Anti-diabetic Agents (oral)

Last Updated

Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.

  • Revision history
    • October 21, 2022; September 2020; September 2018; September 2016; August 2014; July 2014; October 2012; January 2011; February 2008; November 2007; June 2003; July 2002; September 2001; June 2001; June 2000; July 1999; June 1998; June 1997; June 1996; September 1995. 
  • Initially developed
    • April 1994

1. Dosage

Oral antidiabetic agents are FDA-approved for use in patients with type 2 diabetes as monotherapy or in combination with other oral antidiabetic agents or insulin, when the single agent alone, in addition to diet and exercise, does not provide sufficient glycemic control.

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 levels1-4.

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 utilization1,2,5-8.

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 unknown1,2,9.

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 function1,2,10-13 .

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 mechanism1,2,14 .

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 have1,2,15,16.

Meglitinides, such as nateglinide and repaglinide, stimulate insulin secretion by inhibiting ATP-sensitive potassium channels in pancreatic beta-cells1,2,17,18.

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 mellitus1,2,19-22 .

Oral sulfonylureas reduce blood glucose by stimulating insulin from pancreatic beta-cells as well as increasing responsiveness in insulin-sensitive tissues1,2,23-27.

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 output1,2,28,29.

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 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 thiazolidinediones1,2,28,29.

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.

Table 1. Oral Antidiabetic Agents- Monotherapy: Alpha-Glucosidase Inhibitors (AGIs) Maximum Recommended Adult Daily Dosages1-4
Drug Name Dosage Form/Strength Therapeutic Indications Maximum Recommended Dosage
acarbose (generics) 25 mg, 50 mg, 100 mg tablets type 2 diabetes
  • patients less than or equal to 60 kg:
    • 150 mg/day, in three divided doses
  • patients greater than 60 kg:
    • 300 mg/day, in three divided doses
miglitol (generics) 25 mg, 50 mg, 100 mg tablets type 2 diabetes 300 mg/day, in three divided doses
Table 2. Oral Antidiabetic Agents- Monotherapy: Biguanides Maximum Recommended Adult Daily Dosages1,2,5-8
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 (Fortamet®, Glumetza®, various generics) 500 mg, 750 mg, 1000 mg extended-release tablets type 2 diabetes 2000 mg/day (2500 mg/day Fortamet®)
metformin (Riomet®, generics) 500 mg/5 mL oral solution type 2 diabetes 2550 mg/day
Table 3. Oral Antidiabetic Agents- Monotherapy: Bile Acid Sequestrants Maximum Recommended Adult Daily Dosages1,2,9
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
Table 4. Oral Antidiabetic Agents- Monotherapy: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Maximum Recommended Adult Daily Dosages1,2,10-13
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 (Onglyza®) 2.5 mg, 5 mg tablets type 2 diabetes 5 mg/day
sitagliptin (Januvia®) 25 mg, 50 mg, 100 mg tablets type 2 diabetes 100 mg/day
Table 5. Oral Antidiabetic Agents- Monotherapy: Dopamine Agonists Maximum Recommended Adult Daily Dosages1,2,14
Drug Name Dosage Form/Strength Treatment Indication Maximum Recommended Dosage
bromocriptine (Cycloset®) 0.8 mg tablets type 2 diabetes mellitus 4.8 mg/day
Table 6. Oral Antidiabetic Agents- Monotherapy: Glucagon-Like Peptide-1 (GLP-1) Agonist Maximum Recommended Adult Daily Dosages1,2,15
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
Table 7. Oral Antidiabetic Agents- Monotherapy: Meglitinides Maximum Recommended Adult Daily Dosages1,2,17,18
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)
Table 8. Oral Antidiabetic Agents- Monotherapy: Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors Maximum Recommended Adult Daily Dosages1,2,19-22
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, and to reduce the risk of cardiovascular death in adults with type 2 diabetes mellitus and established cardiovascular disease 
Table 9. Oral Antidiabetic Agents- Monotherapy: Sulfonylureas Maximum Recommended Adult Daily Dosages1,2,23-27
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) 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
Table 10. Oral Antidiabetic Agents- Monotherapy: Thiazolidinediones (TZDs) Maximum Recommended Adult Daily Dosages1,2,28,29
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
rosiglitazone (Avandia®) 2 mg, 4 mg tablets Type 2 diabetes 8 mg/day in single or two divided doses
Table 11. Oral Antidiabetic Agents- Combination Therapy: Maximum Recommended Adult Daily Dosages1,2,30-49
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/15 mg, 12.5 mg/30 mg, 12.5 mg/45 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
  • Patients with inadequate glycemic control on diet/exercise alone:
    • 10 mg/2000 mg/day
  • Patients with inadequate glycemic control on sulfonylurea and/or metformin:
    • 20 mg/2000 mg/day
glyburide/metformin (generics) 1.25 mg/250 mg, 2.5 mg/500 mg, 5 mg/500 mg tablets type 2 diabetes
  • Patients with inadequate glycemic control on diet/exercise alone:
    • 10 mg/2000 mg/day
  • Patients with inadequate glycemic control on sulfonylurea and/or metformin:
    • 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

