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Pioglitazone and glimepiride: Drug information

Pioglitazone and glimepiride: Drug information
(For additional information see "Pioglitazone and glimepiride: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Congestive heart failure:

Thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of pioglitazone/glimepiride, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, manage the heart failure according to the current standards of care. Furthermore, consider discontinuation of pioglitazone/glimepiride.

Pioglitazone/glimepiride is not recommended in patients with symptomatic heart failure. Initiation of pioglitazone/glimepiride in patients with established New York Heart Association (NYHA) class III or IV heart failure is contraindicated.

Brand Names: US
  • Duetact
Pharmacologic Category
  • Antidiabetic Agent, Sulfonylurea;
  • Antidiabetic Agent, Thiazolidinedione
Dosing: Adult

Note: May require a dose reduction of other insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia; consider stopping insulin or reducing insulin dose (eg, by 10% to 25%) (ADA/EASD [Davies 2018]; manufacturer's labeling).

Diabetes mellitus, type 2, treatment

Diabetes mellitus, type 2, treatment:

Note: Additional therapeutic considerations may apply; refer to individual agents for information.

Oral: Initial dose should be based on current dose of pioglitazone and/or sulfonylurea.

Patients inadequately controlled on glimepiride alone: Initial dose: Pioglitazone 30 mg/glimepiride 2 mg or pioglitazone 30 mg/glimepiride 4 mg once daily.

Patients inadequately controlled on pioglitazone alone: Initial dose: Pioglitazone 30 mg/glimepiride 2 mg once daily.

Patients currently on sulfonylurea monotherapy (other than glimepiride) or switching from combination therapy of pioglitazone plus a sulfonylurea (other than glimepiride): Initial: Pioglitazone 30 mg/glimepiride 2 mg once daily. When converting patients from other sulfonylureas with longer half-lives (eg, chlorpropamide) to glimepiride, observe patient carefully for 1 to 2 weeks due to overlapping hypoglycemic effects.

Patients with systolic dysfunction (eg, NYHA Class I and II): Initiate only after patient has been safely titrated to 30 mg of pioglitazone. Initial dose: Pioglitazone 30 mg/glimepiride 2 mg once daily.

Dosage adjustment: Dosage may be increased up to a maximum dose of pioglitazone 45 mg/glimepiride 8 mg once daily based on effectiveness and tolerability. Dosage adjustments in patients with systolic dysfunction should be done carefully and patient monitored for symptoms of worsening heart failure.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no specific dosage adjustments provided in the manufacturer’s labeling; initiate and adjust dose conservatively; observe carefully for hypoglycemia.

Dosing: Hepatic Impairment: Adult

Hepatic impairment prior to initiation: There are no specific dosage adjustments provided in the manufacturer’s labeling; use with caution.

Hepatic impairment during therapy: If liver injury is suspected (eg, fatigue, jaundice, dark urine): Interrupt therapy, measure serum liver tests, and investigate possible etiologies:

If an alternative etiology is not identified and ALT >3 x ULN: Do not reinitiate therapy.

If an alternative etiology is identified and ALT elevated (but <3 x ULN) or total bilirubin elevated (but <2 x ULN): May reinitiate with caution.

Dosing: Older Adult

Note: Use of sulfonylureas (eg, glimepiride) is associated with increased risk of hypoglycemia. The American Diabetes Association suggests using sulfonylureas with caution, and notes preference for glimepiride (or glipizide) due to lower relative risk of hypoglycemia compared to other sulfonylureas (Ref). If used, initiate and adjust dose conservatively; observe carefully for hypoglycemia. Refer to adult dosing.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reactions listed are based on reports for other agents in this same pharmacologic class and may not be specifically reported for glimepiride. Also see individual agents.

