Version May 2024
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL.
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years of age, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information.
If metformin-associated lactic acidosis is suspected, immediately discontinue empagliflozin/linagliptin/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Dosage guidance:
Clinical considerations: Correct hypovolemia, if present, prior to initiation of empagliflozin. May require a gradual dose reduction of insulin and/or insulin secretagogues (eg, sulfonylureas, meglitinides) to avoid hypoglycemia (AACE/ACE [Samson 2023]).
Diabetes mellitus, type 2, treatment:
Note: Due to lack of additive glycemic benefit, avoid use of linagliptin in combination with glucagon-like peptide-1 receptor agonist-based therapies. Additional therapeutic considerations may apply; refer to individual agents for information.
Initial: Individualize based on patient's current antidiabetic regimen. Initiation of this combination product is intended for patients who are already on metformin.
Patients not taking empagliflozin: Oral: Switch to combination product containing a similar total daily dose of metformin, empagliflozin 10 mg/day, and linagliptin 5 mg/day given once daily.
Patients taking empagliflozin: Oral: Switch to combination product containing a similar total daily dose of metformin, same total daily dose of empagliflozin, and linagliptin 5 mg/day given once daily.
Dosage adjustment: Oral: May gradually titrate dose based on effectiveness and tolerability; maximum: empagliflozin 25 mg/linagliptin 5 mg/metformin 2 g once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Note: The glycemic efficacy of empagliflozin decreases as kidney function declines.
eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.
eGFR 30 to <45 mL/minute/1.73 m2: The US manufacturer does not recommend initiating therapy; refer also to individual agents.
eGFR <30 mL/minute/1.73 m2: Use is contraindicated.
End-stage kidney disease: Use is contraindicated.
Dialysis: Use is contraindicated.
The manufacturer recommends avoiding metformin because liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy; however, continued use of metformin in patients with diabetes and chronic liver disease with impaired hepatic function may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett 2010; Crowley 2017; Zhang 2014).
Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
1% to 10%:
Gastrointestinal: Constipation (5% to 6%), diarrhea (2% to 7%), gastroenteritis (3% to 6%)
Genitourinary: Urinary tract infection (10%)
Nervous system: Headache (5%)
Respiratory: Nasopharyngitis (6% to 8%), upper respiratory tract infection (8% to 10%)
<1%: Endocrine & metabolic: Hypoglycemia
Frequency not defined: Endocrine & metabolic: Lactic acidosis
Hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions, urticaria, bronchial hyperreactivity) to empagliflozin, linagliptin, metformin or any component of the formulation; severe renal impairment (eGFR <30 mL/minute/1.73 m2), end-stage renal disease, or dialysis; acute or chronic metabolic acidosis, including diabetic ketoacidosis.
Concerns related to adverse effects:
• Arthralgia: Severe and disabling arthralgia has been reported with linagliptin use; onset may occur within 1 day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if linagliptin or other DPP-4 inhibitor therapy is resumed.
• Bone fractures: An increased incidence of bone fractures has been observed with other sodium-glucose transport protein 2 (SGLT2) inhibitors in some clinical trials. However, meta-analyses of trial data for empagliflozin have not demonstrated increased risk of fracture (Ruanpeng 2017; Tang 2016).
• Bullous pemphigoid: DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions.
• Genital mycotic infections: Empagliflozin may increase the risk of genital mycotic infections (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, balanoposthitis). Patients with a history of these infections are at greater risk.
• Hypersensitivity reactions: Patients may experience hypersensitivity reactions (eg, angioedema, urticaria), with some being severe, due to empagliflozin. Hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative dermatologic reactions, have been reported with linagliptin use. Events have generally been noted within the first 3 months of therapy and may occur with the initial dose. Use with caution if patient has experienced angioedema with other DPP-4 inhibitor use.
• Hypotension: Empagliflozin may cause symptomatic hypotension due to intravascular volume depletion; risk may be increased in patients with renal impairment (ie, eGFR <60 mL/minute/1.73 m2), who are >75 years of age, who are taking other antihypertensives (eg, diuretics, angiotensin-converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or with low systolic BP.
