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Empagliflozin / linagliptin Side Effects

In Summary

Commonly reported side effects of empagliflozin/linagliptin include: urinary tract infection. Other side effects include: increased ldl cholesterol. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to empagliflozin / linagliptin: oral tablet, tablet oral

Along with its needed effects, empagliflozin/linagliptin may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking empagliflozin / linagliptin:

More Common

  • Bladder pain
  • bloody or cloudy urine
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • lower back or side pain

Incidence Not Known

Some side effects of empagliflozin / linagliptin may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More Common

  • Body aches or pain
  • difficulty with breathing
  • ear congestion
  • headache
  • loss of voice
  • runny or stuffy nose
  • sneezing
  • sore throat

Incidence Not Known

  • Discharge with a strong odor from the penis
  • redness, itching, swelling, or pain around the penis
  • vaginal discharge, itching, or odor

For Healthcare Professionals

Applies to empagliflozin / linagliptin: oral tablet

General

The most commonly occurring adverse events have included urinary tract infections, nasopharyngitis, and upper respiratory tract infections.[Ref]

Gastrointestinal

Empagliflozin:

Common (1% to 10%): Nausea

Linagliptin:

Common (1% to 10%): Diarrhea

Frequency not reported: Pancreatitis

Postmarketing reports: Acute pancreatitis, mouth ulceration[Ref]

Pancreatitis was reported in 15.2 cases per 10,000 patient year exposure in patients receiving linagliptin compared to 3.7 cases per 10,000 patient year exposure in those receiving active comparator (placebo or sulfonylurea), during clinical trials. Following completing of clinical trials, 3 additional cases of pancreatitis were reported in those receiving linagliptin. Postmarketing reports of acute pancreatitis, including fatalities, have been reported.[Ref]

Dermatologic

Empagliflozin:

Common (1% to 10%): Pruritus

Postmarketing reports: Rash

Linagliptin:

Postmarketing reports: Rash, bullous pemphigoid[Ref]

Postmarketing reports of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitors. Discontinuation of therapy and treatment with topical or systemic immunosuppressive agents led to resolution in reported cases.[Ref]

Metabolic

When this combination product was added to metformin therapy, the overall incidence of hypoglycemia was 2.2% and 3.6% in patients receiving empagliflozin 10 mg-linagliptin 5 mg and empagliflozin 25 mg-linagliptin 5 mg, respectively. There were no reports of serious hypoglycemia.

Twenty reports of acidosis have been identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database during the period March 2013 through 06 June 2014. All patients required emergency room treatment or hospitalization. These cases were not typical of ketoacidosis or diabetic ketoacidosis (DKA) in that they occurred in patients with type 2 diabetes and their blood sugar levels were only slightly increased. Some factors identified as potentially triggering the acidosis included major illness, reduced food and fluid intake, and reduced insulin dose.[Ref]

Empagliflozin-Linagliptin:

Common (1% to 10%): Hypoglycemia, increased cholesterol, thirst

Empagliflozin:

Common (1% to 10%): Increased low-density lipoprotein cholesterol, dyslipidemia

Rare (Less than 0.1%): Ketoacidosis

Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis

Linagliptin:

Common (1% to 10%): Increased uric acid[Ref]

Genitourinary

Empagliflozin-Linagliptin:

Very Common (10% or more): Urinary tract infection (up to 12.5%)

Postmarketing reports: Urosepsis, pyelonephritis

Empagliflozin:

Common (1% to 10%): Urinary tract infection, female genital mycotic infections, vaginal moniliasis, vulvovaginitis, balanitis, increased urination, male genital mycotic infections

Uncommon (0.1% to 1%): Dysuria[Ref]

Hypersensitivity

Empagliflozin-linagliptin:

Uncommon (0.1% to 1%): Hypersensitivity

Linagliptin:

Frequency not reported: Hypersensitivity reactions including urticaria, angioedema, localized skin exfoliation, or bronchial hyper-reactivity

Postmarketing reports: Serious hypersensitivity reactions including anaphylaxis, angioedema[Ref]

Postmarketing, serious hypersensitivity reactions including angioedema, anaphylaxis, and exfoliative skin conditions have been reported in patients treated with linagliptin. These reactions have occurred within the first 3 months and some have occurred after the first dose.[Ref]

Renal

Empagliflozin:

Frequency not reported: Increased serum creatinine, decreased eGFR

Postmarketing reports: Acute kidney injury (AKI)[Ref]

Postmarketing reports of AKI, some requiring hospitalization and dialysis, have been received for patients treated with SGLT2 inhibitors including empagliflozin. Some reports involved patients younger than 65 years old.[Ref]

Respiratory

Empagliflozin-Linagliptin:

Common (1% to 10%): Nasopharyngitis, upper respiratory infection

Empagliflozin:

Common (1% to 10%): Upper respiratory infection

Linagliptin:

Common (1% to 10%): Nasopharyngitis, cough[Ref]

Musculoskeletal

Between October 2006 and December 2013, thirty-three cases of severe arthralgia have been reported to the FDA Adverse Event Reporting System Database. Each case involved the use of 1 or more dipeptidyl peptidase-4 (DPP-4) inhibitor. In all cases, substantial reduction in prior activity level was reported, 10 patients were hospitalized due to disabling joint pain. In 22 cases, symptoms appeared within 1 month of starting therapy, in 23 cases symptoms resolved less than 1 month after discontinuation. A positive rechallenge was reported in 8 cases, with 6 cases involving use of a different DPP-4 inhibitor. Sitagliptin had the greatest number of cases reported (n=28) followed by saxagliptin (n=5), linagliptin (n=2), alogliptin (n=1), and vildagliptin (n=2).[Ref]

Dipeptidyl peptidase-4 (DPP-4) inhibitors:

-Common (1% to 10%): Arthralgia

-Postmarketing cases: Severe and disabling arthralgia[Ref]

Cardiovascular

Empagliflozin:

Uncommon (0.1% to 1%): Volume depletion

Hematologic

Empagliflozin-Linagliptin:

Frequency not reported: Increased hematocrit

Empagliflozin:

Common (1% to 10%): Increased hematocrit[Ref]

References

1. EMA. European Medicines Agency. European Union "European Medicines Agency. Available from: URL: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/document_listing_000366.jsp&mid=WC0b01ac058067c852" ([2013 - ]):

2. "Product Information. Glyxambi (empagliflozin-linagliptin)." Boehringer Ingelheim, Ridgefield, CT.

3. FDA. U.S. Food and Drug Administration "FDA: SGLT2 inhibitors: Drug Safety Communication - FDA Warns Medicines May Result in a Serious Condition of Too Much Acid in the Blood Available from: URL: http://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm44699" (2015 May 15):

4. US Food and Drug Administration "FDA Drug Safety Communication: FDA warns that DPP-4 inhibitors for type 2 diabetes may cause severe joint pain. Available from: URL: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM460038.pdf." ([2015, Aug 28]):

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Some side effects may not be reported. You may report them to the FDA.

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