>10%:

Cardiovascular: Peripheral edema (≤12%)

Endocrine & metabolic: Hypoglycemia (13% to 16%), weight gain (9% to 13%)

Respiratory: Upper respiratory tract infection (12% to 17%)

1% to 10%:

Cardiovascular: Edema (≤7%)

Gastrointestinal: Diarrhea (4% to 6%), nausea (4% to 5%)

Genitourinary: Urinary tract infection (6% to 7%)

Hematologic & oncologic: Anemia (≤2%)

Nervous system: Headache (4% to 7%)

Neuromuscular & skeletal: Limb pain (4% to 5%)

Frequency not defined: Cardiovascular: Heart failure (including worsening of heart failure)

Postmarketing: Genitourinary: Bladder carcinoma (FDA 2016)

Contraindications

Hypersensitivity to glimepiride, pioglitazone, or any component of the formulation; history of allergic reaction to sulfonamide derivatives; NYHA Class III/IV heart failure (initiation of therapy).

Note: Although the FDA-approved product labeling states this medication is contraindicated in patients with hypersensitivity to sulfonamide-containing drugs, the scientific basis of this cross-sensitivity has been challenged. See “Warnings/Precautions” for more detail.

Warnings/Precautions

Concerns related to adverse effects:

• Bladder cancer: An FDA review concluded that, although clinical trial data are inconsistent regarding the risk of bladder cancer in patients exposed to pioglitazone, there is still the potential for an increased risk and package labeling has been updated to reflect this. Avoid use of pioglitazone in patients with active bladder cancer and consider risks vs. benefits prior to initiating therapy in patients with a history of bladder cancer.

• Cardiovascular mortality: Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS 1998), have not supported an association. In a prospective, active-controlled study comparing linagliptin to glimepiride in patients with high baseline cardiovascular risk, the rates of cardiovascular events were similar over ~6 years (Rosenstock 2019). In patients with established atherosclerotic cardiovascular disease, other agents (eg, with demonstrated cardiovascular risk reduction) are preferred (ADA 2020).

• Edema: Dose-related edema, including new-onset or exacerbation of existing edema, has been reported with pioglitazone; use with caution in patients with edema. Monitor for signs/symptoms of heart failure (HF).

• Fractures: An increased incidence of bone fractures has been observed in females treated with pioglitazone; majority of fractures occurred in the lower limb and distal upper limb. Consider risk of fracture prior to initiation and during use.

• Heart failure/cardiac effects: [US Boxed Warning]: Thiazolidinediones, including pioglitazone, may cause or exacerbate HF; closely monitor for signs and symptoms of HF (eg, rapid weight gain, dyspnea, edema), particularly after initiation or dose increases; if HF develops, treat accordingly and consider dose reduction or discontinuation. Not recommended for use in any patient with symptomatic HF; initiation of therapy is contraindicated in patients with New York Heart Association (NYHA) class III or IV HF. If used in patients with NYHA class I or II (systolic) HF, initiate at lowest dosage and monitor closely.

• Hematologic effects: Pioglitazone may decrease hemoglobin/hematocrit; effects may be related to increased plasma volume.

• Hepatic effects: Hepatic failure, including fatalities, has been reported with pioglitazone use. Monitor for signs/symptoms of liver injury closely during therapy; discontinuation of therapy may be necessary.

• Hypersensitivity reactions: Hypersensitivity reactions to glimepiride (eg, cutaneous eruptions, anaphylaxis, angioedema, Stevens-Johnson syndrome [SJS]) have occurred. If hypersensitivity reactions occur, discontinue use immediately and institute alternative treatment.

• Hypoglycemia: All sulfonylurea drugs are capable of producing severe hypoglycemia. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when ethanol is ingested, or when more than one glucose-lowering drug is used. It is also more likely in elderly patients, malnourished patients and in patients with impaired renal or hepatic function; use with caution.

• Macular edema: Has been reported with thiazolidinedione use, including pioglitazone; some patients with macular edema presented with blurred vision or decreased visual acuity, and most had peripheral edema at time of diagnosis. Patients should be seen by an ophthalmologist if any visual symptoms arise during therapy and all diabetic patients should have regular eye exams.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, 2 antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (SJS/toxic epidermal necrolysis), some clinicians choose to avoid exposure to these classes.

• Weight gain: Dose-related weight gain observed with pioglitazone use; mechanism unknown but likely associated with fluid retention and fat accumulation.