• Ketoacidosis: Cases of ketoacidosis (some fatal) have been reported in patients with type 1 and type 2 diabetes mellitus receiving SGLT2 inhibitors; in some cases, patients have presented with normal or only modestly elevated blood glucose (<250 mg/dL). Before initiating treatment, consider risk factors that may predispose to ketoacidosis (eg, pancreatic insulin deficiency, dose decreases of insulin, caloric restriction, alcohol abuse, acute febrile illness, surgery, any other extreme stress event). Consider temporary discontinuation of therapy ≥3 days prior to surgery or any event that may precipitate ketoacidosis; ensure risk factors are resolved prior to reinitiating therapy. Patients presenting with nausea/vomiting, abdominal pain, generalized malaise, and/or shortness of breath should be assessed immediately for ketoacidosis.
• Lactic acidosis: Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.
• Lower limb amputation: There are conflicting data involving the risk of lower limb amputations with SGLT2 inhibitor therapy. Canagliflozin was associated with almost a 2-fold increased risk of lower limb amputations compared to placebo in the CANVAS and CANVAS-R trials, which included patients with type 2 diabetes at high cardiovascular risk (Neal 2017). Trials involving empagliflozin have not consistently shown an increased risk of lower limb amputation associated with its use (Khouri 2018; Inzucchi 2018). Prior to initiation, consider risk factors for amputation including prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. Counsel patients about the importance of preventative foot care.
• Necrotizing fasciitis: Cases of necrotizing fasciitis of the perineum (Fournier gangrene), a rare but serious and potentially fatal infection, have been reported in patients receiving empagliflozin. Assess patients presenting with fever or malaise along with genital or perianal pain, tenderness, erythema, or swelling for necrotizing fasciitis.
• Pancreatitis: Cases of acute pancreatitis, including fatalities, have been reported with linagliptin. Use with caution in patients with a history of pancreatitis, because it is not known if this population is at greater risk; has not been studied. Discontinue use and institute appropriate therapy if pancreatitis is suspected.
• Renal effects: Acute kidney injury (AKI) has been reported with empagliflozin. Prior to initiation, consider risk factors for AKI (eg, hypovolemia, chronic renal insufficiency, HF, use of concomitant medications [eg, diuretics, ACE inhibitors, ARBs, nonsteroidal anti-inflammatory drugs]). Additional abnormalities in renal function (decreased eGFR, increased serum creatinine) and adverse effects related to renal function may occur. In the EMPA-REG OUTCOME study, administration of empagliflozin caused early decline in eGFR that tended to stabilize after ~4 weeks, but also an overall reduction in adverse kidney outcomes (eg, initiation of renal replacement therapy, doubling of serum creatinine with eGFR ≤45 mL/minute/1.73 m2, progression to macroalbuminuria, death from kidney disease) (Wanner 2016).
• Urinary tract infection: Serious urinary infections, including urosepsis and pyelonephritis requiring hospitalization, have been reported with empagliflozin; treatment with empagliflozin increases the risk for urinary tract infection.
• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency.
Disease-related concerns:
• Bariatric surgery:
– Altered absorption: Use alternative agents after surgery. Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery. Extended-release tablets may have a reduced effect after gastric bypass or sleeve gastrectomy due to the direct bypass of the stomach and proximal small bowel with gastric bypass or a more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy (Mechanick 2020; Melissas 2013).
– Dehydration: Evaluate, correct, and maintain postsurgical fluid requirements and volume status prior to initiating therapy and closely monitor the patient for the duration of therapy; volume depletion and related adverse events (eg, hypotension, orthostatic hypotension, syncope) have occurred. Fluid intake may be more difficult after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020).
– Euglycemic diabetic ketoacidosis: Discontinue therapy 3 to 5 days prior to surgery (Bobart 2016). Postoperatively, assess volume status, caloric intake, and need for diabetes treatment and withhold antidiabetic medication if type 2 diabetes is in remission. Ketoacidosis has been reported in patients with type 1 and type 2 diabetes on SGLT2 inhibitors. In some cases, normal or only modestly elevated blood glucose was present (<250 mg/dL) (van Niekerk 2018). Risk factors include significant reduction in insulin, caloric restriction, stress of surgery, and infection.
– Glucagon-like peptide-1 exposure and therapeutic efficacy: Closely monitor for signs and symptoms of pancreatitis; gastric bypass and sleeve gastrectomy may increase endogenous secretion of glucagon-like peptide-1 (Korner 2009; Peterli 2012). A single-dose, placebo-controlled study evaluated short-term therapy (4 weeks) with sitagliptin in gastric bypass patients having persistent or recurrent type 2 diabetes and found it to be well tolerated and provided a small, but significant, reduction in postprandial blood glucose (Shah 2018).