1.2. Pediatrics

Risperidone has been FDA-approved to manage symptoms of irritability in autistic children greater than 5 years of age and adolescents, and has recently gained FDA-approved indications for bipolar mania in children and adolescents 10 to 17 years of age and schizophrenia in adolescents 13 to 17 years of age. Aripiprazole has received recent FDA approval for treating Tourette’s disorder in pediatric patients 6 to 18 years of age, and is also FDA-approved for managing schizophrenia in adolescents 13 to 17 years of age, bipolar disorder with or without psychotic features in children 10 to 17 years of age, and irritability associated with autistic disorder in children 6 to 17 years of age. Olanzapine has been granted FDA approval for bipolar disorder and schizophrenia in adolescents 13 years of age and older. Quetiapine is FDA approved for acute treatment of bipolar disorder mania episodes in children and adolescents 10 to 17 years of age and schizophrenia management in adolescents 13 to 17 years of age. Paliperidone is approved FDA for the management of schizophrenia in adolescents 12 to 17 years of age. Lurasidone is approved for the management of depressed phase bipolar disorder in children 10 to 17 years of age, and it is approved for the management of schizophrenia in patients 13 to 17 years of age. Brexpiprazole, cariprazine, clozapine, iloperidone, Lumateperone, ziprasidone, and aripiprazole tablets with sensors (Abilify MyCite®) are not recommended for use in pediatric patients as safety and efficacy have not been established in this patient population. Additionally, pimavanserin is not approved for use in pediatric patients as Parkinson’s disease is typically not observed in pediatric patients, and safety and efficacy data are not available for pimavanserin in the pediatric population 1-25.

Atypical antipsychotic pediatric dosages are summarized in Table 3. An additional column reflecting literature-based dosing included in the Texas Health and Human Services Psychotropic Medication Utilization Parameters for Children and Youth in Texas Public Behavioral Health (6th Version) is included in Tables 3 1-21, 23, 26 and 4 26.

The olanzapine/fluoxetine combination has been approved for use in pediatric patients 10-17 years of age with depression associated with BD 1-4, 22. Recommended pediatric dosages are summarized in Table 4 1-4, 22, 26.

2. Renal Impairment

Acarbose should be avoided in patients with an estimated glomerular filtration rate (eGFR) less than 25 mL/minute/ 1.73m2. Miglitol should be avoided in patients with an eGFR less than 25 mL/minute/ 1.73m21-4.

Metformin should be used cautiously in patients with an eGFR below 60 mL/ minute/1.73m2. Renal function should be closely monitored in patients with an eGFR of 30-59 mL/ minute/1.73m2, with doses decreased by 50% in patients with an eGFR of 30-59 mL/ minute/1.73m2. Metformin doses should be discontinued in patients with an eGFR less than 30 mL/ minute/1.73m21,2,5-8.