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013). Use IR formulations after surgery to minimize the potential effects of bypassing stomach and proximal small bowel with gastric bypass or more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Apovian 2015). ER formulations may have altered release and absorption patterns after gastric bypass or sleeve gastrectomy (but not gastric band). Compared to control, Tmax in a gastric bypass cohort administered tolbutamide was significantly shorter (1.4 ± 1.8 vs 5.1 ± 1.7 hours; P < 0.001) while Cmax and AUC0- were not altered (Tandra 2013).

– Hypoglycemia: Use an antidiabetic agent without the potential for hypoglycemia if possible; hypoglycemia may occur after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve and finally band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period postsurgery (Mingrone 2016).

– Weight gain: Evaluate risk vs benefit and consider alternative therapy after gastric bypass, sleeve gastrectomy, and gastric banding; weight gain may occur (Apovian 2015).

• Glucose-6-phosphate dehydrogenase deficiency: Patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency may be at an increased risk of sulfonylurea-induced hemolytic anemia; however, cases have also been described in patients without G6PD deficiency during postmarketing surveillance. Use with caution and consider a nonsulfonylurea alternative in patients with G6PD deficiency.

• Hepatic impairment: Due to the possible risk of drug-induced liver injury with pioglitazone, serum LFTs (ALT, AST, alkaline phosphatase, and total bilirubin) should be obtained prior to initiation in all patients. In patients with abnormal hepatic tests, therapy should be initiated with caution. During therapy, if signs/symptoms of liver injury (eg, fatigue, anorexia, jaundice, dark urine, right upper abdominal discomfort) arise, interrupt pioglitazone therapy, obtain liver tests immediately and evaluate alternative etiologies. If an alternative etiology is not identified and serum ALT is >3 times ULN, do not resume therapy. Patients with serum ALT >3 times ULN and serum total bilirubin >2 times ULN are at risk for severe drug-induced liver injury. Risk of hypoglycemia may be increased in patients with hepatic impairment and receiving glimepiride.

• Renal function impairment: Use glimepiride with caution; patients with renal impairment are more likely to develop hypoglycemia.

• Stress-related states: It may be necessary to discontinue therapy and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Special populations:

• CYP2C9 genotype: Systemic exposure of glimepiride is increased in patients with CYP2C9*3 allele (Niemi 2002).

• Older adult: Use with caution; elderly patients are more likely to develop hypoglycemia.

Other warnings/precautions:

• Appropriate use: Not for use in patients with diabetic ketoacidosis or patients with type 1 diabetes mellitus.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet: 30/2: Pioglitazone 30 mg and glimepiride 2 mg; 30/4: Pioglitazone 30 mg and glimepiride 4 mg

Duetact:

30 mg/2 mg: Pioglitazone 30 mg and glimepiride 2 mg

30 mg/4 mg: Pioglitazone 30 mg and glimepiride 4 mg

Generic Equivalent Available: US

Yes

Pricing: US

Tablets (Duetact Oral)

30-2 mg (per each): $23.75

30-4 mg (per each): $23.75

Tablets (Pioglitazone HCl-Glimepiride Oral)

30-2 mg (per each): $15.62 - $16.29

30-4 mg (per each): $15.62 - $16.29

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Adult

Oral: Administer once daily with the first main meal of the day. To avoid hypoglycemia, patients without oral intake may need to have the dose held.

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021925s017lbl.pdf#page=39, must be dispensed with this medication.

Use: Labeled Indications

Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both pioglitazone and glimepiride is appropriate.

Medication Safety Issues
High alert medication:

The Institute for Safe Medication Practices (ISMP) includes glimepiride among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

Older Adult: High-Risk Medication:

Beers Criteria: Avoid routine use of sulfonylureas due to increased risk of hypoglycemia. If a sulfonylurea is needed, one with a lower relative risk of hypoglycemia (eg, glimepiride, glipizide) is preferred (ADA 2021; Beers Criteria [AGS 2023]).

