1.1. Adults

Alpha glucosidase inhibitors such as acarbose inhibit the ability of alpha glucosidase to convert nonabsorbable dietary starch and sucrose into absorbable glucose, which results in slower glucose absorption and reduced postprandial glucose levels^1-4.

Metformin is an oral biguanide antihyperglycemic agent that improves glycemic control by decreasing hepatic glucose production and intestinal glucose absorption as well as improving insulin sensitivity through increased peripheral glucose uptake and utilization^1,2,5-8.

The bile acid sequestrant, colesevelam, is FDA-approved for use to manage primary hyperlipidemia as well as type 2 diabetes as an adjunct to diet and exercise. The mechanism by which colesevelam lowers hemoglobin A1c (HbA1c) and improves glycemic control is unknown^1,2,9.

DPP-IV inhibitors reduce inactivation of incretin hormones and improve glycemic control in type 2 diabetic patients without significant weight gain. The incretin hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptide (GIP), have been identified as important factors in glucose homeostasis. Released from the gut postprandially, GLP-1 and GIP stimulate insulin secretion from pancreatic beta cells in response to normal or elevated blood glucose concentrations. GLP-1 also lowers glucagon excretion from pancreatic beta cells, which results in reduced hepatic glucose production, reduced appetite, slowed gastric emptying, and improved β-cell function^1,2,10-13 .

Bromocriptine, a dopamine agonist, is FDA-approved as Cycloset® to manage glycemic control in type 2 diabetes as an adjunct to diet and exercise through a currently undetermined mechanism^1,2,14 .

Although GLP-1 agonists are primarily administered as a subcutaneous injection, semaglutide (Rybelsus®) received FDA approval as the first oral GLP-1 agonist used for the management of type 2 diabetes. Of note, semaglutide has not demonstrated a reduction in adverse cardiovascular outcomes while several injectable formulations have^1,2,15,16.

Meglitinides, such as nateglinide and repaglinide, stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in pancreatic beta-cells^1,2,17,18.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors work by inhibiting SGLT2 transporters in the proximal renal tubule and reduce reabsorption of filtered glucose causing increased glucose excretion and lower serum glucose concentrations. Recent studies regarding these medications have provided the support for the addition of new indications. Canagliflozin, empagliflozin, and dapagliflozin have demonstrated a reduction of risk of cardiovascular death and reduction of risk of hospitalization for heart failure in patients with type 2 diabetes. Additionally, canagliflozin and dapagliflozin also have a new indication for the reduction of major cardiovascular events, and reduction of risk of sustained eGFR decline and end-stage renal disease in patients with type 2 diabetes. Empagliflozin and dapagliflozin have additional FDA approvals for patients without type 2 diabetes mellitus^1,2,19-22 .

Oral sulfonylureas reduce blood glucose by stimulating insulin from pancreatic beta-cells as well as increasing responsiveness in insulin-sensitive tissues^1,2,23-27.

Thiazolidinediones are potent agonists of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), receptors important for insulin action which are in adipose tissue, the liver, and skeletal muscle. Activation of these receptors affects the transcription of genes responsible for control of glucose and lipid metabolism. These agents, in the presence of insulin, decrease insulin resistance in the liver and at peripheral sites and improve insulin-dependent glucose disposal and reduce hepatic glucose output^1,2,28,29.

Thiazolidinediones have been associated with an increased risk of congestive heart failure most likely due to a greater incidence of fluid retention/edema associated with this drug class. Patients should be closely monitored for signs and symptoms of CHF, and thiazolidinedione dosages reduced or discontinued should symptoms develop. Thiazolidinediones are contraindicated for use in NYHA Class III or IV heart failure and are not recommended in patients with symptomatic heart failure^1,2,28,29.

Female patients treated with thiazolidinediones may be at increased risk for developing fractures. These agents have been shown to stimulate formation of more adipocytes rather than osteoblasts in bone. Thiazolidinediones may also decrease hip and femoral neck bone mineral density in older diabetic patients. Fractures currently reported with thiazolidinedione use have been limited to the humerus, hand, and foot in female patients only. Further assessment of thiazolidinedione adverse skeletal effects is necessary to determine the risk-benefit ratio of these agents in diabetic patients. Female patients at higher fracture risk should be considered for bone mineral density assessment and bone strengthening therapies (e.g., calcium, vitamin D, bisphosphonates) prior to therapy initiation with thiazolidinediones^1,2,28,29.

Maximum recommended daily doses for available oral antidiabetic agents, both as monotherapy and as combination therapy, are summarized in Tables 1 and 2. Prescribed dosages exceeding these recommendations will be reviewed.

Legend:

• # dissolve in 4-8 ounces of water, fruit juice or diet soda and administer with a meal

Legend:

• * FDA approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease; to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria
• ! FDA approved to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors, reduce the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV), and to reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression
• # FDA approved to reduce the risk of cardiovascular death and hospitalization due to heart failure in adults with heart failure, and to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease 

Legend:

• * FDA approved to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease; to reduce the risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes mellitus and diabetic nephropathy with albuminuria
• ! FDA approved to reduce the risk of hospitalization for heart failure in adults with type 2 diabetes mellitus and either established cardiovascular disease or multiple cardiovascular risk factors, reduce the risk of cardiovascular death and hospitalization due to heart failure in adults with heart failure with reduced ejection fraction (NYHA class II-IV), and to reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression
• ^ Empagliflozin is FDA approved to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease