14)
• decreases triglycerides and LDL, and increases HDL

 

adverse effects

• can be hard on the GI system: diarrhea, nausea, anorexia
• rarely, can increase anaerobic glycolysis and thereby lactic acidosis
• metallic taste, dec. B12 patients,

 

contraindications

• Lactic acidosis in renal/hepatic failure, hypoxemia/hypoperfusion due to pulmonary or cardiac diseases
• Use caution in people with excessive alcohol intake
• 90% renally excreted as unchanged drug; use caution in renal impairment. Use caution if CrCl is under 60, and avoid if under 30

 

 

other

Sulfonylureas

gliclizide, glimepriride (Diamicron), glyburide

 

mechanism

• insulin secretagogue: close K channels on beta cells, leading to increased insulin secretion
• given orally, absorbed from GI tract

 

benefits

• expected decrease 1.0-1.5% HbA1C with monotherapy

 

adverse effects

• can cause vasoconstriction, increased weight gain
• can cause hypoglycemia; though 2nd gen agents such as glicizide decrease this

 

contraindications

Use caution with renal impairment

 

other

 

 

Meglitinides

Meglitinides such as repaglinide and nateglinide are best for post-prandial hyperglycemia.

 

 

mechanism

Rapid-acting insulin secretagogue; faster onset than sulfonylureas and are taken with meals.

 

 

benefits

• close K channels on beta cells, leading to increased insulin secretion

 

 

adverse effects

 

 

contraindications

should be avoided in people with impaired renal function

 

other

 

 

Glitizones

Thiazolidinediones (TZDs) include pioglitazone and rosiglitazone. Expected decrease 1.0-1.5% of A1C monotherapy.

 

 

mechanism

Insulin sensitizers in muscle and adipose tissue.

 

 

benefits

 

 

adverse effects

Do gain weight.

 

 

contraindications

Avoid in patients with CHF, CV disease, hepatic dysfunction, or patients taking insulin.

 

 

other

 

Incretin mimetics

Incretins are gut-produced hormones that act across the body to increase insulin production and sensitivity while reducing glucagon. They can be used alone, or as an adjunct for sulfonylureas or metformin. They are, however, quite expensive.

 

GLP-1 agonists must be injected daily, but lower A1C by 1-1.6% and do not cause hypoglycemia. They may also help some people lose weight.

 

DPP-IV inhibitors are weight-neutral.

Staglitipin (Januvia) is a DPP-IV inhibitor.

Incretin stimulates insulin release and decreased glucagon secretion.

• GLP-1 is proteolyzed by DPP-IV

 

mechanism

 

benefits

 

adverse effects

 

contraindications

 

other

 

 

PPARs (peroxizome proliferator-activated receptor) Agonists

• target PPARγ receptor in adipocytes
• Thiazolidinediones (glitizones)
• insulin sensitizer; need functioning beta cells but does not increase insulin secretion
• works on muscle and fat to increase glucose uptake and metabolism
• lowers lipolysis, causes redistribution of fat from visceral to subcutaneous stores
• does not cause hypoglycemia
• can cause weight gain, possibly fluid-related : beware edema and CHF
• effective in ~70% of new users
• slow onset and off-set (3-4 weeks) due to their activity in the nucleus
• full effects around 12 weeks

mechanism

 

benefits

 

adverse effects

 

contraindications

 

other

 

Alpha-glucosidase Inhibitors (Acarbose)

Competitive inhibitors of alpha-glucosidase in the small intestine brush border, reducing starch breakdown and absorption.

• typically used in combination with sulfonylureas or biguanides
• oral ingestion prior to meal
• prominent side effects, including farting and diarrhea
• appears to help prevent disease in prediabetic patients
• avoid in hepatic dysfunction or IBD

 

mechanism

 

benefits

 

adverse effects

 

contraindications

 

other

 

 

Anti-obesity drugs

Inhibits gastric/pancreatic lipases

 

Miridia - satiety inhibitor

 

 

Glucoagon secretion inhibitors

• slows gastric emptying, decreases appetite