In moderate renal impairment (CrCl 30 to 59 ml/min), alogliptin dosages should be reduced to 12.5 mg daily, while in patients with severe renal impairment (CrCl less than 30 ml/min), alogliptin dosages should not exceed 6.25 mg daily1,2,10.

Linagliptin dosages do not need to be adjusted for renal insufficiency. Patients on linagliptin combination therapy with a CrCl less than 30 ml/min may have increased risk of hypoglycemia and may need more frequent monitoring and/or dose adjustments1,2,11.

Saxagliptin dosages should be reduced to 2.5 mg once daily in patients with CrCl less than 45 ml/min or in patients prescribed a strong CYP3A4 inhibitor (e.g., ketoconazole)1,2,12.

Sitagliptin dosages should be adjusted in adult patients with renal insufficiency.  Patients with CrCl 30 – 44 ml/min should receive sitagliptin 50 mg daily, while patients with severe renal insufficiency CrCl less than 30 ml/min or those patients with end stage renal disease requiring hemodialysis or peritoneal dialysis should receive sitagliptin 25 mg daily1,2,13.

Repaglinide should be initiated at a dose of 0.5 mg before each meal in patients with a CrCl between 20-39 mL/min1,2,18.

Canagliflozin doses in patients with renal impairment should be reduced to 100 mg daily when the estimated glomerular filtration rate (eGFR) is 30-59 ml/min/1.73 m2 and avoided when eGFR is less than 30 ml/min/1.73 m2. Patients may continue up to 100 mg daily of canagliflozin when eGFR is less than 30 ml/min/1.73 m2 if they have albuminuria greater than 300 mg/day1,2,19.

Dapagliflozin dosages should be adjusted in patients with renal impairment. For patients with an eGFR of 25-44 ml/min/1.73m2 the maximum dose is 10 mg daily. Initiating dapagliflozin in patients with an eGFR less than 25 ml/min/1.73m2 is not recommended. However, patients may continue therapy if eGFR declines to less than 25 ml/min/1.73m2. Dapagliflozin is contraindicated in patients on dialysis1,2,20.

Empagliflozin therapy should not be initiated in patients with eGFR less than 30 ml/min/1.73m2 for glycemic control if they do not have established cardiovascular disease or cardiovascular risk factors. Studies in patients with heart failure enrolled patients with an eGFR equal to or above 20 ml/min/1.73m2, and there is insufficient data to recommend use in patients with an eGFR below 20 ml/min/1.73m2. Empagliflozin is contraindicated in patients with an eGFR less than 20 ml/min/1.73m21,2,21.

Ertugliflozin therapy is not recommended in patients with an eGFR less than 45 mL/min/1.73m21,2,22.

Glimepiride should be initiated at 1 mg daily and slowly titrated in patients with renal impairment1,2,23.

Glyburide should be avoided in patients with renal impairment. If use is necessary, start at 1.25 mg daily conventional glyburide, 0.75 mg daily for micronized glyburide. All sulfonylurea medications should be initiated with caution and at a reduced starting dose to minimize the risk of hypoglycemic events1,2,23-27.

3. Duration of Therapy

There is no basis for limiting the duration of oral antidiabetic therapy as diabetes is a chronic disorder50.

4. Duplicative Therapy

Administering two or more oral sulfonylureas concurrently is not justified. The concomitant use of two or more oral sulfonylureas will be reviewed.

Combined administration of nateglinide or repaglinide and oral sulfonylureas is not justified as both drug classes stimulate insulin secretion. Adjunctive use of meglitinides and oral sulfonylureas will be reviewed.

The risk of hypoglycemia may increase when acarbose or miglitol is added to pre-existing oral hypoglycemic or insulin therapy. Blood glucose levels should be monitored closely when alpha glucosidase inhibitor therapy is initiated in patients already receiving oral hypoglycemic or insulin therapy.

Adjunctive administration of rosiglitazone and insulin is not recommended as a greater incidence of myocardial ischemic events was observed in clinical trials when rosiglitazone was added to insulin therapy.

