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 levels1-3.
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 utilization1, 4-7.
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 unknown1, 8.
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 function1, 9-12 .
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 mechanism1, 13 .
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.
Meglitinides, such as nateglinide and repaglinide, stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in pancreatic beta-cells1, 15,16.
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. Several SGLT2 inhibitors have additional indications for patients with heart failure, cardiovascular disease or multiple cardiovascular risk factors, diabetic nephropathy with albuminuria, and chronic kidney disease 1, 17-22 .
Oral sulfonylureas reduce blood glucose by stimulating insulin from pancreatic beta-cells as well as increasing responsiveness in insulin-sensitive tissues1, 23-28.
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 output1, 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 failure1,2,28,29.
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 thiazolidinediones1, 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.
| Drug Name | Dosage Form/Strength | Therapeutic Indications | Maximum Recommended Dosage |
|---|---|---|---|
| acarbose (generics) | 25 mg, 50 mg, 100 mg tablets | type 2 diabetes |
|
| miglitol (generics) | 25 mg, 50 mg, 100 mg tablets | type 2 diabetes | 300 mg/day, in three divided doses |
| Drug Name | Dosage Form/Strength | Therapeutic Indications | Maximum Recommended Dosage |
|---|---|---|---|
| metformin (generics) | 500 mg, 850 mg, 1000 mg immediate-release tablets | type 2 diabetes | 2550 mg/day |
| metformin (Glumetza, various generics) | 500 mg, 750 mg, 1000 mg extended-release tablets | type 2 diabetes | 2000 mg/day |
| metformin (generics) | 500 mg/5 mL oral solution | type 2 diabetes | 2550 mg/day |
| Drug Name | Dosage Form/Strength | Therapeutic Indication | Maximum Recommended Dosage |
|---|---|---|---|
| colesevelam (Welchol, generic)) | 625 mg tablets | type 2 diabetes | 3.75 g/day, in single or two divided doses |
| colesevelam (Welchol, generic)) | 3.75 g powder packet for oral suspension# | type 2 diabetes | 3.75 g/day as single dose |
Legend:
- # dissolve in 4-8 ounces of water, fruit juice or diet soda and administer with a meal
| Drug Name | Dosage Form/Strength | Therapeutic Indication | Maximum Recommended Dosage |
|---|---|---|---|
| alogliptin (Nesina, generics) | 6.25 mg, 12.5 mg, 25 mg tablets | type 2 diabetes | 25 mg/day |
| linagliptin (Tradjenta) | 5 mg | type 2 diabetes | 5 mg/day |
| saxagliptin (generics) | 2.5 mg, 5 mg tablets | type 2 diabetes | 5 mg/day |
| sitagliptin (phosphate Januvia) | 25 mg, 50 mg, 100 mg tablets | type 2 diabetes | 100 mg/day |
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| bromocriptine (Cycloset) | 0.8 mg tablets | type 2 diabetes mellitus | 4.8 mg/day |
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| semaglutide (Rybelsus) | 3 mg, 7 mg, 14 mg tablets | type 2 diabetes | 14 mg/day |
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| nateglinide (generics) | 60 mg, 120 mg tablets | type 2 diabetes | 360 mg/day, in three divided doses |
| repaglinide (generics) | 0.5 mg, 1 mg, 2 mg tablets | type 2 diabetes | 16 mg/day (in divided doses before meals, up to 4 times daily depending on meal number) |
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| Canagliflozin (Invokana) | 100 mg, 300 mg tablets | type 2 diabetes* | 300 mg/day |
| dapagliflozin (Farxiga) | 5 mg, 10 mg tablets | type 2 diabetes! | 10 mg/day |
| empagliflozin (Jardiance) | 10 mg, 25 mg tablets | type 2 diabetes# | 25 mg/day |
| ertugliflozin (Steglatro) | 5 mg, 15 mg tablets | type 2 diabetes | 15 mg/day |
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; to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease; to reduce the risk of sustained decline in eGFR, end-stage kidney disease, cardiovascular death, and hospitalization in adults with chronic kidney disease at risk of progression