• Heart failure: Metformin may be used in patients with stable heart failure; use cautiously or avoid in hypoperfusion (ADA 2023). In cardiovascular outcome trials of patients with type 2 diabetes and atherosclerotic cardiovascular disease, treatment with other DPP-4 inhibitors has been associated with heart failure. However, in a randomized, double-blind, placebo-controlled trial of linagliptin in patients with type 2 diabetes mellitus and high cardiovascular and renal risks, the rate of hospitalization for heart failure did not differ from placebo, including in patients with preexisting heart failure. Median follow-up was 2.2 years (McGuire 2018; Rosenstock 2018). The American Diabetes Association suggests DPP-4 inhibitors (except saxagliptin) may be considered in patients with heart failure (ADA 2023).
• Hepatic impairment: Use metformin cautiously in patients at risk for lactic acidosis (Brackett 2010; Crowley 2017; Zhang 2014).
• Renal impairment: Metformin is substantially excreted by the kidney; the risk of metformin accumulation and lactic acidosis increases with degree of renal impairment. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia. Glycemic efficacy of empagliflozin may be decreased in renal impairment.
Special populations:
• Elderly: Use with caution; risk of metformin-associated lactic acidosis increases with age.
• Hospitalized patients: Use of SGLT2 inhibitors is not routinely recommended for glycemic control in hospitalized patients (ADA 2023).
Dosage form specific issues:
• Extended-release tablet: Incompletely dissolved tablets may appear in the stool. Assess glycemic control if patient observes tablets in the stool.
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis or for glycemic control in patients with type 1 diabetes mellitus.
• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.
• Iodinated contrast: Administration of iodinated contrast agents has been associated with post-contrast acute kidney injury; in patients taking metformin, acute decreases in renal function have been associated with an increased risk of lactic acidosis due to reduced metformin excretion (ACR 2021; manufacturer’s labeling). Refer to metformin monograph for additional information.
• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (eg, fever, trauma, infection, surgery).
• Surgical procedures: Consider temporary discontinuation of empagliflozin-containing products 3 days prior to surgery; ensure risk factors for ketoacidosis are resolved prior to reinitiating therapy.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release 24 Hour, Oral:
Trijardy XR: empagliflozin 10 mg, linagliptin 5 mg, and metformin 1,000 mg, empagliflozin 25 mg, linagliptin 5 mg, and metformin 1,000 mg, empagliflozin 5 mg, linagliptin 2.5 mg, and metformin 1,000 mg, empagliflozin 12.5 mg, linagliptin 2.5 mg, and metformin 1,000 mg
No
Tablet, 24-hour (Trijardy XR Oral)
5-2.5-1000 mg (per each): $12.22
10-5-1000 mg (per each): $24.44
12.5-2.5-1000 mg (per each): $12.22
25-5-1000 mg (per each): $24.44
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.
Oral: Administer once daily with morning meal. Swallow tablets whole; do not split, crush, dissolve, or chew.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Trijardy XR: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212614s020lbl.pdf#page=44
Diabetes mellitus, type 2, treatment: Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Beers Criteria: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to increased risk of urogenital infections, especially in women during the first month of use. In addition, a higher risk of euglycemic diabetic ketoacidosis has been observed in older adults (Beers Criteria [AGS 2023]).
Refer to individual components.
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.