Concurrent administration of thiazolidinediones or metformin with sulfonylureas may result in an increased frequency of hypoglycemic episodes. Blood glucose levels should be closely monitored if patients are prescribed thiazolidinediones or metformin and oral sulfonylureas concomitantly, and oral sulfonylurea dosage reductions should be considered.

Concurrent administration DDP-4 inhibitors and sulfonylureas, with or without metformin, have resulted in significant reductions in HbA1c and fasting plasma glucose compared to placebo. The risk of hypoglycemia with DDP-4 inhibitors in combination with metformin and TZDs is comparable to that observed with placebo; however, the incidence of hypoglycemia in patients prescribed DDP-4 inhibitors concurrently with sulfonylureas is greater than that seen with placebo. The incidence of hypoglycemia in patients prescribed DDP-4 inhibitors and insulin concurrently has not been adequately evaluated. Therefore, blood glucose levels should be closely monitored if patients are prescribed DDP-4 inhibitors and oral sulfonylureas or insulin concomitantly, and oral sulfonylurea dosage reductions should be considered.

Concomitant use of multiple SGLT2 inhibitors is not recommended due to similar pharmacologic mechanisms and increased risk of adverse events. Combined administration is not advised and will be reviewed.

The concurrent use of oral semaglutide when combined with an insulin secretagogue, such as a sulfonylurea, or insulin may increase the risk of hypoglycemia, including severe hypoglycemia. The risk of hypoglycemia may be reduced by decreasing the dose of the insulin secretagogue or insulin.

5. Drug-Drug Interactions

Patient profiles will be reviewed to identify those drug regimens, which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for oral antidiabetic agents are summarized in Table 13. Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed.