Metabolism/Transport Effects

Refer to individual components.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Abiraterone Acetate: May enhance the hypoglycemic effect of Thiazolidinediones. Risk C: Monitor therapy

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy

Alcohol (Ethyl): Sulfonylureas may enhance the adverse/toxic effect of Alcohol (Ethyl). A flushing reaction may occur. Risk C: Monitor therapy

Alpelisib: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy

Alpha-Glucosidase Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with an alpha-glucosidase inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Aminolevulinic Acid (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Systemic). Risk X: Avoid combination

Aminolevulinic Acid (Topical): Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid (Topical). Risk C: Monitor therapy

Amiodarone: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Sulfonylureas. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Sulfonylureas. Risk C: Monitor therapy

Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Carbocisteine: Sulfonylureas may enhance the adverse/toxic effect of Carbocisteine. Specifically, sulfonylureas may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Risk C: Monitor therapy

Chloramphenicol (Systemic): May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy

Clarithromycin: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Colesevelam: May decrease the serum concentration of Glimepiride. Management: Administer glimepiride at least 4 hours prior to colesevelam. Risk D: Consider therapy modification

CYP2C8 Inducers (Moderate): May decrease the serum concentration of Pioglitazone. Risk C: Monitor therapy

CYP2C8 Inhibitors (Moderate): May increase the serum concentration of Pioglitazone. Risk C: Monitor therapy

CYP2C8 Inhibitors (Strong): May increase the serum concentration of Pioglitazone. Management: Limit the pioglitazone dose to 15 mg daily and monitor for increased pioglitazone toxicities (eg, hypoglycemia) when used in combination with strong CYP2C8 inhibitors. Risk D: Consider therapy modification

CYP2C9 Inducers (Moderate): May decrease the serum concentration of Sulfonylureas. Risk C: Monitor therapy

CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Risk C: Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Elexacaftor, Tezacaftor, and Ivacaftor: May increase the serum concentration of Glimepiride. Risk C: Monitor therapy

Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Fibric Acid Derivatives: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose reductions when used in combination with glucagon-like peptide-1 agonists. Risk D: Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Inhibitors of the Proton Pump (PPIs and PCABs): May enhance the adverse/toxic effect of Thiazolidinediones. Specifically, the risk of osteoporosis or fracture may be increased. Risk C: Monitor therapy

Insulins: Pioglitazone may enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, consider insulin dose reductions to avoid hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure, and consider pioglitazone dose reduction or discontinuation if heart failure occurs Risk D: Consider therapy modification

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C8 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy

Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Risk X: Avoid combination

Methoxsalen (Systemic): Photosensitizing Agents may enhance the photosensitizing effect of Methoxsalen (Systemic). Risk C: Monitor therapy

Metreleptin: May enhance the hypoglycemic effect of Sulfonylureas. Management: Sulfonylurea dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely for signs or symptoms of hypoglycemia. Risk D: Consider therapy modification

Miconazole (Oral): May enhance the hypoglycemic effect of Sulfonylureas. Miconazole (Oral) may increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy

Mitiglinide: May enhance the adverse/toxic effect of Sulfonylureas. Risk X: Avoid combination

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy

Pregabalin: May enhance the fluid-retaining effect of Thiazolidinediones. Risk C: Monitor therapy

Probenecid: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy

Rifapentine: May decrease the serum concentration of CYP2C9 Substrates (High risk with Inducers). Risk C: Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification

Sulfonamide Antibiotics: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Sulfonylureas: Thiazolidinediones may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Risk D: Consider therapy modification

Tetracyclines: May enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Tezacaftor and Ivacaftor: May increase the serum concentration of Glimepiride. Risk C: Monitor therapy

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Thiazolidinediones: May enhance the hypoglycemic effect of Sulfonylureas. Management: Consider sulfonylurea dose adjustments in patients taking thiazolidinediones and monitor for hypoglycemia. Risk D: Consider therapy modification

Topiramate: May decrease the serum concentration of Pioglitazone. Risk C: Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Sulfonylureas may enhance the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Voriconazole: May increase the serum concentration of Sulfonylureas. Risk C: Monitor therapy

Food Interactions

See individual agents

Reproductive Considerations

Pioglitazone may increase ovulation in premenopausal anovulatory patients resulting in unintended pregnancies.