Abemaciclib: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, excessive alcohol ingestion (acute or chronic) may potentiate the risk of lactic acidosis. Risk X: Avoid combination
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. 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 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
Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Risk C: Monitor therapy
Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of LinaGLIPtin. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to this combination or use of lower metformin doses. Carefully weigh the risk of metformin toxicities (including lactic acidosis) against the benefit of combining dolutegravir with metformin. Risk D: Consider therapy modification
Erdafitinib: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Consider alternatives to this combination when possible. If combined, monitor for increased effects/toxicities of OCT2 substrates and consider OCT2 substrate dose reductions when appropriate. Risk D: Consider therapy modification
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Fexinidazole: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with MATE1/2-K substrates when possible. If combined, monitor for increased MATE1/2-K substrate toxicities. Risk D: Consider therapy modification
Fexinidazole: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with OCT2 substrates when possible. If combined, monitor for increased OCT2 substrate toxicities. Risk D: Consider therapy modification
Fludeoxyglucose F 18: MetFORMIN may diminish the diagnostic effect of Fludeoxyglucose F 18. Management: Consider holding metformin for 48 hours or longer prior to PET scans using fludeoxyglucose F18 (FDG-F18) when imaging of the colon or intestine is required. Consider increased monitoring of blood glucose when metformin is held. Risk D: Consider therapy modification
Foslevodopa: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Gilteritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor therapy
Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Guar Gum (Partially Hydrolyzed): May decrease the serum concentration of MetFORMIN. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Insulins: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Insulins: Dipeptidyl Peptidase-IV Inhibitors may enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Risk D: Consider therapy modification
Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Risk D: Consider therapy modification
LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Risk C: Monitor therapy
Lithium: Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: Empagliflozin may enhance the hypotensive effect of Loop Diuretics. Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
MATE1/2-K Inhibitors: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Methylol Cephalexin: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of MetFORMIN. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Risk C: Monitor therapy
Ondansetron: May increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Pacritinib: May increase the serum concentration of OCT1 Substrates (Clinically Relevant with Inhibitors). Risk X: Avoid combination
Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Risk D: Consider therapy modification
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of LinaGLIPtin. Management: Strongly consider using an alternative to any P-glycoprotein inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Risk D: Consider therapy modification
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
Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1,700 mg per day when used together with ranolazine 1,000 mg twice daily. Monitor patients for metformin toxicities, including lactic acidosis and carefully weigh the risks and benefits of this combination. Risk D: Consider therapy modification
Risdiplam: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of risdiplam with MATE substrates if possible. If the combination cannot be avoided, monitor closely for adverse effects. Consider a reduced dose of the MATE substrate according to that substrate's labeling if appropriate. Risk D: Consider therapy modification
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
Sulfonylureas: 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
Sulfonylureas: 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
Tafenoquine: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Risk D: Consider therapy modification
Tafenoquine: May increase the serum concentration of OCT2 Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of OCT2 substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the OCT2 substrate and consider a reduced dose of the OCT2 substrate according to that substrate's labeling. Risk D: Consider therapy modification
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. MetFORMIN may increase the serum concentration of Topiramate. Topiramate may increase the serum concentration of MetFORMIN. Risk C: Monitor therapy
Verapamil: May diminish the therapeutic effect of MetFORMIN. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): MetFORMIN may diminish the anticoagulant effect of Vitamin K Antagonists. Vitamin K Antagonists may enhance the hypoglycemic effect of MetFORMIN. Risk C: Monitor therapy
Metformin may increase ovulation in premenopausal anovulatory patients resulting in unintended pregnancies.
Refer to individual monographs for additional information.
Metformin crosses the placenta (ADA 2023).
The manufacturer does not recommend use of this combination product during the second and third trimesters of pregnancy.
Refer to individual monographs for information related to the treatment of diabetes mellitus in pregnancy.
Metformin is present in breast milk; excretion of empagliflozin and linagliptin is not known.
Due to the potential for serious adverse reactions in the breastfed infant, breastfeeding is not recommended by the manufacturer. Refer to individual monographs for additional information.
Individualized medical nutrition therapy based on the American Diabetes Association recommendations is an integral part of therapy.
Plasma glucose (individualize frequency based on treatment regimen, hypoglycemia risk, and other patient-specific factors) (ADA 2023). Monitor renal function (eGFR) prior to therapy initiation and at least annually or at least every 3 to 6 months if eGFR is <60 mL/minute/1.73 m2 (KDIGO 2020). Monitor hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) annually; folate if megaloblastic anemia is suspected; volume status (eg, BP, hematocrit, electrolytes); signs/symptoms of pancreatitis; signs/symptoms of genital mycotic infections and urinary tract infection; signs/symptoms of heart failure; signs and symptoms of diabetic foot infection (including osteomyelitis) including new pain or tenderness, sores, or ulcers involving the lower limbs. If signs/symptoms of ketoacidosis (eg, nausea/vomiting, abdominal pain, malaise, shortness of breath), confirm diagnosis by direct measurement of blood ketones and arterial pH (measurement of serum bicarbonate or urinary ketones may not be adequate) (AACE [Handelsman 2016]). Monitor vitamin B12 serum concentrations every 1 to 2 years, particularly in patients who have been treated with metformin for ≥4 years, or in patients with peripheral neuropathy, anemia, or risk factors for vitamin B12 deficiency (eg, malabsorption syndromes, reduced dietary intake) (ADA 2023; KDIGO 2020; manufacturer’s labeling).
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 2023; KDIGO 2020).
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 (eg, sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences. 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.
See individual agents.
See individual agents.
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