Table 13. Oral Antidiabetic Agent Drug-Drug Interactions1,2
Target Drug Interacting Drug Interaction Recommendation Clinical Significance Level*
acarbose digoxin adjunctive administration may result in decreased digoxin levels; acarbose most likely impairs digoxin absorption avoid concurrent administration; separate administration by 6 hours to avoid interaction; monitor digoxin levels 2-major (CP)
alpha-glucosidase inhibitors (AGIs) intestinal adsorbents (e.g. charcoal) and digestive enzymes (e.g. amylase, pancreatin) combined therapy may result in decreased AGI absorption, reduced pharmacologic effects avoid concurrent administration; separate administration times moderate (DrugReax) 2-major (CP)
antidiabetic agents (ADAs) ACE inhibitors/ angiotensin receptor blockers (ARBs) combined therapy may result in increased risk of hypoglycemia, most likely due to ACE inhibitor/ARB improved insulin sensitivity monitor glycemic control when initiating or changing therapy 3-moderate (CP)
ADAs atypical antipsychotics (AAs) combined therapy may result in loss of glycemic control; AAs may increase insulin resistance or inhibit beta cells monitor for loss of glycemic control; adjust doses as necessary 3-moderate (CP)
ADAs beta blockers (BB) BB may prolong hypoglycemia (interference with mobilization of glycogen stores), promote hyperglycemia (inhibit insulin secretion/decrease tissue insulin sensitivity), as well as mask signs/symptoms of hypoglycemia administer cautiously together; consider cardioselective BB due to lesser effects on glucose metabolism, less masking of hypoglycemic signs/ symptoms moderate (DrugReax) 3-moderate (CP)
ADAs fluoroquinolones combined administration may increase risk of hyper- or hypoglycemia; mechanism unknown closely monitor serum glucose levels; adjust ADA doses as needed major (DrugReax) 3-moderate (CP)
ADAs MAOIs adjunctive therapy may result in additive glucose-lowering effects; MAOIs may stimulate insulin secretion closely monitor serum glucose levels; decrease antidiabetic agent doses as necessary moderate (DrugReax) 3-moderate (CP)
ADAs somatostatin analogues (SAs) (e.g., octreotide, pasireotide) concurrent use may impair glucose regulation as SAs inhibit insulin and glucagon secretion; substantially increased blood glucose levels may result monitor closely for changes in blood glucose control before and throughout SA therapy; adjust antidiabetic doses as needed major (DrugReax) 2-major (CP)
ADAs thiazide diuretics combined therapy may antagonize hypoglycemic effects of ADAs as thiazides increase blood glucose levels in dose-related manner utilize lower thiazide doses, if possible; monitor serum glucose levels; adjust ADA doses as needed 3-moderate (CP)
bromocriptine ergot alkaloids combined therapy may increase risk of ergot toxicity (e.g., angina, paresthesias) as bromocriptine is ergot derivative avoid using together 1-severe (CP)
bromocriptine metoclopramide combined therapy may attenuate bromocriptine pharmacological effects; metoclopramide is dopamine antagonist avoid concurrent use 2-major (CP)
bromocriptine select macrolides (e.g., clarithromycin, erythromycin) potential for increased bromocriptine pharmacologic/ adverse effects due to decreased hepatic metabolism by macrolide monitor patient for adverse effects; decrease bromocriptine dose as necessary moderate (DrugReax) 3-moderate (CP)
bromocriptine serotonin-receptor agonists (e.g., sumatriptan) increased risk of serious coronary ischemia due to potential for additive vasospasm avoid concurrent administration within 24 hours of each other 2-major (CP)
bromocriptine drugs metabolized by CYP3A4 (e.g., tacrolimus, cyclosporine, sirolimus) potential for decreased  cyclosporine/ sirolimus/ tacrolimus clearance, enhanced pharmacologic/ adverse effects; bromocriptine  is CYP3A4 inhibitor monitor for increased pharmacologic/adverse effects; consider reducing dose of CYP3A4 substrate 2-major (CP)
bromocriptine first generation antipsychotics decreased efficacy of bromocriptine due to antagonization of prolactin-lowering effects and elevation of prolactin levels with chronic administration of these antipsychotics avoid concurrent administration together; closely monitor for adverse events if they must be co-administered 2-major (CP)
canagliflozin UGT enzyme inducers (e.g., rifampin) adjunctive administration may decrease canagliflozin AUC by 51% and reduce therapeutic efficacy as canagliflozin is metabolized through O-glucuronidation by several UGT enzymes (UGT1A9 and UGT2B4) administer cautiously together; may increase canagliflozin dose to 300 mg daily during adjunctive therapy with UGT enzyme inducers or may consider alternative antidiabetic agents metabolized by different mechanisms major (DrugReax) 2-major (CP)
colesevelam cyclosporine decreased cyclosporine peak serum concentrations and AUC with combined therapy administer cyclosporine at least 4 hours prior to colesevelam; monitor serum cyclosporine levels 3-moderate (CP)
colesevelam oral contraceptives (OC) decreased peak ethinyl estradiol/ norethindrone serum levels, AUC with combined therapy administer OC at least 4 hours before colesevelam 3-moderate (CP)