- ^ - FDA approved to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| glimepiride (Amaryl, generics) | 1 mg, 2 mg, 4 mg tablets | type 2 diabetes | 8 mg/day |
| glipizide (generics) | 2.5 mg, 5 mg, 10 mg immediate-release tablets | type 2 diabetes | 40 mg/day |
| glipizide (Glucotrol XL, generics) | 2.5 mg, 5 mg, 10 mg extended-release tablets | type 2 diabetes | 20 mg/day |
| glyburide (generics) | 1.25 mg, 2.5 mg, 5 mg non-micronized tablets | type 2 diabetes | 20 mg/day |
| glyburide (Glynase, generics) | 1.5 mg, 3 mg, 6 mg micronized tablets | type 2 diabetes | 12 mg/day |
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| pioglitazone (Actos, generics) | 15 mg, 30 mg, 45 mg tablets | type 2 diabetes | 45 mg/day |
| Drug Name | Dosage Form/Strength | Treatment Indication | Maximum Recommended Dosage |
|---|---|---|---|
| alogliptin/metformin (Kazano, generics) | 12.5 mg/500 mg, 12.5 mg/1000 mg tablets | type 2 diabetes | 25 mg/2000 mg/day |
| alogliptin/pioglitazone (Oseni, generics) | 12.5 mg/30 mg, 25 mg/15 mg, 25 mg/30 mg, 25 mg/45 mg tablets | type 2 diabetes | 25 mg/45 mg/day |
| canagliflozin/metformin (Invokamet) | 50 mg/500 mg, 50 mg/1000 mg, 150 mg/500 mg, 150 mg/1000 mg tablets | type 2 diabetes* | 300 mg/2000 mg/day in two divided doses |
| canagliflozin/metformin (Invokamet XR) | 50 mg/500 mg, 50 mg/1000 mg, 150 mg/500 mg, 150 mg/1000 mg extended-release tablets | type 2 diabetes* | 300 mg/2000 mg/day once daily |
| dapagliflozin/ metformin (Xigduo XR) | 2.5 mg/1000 mg, 5 mg/500 mg, 5 mg/1000 mg, 10 mg/500 mg, 10 mg/1000 mg tablets | type 2 diabetes! | 10 mg/2000 mg/day once daily |
| dapagliflozin/saxagliptin (Qtern) | 5 mg/ 5 mg, 10 mg/5 mg tablets | type 2 diabetes | 10 mg/5 mg/day once daily |
| empagliflozin/ linagliptin (Glyxambi) | 10 mg/5 mg, 25 mg/5 mg tablets | type 2 diabetes^ | 25 mg/5 mg/day |
| empagliflozin/metformin (Synjardy) | 5 mg/500 mg, 5 mg/1000 mg, 12.5 mg/500 mg, 12.5 mg/1000 mg tablets | type 2 diabetes^ | 25 mg/2000 mg/day in two divided doses |
| empagliflozin/ metformin (Synjardy XR) | 5 mg/ 1000 mg, 10 mg/1000 mg, 12.5 mg/1000 mg, 25 mg/1000 mg extended-release tablets | type 2 diabetes^ | 25 mg/2000 mg/day once daily |
| empagliflozin/linagliptin/metformin (Trijardy XR) | 5 mg/2.5 mg/1000 mg, 10 mg/5 mg/1000 mg, 12.5 mg/2.5 mg/1000mg, 25 mg/5 mg/1000 mg extended-release tablets | type 2 diabetes^ | 25 mg/ 5 mg/ 2000 mg daily |
| ertugliflozin/metformin (Segluromet) | 2.5 mg/500 mg, 2.5 mg/1000 mg, 7.5 mg/500 mg, 7.5 mg/1000 mg tablets | type 2 diabetes | 15 mg/2000 mg/day in two divided doses |
| ertugliflozin/sitagliptin (Steglujan) | 5 mg/100 mg, 15 mg/100 mg tablets | type 2 diabetes | 15 mg/100 mg/day once daily |
| glipizide/ metformin (generics) | 2.5 mg/250 mg, 2.5 mg/500 mg, 5 mg/500 mg | type 2 diabetes |
|
| glyburide/metformin (generics) | 1.25 mg/250 mg, 2.5 mg/500 mg, 5 mg/500 mg tablets | type 2 diabetes | 20 mg/2000 mg/day |
| linagliptin/ metformin (Jentadueto) | 2.5 mg/500 mg, 2.5 mg/850 mg, 2.5 mg/1000 mg immediate-release tablets | type 2 diabetes | 5 mg/2000 mg/day in two divided doses |
| linagliptin/metformin (Jentadueto XR) | 2.5 mg/1000 mg, 5 mg/1000 mg extended-release tablets | type 2 diabetes | 5 mg/2000 mg/day once daily |
| pioglitazone/glimepiride (Duetact, generics) | 30 mg/2 mg, 30 mg/4 mg tablets | type 2 diabetes | 30 mg/4 mg once daily |
| pioglitazone/metformin (ActoPlus Met, generics) | 15 mg/500 mg, 15 mg/850 mg immediate-release tablets | type 2 diabetes | 45 mg/2550 mg/day |
| saxagliptin/metformin (Kombiglyze XR) | 5 mg/500 mg, 5 mg/1000 mg, 2.5 mg/1000 mg extended-release tablets | type 2 diabetes | 5 mg/2000 mg/day |
| sitagliptin/ metformin (Janumet) | 50 mg/500 mg, 50 mg/1000 mg immediate-release tablets | type 2 diabetes | 100 mg/2000 mg/day in two divided doses |
| sitagliptin/ metformin (Janumet XR) | 50 mg/500 mg, 50 mg/1000 mg, 100 mg/1000 mg extended-release tablets | type 2 diabetes | 100 mg/2000 mg/day once daily |
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
- # - Empagliflozin is FDA approved to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease and to reduce cardiovascular death and hospitalization for heart failure in adults with heart failure