Refer to individual monographs for additional information.

Pregnancy Considerations

If exposure during pregnancy occurs, discontinue at least 2 weeks prior to expected delivery.

Refer to individual monographs for information related to the treatment of diabetes mellitus in pregnancy.

Breastfeeding Considerations

It is not known if glimepiride or pioglitazone is excreted in breast milk.

According to the manufacturer, the decision breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Refer to individual monographs for additional information.

Monitoring Parameters

Serum glucose.

HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).

Liver enzymes (ALT, AST, alkaline phosphatase, and total bilirubin) prior to initiation in all patients (with or without liver disease); continue routine periodic monitoring during treatment only in patients with liver disease or suspected liver disease.

Signs and symptoms of heart failure; weight gain; signs/symptoms of bladder cancer (dysuria, macroscopic hematuria, dysuria, urinary urgency); ophthalmic exams.

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults with diabetes (AACE [Samson 2023]; ADA 2023):

HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.

Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).

Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (SI: <10 mmol/L) (more or less stringent goals may be appropriate based on patient-specific characteristics).

Older adults (≥65 years of age) (ADA 2023):

Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (LeRoith 2019).

HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.

Preprandial capillary blood glucose: 80 to 130 mg/dL (SI: 4.4 to 7.2 mmol/L) (healthy); 90 to 150 mg/dL (SI: 5 to 8.3 mmol/L) (complex/intermediate health); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (very complex/poor health).

Bedtime capillary blood glucose: 80 to 180 mg/dL (SI: 4.4 to 10 mmol/L) (healthy); 100 to 180 mg/dL (SI: 5.6 to 10 mmol/L) (complex/intermediate health); 110 to 200 mg/dL (SI: 6.1 to 11.1 mmol/L) (very complex/poor health).

Classification of hypoglycemia (ADA 2023):

Level 1: 54 to 70 mg/dL (SI: 3 to 3.9 mmol/L); hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.

Level 2: <54 mg/dL (SI: <3 mmol/L); threshold for neuroglycopenic symptoms; requires immediate action.

Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.

Mechanism of Action

Pioglitazone: A thiazolidinedione that lowers blood glucose by improving target cell response to insulin, without increasing pancreatic insulin secretion. It has a mechanism of action that is dependent on the presence of insulin for activity.

Glimepiride: A sulfonylurea that stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites.

Pharmacokinetics (Adult Data Unless Noted)

See individual agents.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Duetact;
  • (AT) Austria: Tandemact;
  • (BD) Bangladesh: Dieta Plus | Tosirin;
  • (EG) Egypt: Amaglust | Glimepiride plus | Piompride | Zanoglide;
  • (ES) Spain: Tandemact;
  • (IN) India: Adride p | Dibiglim-p | Euglim-p | G-tase g | Glimiprex-pg | Glimtaz | Glimy-p | K-pio-g | Normaglim P | Piobeta | Pioglar g | Pioglar gf | Pioglit-g | Pionorm-g | Pioride | Pioryl | Piotop ud | Pioz g | Piozone g | Zorep;
  • (IT) Italy: Tandemact;
  • (JO) Jordan: Duetact;
  • (KR) Korea, Republic of: Actosryl;
  • (LB) Lebanon: Duetact;
  • (MX) Mexico: Diaberil | Novoberil;
  • (PE) Peru: Zorep;
  • (PH) Philippines: Asenza plus | Zoliget;
  • (PK) Pakistan: Dazemep plus | Fantasmic plus | Glibetic | Glio P | Glitamap | Pio glee | Piobetic G | Pioglimp ds | Piotone gem | Piozer g | Poze G | Thiozer | Zoliget;
  • (PR) Puerto Rico: Pioglitazone and Glimepiride;
  • (PT) Portugal: Tandemact;
  • (QA) Qatar: Duetact;
  • (SA) Saudi Arabia: Duetact;
  • (SK) Slovakia: Tandemact
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