colesevelam thyroid hormones (TH) (e.g., levothyroxine, liothyronine) combined therapy may cause reduced thyroid hormone absorption due to nonspecific binding to colesevelam take TH at least 4 hours prior to colesevelam; monitor for adequate thyroid response; adjust TH dose as needed moderate (DrugReax) 3-moderate (CP)
glimepiride voriconazole combined therapy may increase glimepiride levels and risk of hypoglycemia; voriconazole inhibits CYP2C9, glimepiride metabolized by CYP2C9 monitor for hypoglycemia; consider lowering glimepiride dose major (DrugReax) 3-moderate (CP)
glyburide, TZDs bosentan increased risk of elevated liver enzymes when used concurrently; bosentan, a CYP2C9 and CYP3A4 inducer, may decrease glyburide and TZD levels/reduce hypoglycemic effects; glyburide, rosiglitazone metabolized by CYP2C9, pioglitazone metabolized by CYP3A4 combined therapy contraindicated; choose alternative ADA glyburide -1-severe; TZDs - 2-major (CP) glyburide -contraindicated (DrugReax)
linagliptin CYP3A4 and p-glycoprotein inducers combined therapy may significantly decrease linagliptin concentrations decrease efficacy; linagliptin metabolized by CYP3A4 administer cautiously together; monitor serum glucose levels rifampin, rifabutin, phenobarbital, phenytoin, carbamazepine, St. John’s wort - major (DrugReax) others - moderate (DrugReax)
meglitinides, sulfonylureas, TZDs CYP2C8 Inducers (e.g. rifamycins) combined therapy may result in reduced ADA serum levels and loss of hypoglycemic control due to enhanced ADA hepatic metabolism by rifamycin closely monitor serum glucose levels; adjust ADA dose as necessary moderate (DrugReax) 4-minor (CP)
metformin dofetilide increased risk of lactic acidosis; dofetilide decreases metformin elimination by competing for renal tubular transport system; potential for increased dofetilide serum concentrations and cardiotoxicity risk manufacturer recommends avoiding concurrent use 1-severe (CP) major (DrugReax)
pioglitazone tolvaptan combined therapy may decreases tolvaptan concentrations; pioglitazone is CYP3A4 inducer,  tolvaptan is metabolized by CYP3A4 avoid concurrent use if possible; if combined therapy necessary, increase tolvaptan dose and monitor efficacy major (DrugReax)
repaglinide, TZDs Strong CYP2C8 inhibitors (e.g. gemfibrozil, clopidogrel) combined therapy increases potential for elevated repaglinide or TZD levels/amplified repaglinide or TZD hypoglycemic effects due to inhibition of CYP2C8; repaglinide, TZDs metabolized by CYP2C8 avoid concurrent administration; if combination cannot be avoided, use lower repaglinide dose contraindicated (DrugReax) 1-severe
repaglinide CYP3A4 inhibitors (e.g., rifamycins, macrolides, itraconazole) combined therapy may significantly increase repaglinide concentrations and increase hypoglycemia risk; repaglinide  metabolized by CYP3A4 administer cautiously together; monitor for hypoglycemia; adjust repaglinide dose as necessary itraconazole-major; others – moderate (DrugReax) 2-major (CP)
repaglinide cyclosporine cyclosporine is CYP3A4 inhibitor, also inhibits uptake of repaglinide into liver by inhibiting OATP1B1, which increases risk of elevated repaglinide levels and hypoglycemia when given concurrently administer cautiously together; closely monitor glycemic control; adjust repaglinide dose as necessary 2-major (CP)
repaglinide isophane insulin (NPH) combined therapy caused myocardial ischemia in clinical trials avoid concurrent administration 2-major (CP)
rosiglitazone nitrates in clinical trials, increased risk of myocardial ischemia in patients receiving combined therapy avoid concurrent administration (manufacturer recommendations) 2-major (CP)
saxagliptin CYP3A4/5 inhibitors (e.g., ketoconazole, erythromycin, fluconazole) combined therapy may increase saxagliptin levels and risk of hypoglycemia; saxagliptin metabolized by CYP3A4/5 utilize lower saxagliptin dose (2.5 mg daily) with strong CYP3A4/5 inhibitors (e.g., ketoconazole); adjunctive therapy with moderate CYP3A4/5 inhibitors does not warrant dosage adjustments 2-major (CP)
sulfonylureas methotrexate concurrent administration may result in methotrexate displacement from protein binding sites and increased risk of methotrexate toxicity consider avoiding combination; watch for signs of toxicity 2-major (CP)
sulfonylureas sulfonamides combined therapy may exaggerate sulfonylurea hypoglycemic effects; sulfonamides may inhibit sulfonylurea metabolism or displace sulfonylurea from protein binding site; glipizide, glyburide not significantly affected due to nonionic binding of these agents use combination cautiously; closely monitor serum glucose levels, observe for signs/symptoms of hypoglycemia, reduce sulfonylurea dose as necessary moderate (DrugReax) 3-moderate (CP)
TZDs insulins combined therapy associated with increased risk of heart failure and/or edema and myocardial ischemic events manufacturer recommends avoiding concurrent use 2-major (CP)

Legend:

  • *CP = Clinical Pharmacology

6. References

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