Does metformin make you urinate more

Metformin / pioglitazone Side Effects

Medically reviewed by Drugs.com. Last updated on Feb 7, 2019.

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In Summary

More frequently reported side effects include: dental disease, edema, myalgia, pharyngitis, weight gain, and decreased vitamin b12 serum concentrate. See below for a comprehensive list of adverse effects.

For the Consumer

Applies to metformin / pioglitazone: oral tablet, oral tablet extended release

Warning

Oral route (Tablet; Tablet, Extended Release)

May cause or worsen congestive heart failure, is not recommended in patients with symptomatic heart failure, and is contraindicated in patients with established NYHA Class III or IV heart failure. Monitor patients for signs and symptoms of heart failure after initiation or dose increases and if heart failure occurs, consider dose reduction or discontinuing metformin/pioglitazone (immediate and extended-release formulations) and manage according to current standards of care. Lactic acidosis can occur due to metformin accumulation during treatment with metformin / pioglitazone (immediate and extended-release formulations) and may result in death, hypothermia, hypotension, and resistant bradyarrhythmias; risk factors include renal impairment, concomitant carbonic anhydrase inhibitor use (eg, topiramate), age 65 years or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment. Onset is often subtle with nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain; laboratory abnormalities include elevated blood lactate (greater than 5 mmol/L), anion gap acidosis (without ketonuria or ketonemia), increased lactate:pyruvate ratio, and metformin levels generally greater than 5 mcg/mL. If acidosis is suspected, discontinue treatment, hospitalize the patient immediately, and promptly initiate hemodialysis.

Along with its needed effects, metformin / pioglitazone 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 metformin / pioglitazone:

More common

  • Bladder pain
  • bloody or cloudy urine
  • difficult, burning, or painful urination
  • frequent urge to urinate
  • lower back or side pain
  • swelling of the face, fingers, feet, or lower legs
  • weight gain

Less common

  • Pain or swelling in the arms or legs without any injury
  • pale skin
  • troubled breathing with exertion
  • unusual bleeding or bruising
  • unusual tiredness or weakness

Rare

  • Anxiety
  • blurred vision
  • chills
  • cold sweats
  • confusion
  • cool, pale skin
  • decreased appetite
  • depression
  • diarrhea
  • dizziness
  • fast heartbeat
  • fast, shallow breathing
  • general feeling of discomfort
  • headache
  • increased hunger
  • loss of consciousness
  • muscle pain or cramping
  • nausea
  • nightmares
  • seizures
  • shakiness
  • sleepiness
  • slurred speech
  • stomach discomfort

Some side effects of metformin / pioglitazone 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
  • cough
  • ear congestion
  • fever
  • loss of voice
  • runny or stuffy nose
  • sneezing
  • sore throat

For Healthcare Professionals

Applies to metformin / pioglitazone: oral tablet, oral tablet extended release

Cardiovascular

Metformin-pioglitazone:

Common (1% to 10%): Edema

Pioglitazone:

Very common (10% or more): Edema (26.7%)

Common (1% to 10%): Cardiac failure, chest pain

Thiazolidinediones, including pioglitazone can cause dose-related fluid retention which can cause or exacerbate congestive heart failure in some patients. Combination with insulin and use in patients with NYHA Class I and II congestive heart failure may increase risk.

Gastrointestinal

Metformin-pioglitazone:

Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting

Uncommon (0.1% to 1%): Flatulence

Metformin:

Very common (10% or more): Abdominal pain, diarrhea, loss of appetite, nausea, vomiting

Gastrointestinal events occur most frequently during initiation of therapy and resolve spontaneously in most cases.

Hematologic

Metformin-pioglitazone

Common (1% to 10%): Anemia

Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis

Metformin:

Very rare (less than 0.01%): Vitamin B12 absorption decreased, lactic acidosis

Metabolic

Metformin-pioglitazone:

Common (1% to 10%): Weight increased

Pioglitazone:

Very common (10% or more): Hypoglycemia (27.3%)

Common (1% to 10%): Weight gain

Mean weight increase in patients receiving pioglitazone monotherapy for 1 year was 2 to 3 kg. In combination with metformin, mean weight increase over 1 year was 1.5 kg. The mechanism of weight gain is unclear, but probably involves a combination of fluid retention and fat accumulation.

Respiratory

Metformin-pioglitazone

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

Uncommon (0.1% to 1%): Sinusitis

Pioglitazone:

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

Uncommon (0.1% to 1%): Sinusitis

Nervous system

Metformin-pioglitazone:

Common (1% to 10%): Hypoesthesia, headache, taste disturbance

Uncommon (0.1% to 1%): Insomnia

Metformin:

Common (1% to 10%): Taste disturbance

Pioglitazone:

Common (1% to 10%): Hypoesthesia, headache

Ocular

Visual disturbances have been reported early in treatment and may be related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens. Macular edema has been reported postmarketing in patients taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, although some were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at time of diagnosis. Some patients improved with drug discontinuation.

Metformin-pioglitazone:

Common (1% to 10%): Visual disturbances

Postmarketing reports: Macular edema

Pioglitazone:

Common (1% to 10%): Visual disturbances

Frequency not reported: Macular edema

Dermatologic

Metformin-pioglitazone:

Very rare (less than 0.01%): Erythema, pruritus, urticaria

Metformin:

Very rare (less than 0.01%): Erythema, pruritus, urticaria

Endocrine

Common (1% to 10%): Erectile dysfunction

General

The most commonly reported adverse events included upper respiratory tract infection, edema, diarrhea, headache, and weight gain.

Hepatic

There have been postmarketing reports of hepatic failure, including fatalities, in patients taking pioglitazone. The reports contain insufficient information to establish causality.

Metformin-pioglitazone:

Frequency not reported: Hepatitis, alanine aminotransferase increased, abnormal liver function tests

Metformin:

Frequency not reported: Hepatitis, abnormal liver function tests

Pioglitazone:

Frequency not reported: Alanine aminotransferase increased

Postmarketing reports: Hepatic failure

Musculoskeletal

In pooled analysis of bone fractures in 8100 patients receiving pioglitazone and 7400 receiving comparator treatment; a higher rate of fractures was observed in women receiving pioglitazone (2.6% versus 1.7%). Some epidemiologic studies have suggested a similarly increased risk of fracture in men.

Metformin-pioglitazone:

Common (1% to 10%): Bone fracture, arthralgia

Pioglitazone:

Common (1% to 10%): Bone fracture, myalgia, extremity pain, back pain

Uncommon (0.1% to 1%): Serum creatine phosphokinase elevations

Oncologic

The US FDA has released results of its review of pioglitazone and bladder cancer and concluded that the data suggests use of this drug may be linked to an increase risk of bladder cancer. A 10-year prospective cohort study in diabetic patients performed by the manufacturer (n=158,918 never users; n=34,181 ever users) identified 1075 newly diagnosed cases of bladder cancer in never users and 186 cases in ever users. The fully adjusted hazard ratio (HR) showed pioglitazone use was not associated with an increased risk (HR 1.06 (95% confidence interval 0.89 to 1.26). And while a modest trend towards higher risk with increasing duration was observed, this trend was not statistically significant. Compared to the interim 5-year results, the 10-year results found weaker associations that were not statistically significant. However, there are studies that have shown a statistically significant association between exposure to this drug and bladder cancer and an association between cumulative dose or cumulative duration of exposure and bladder cancer. Overall, this drug may be associated with an increase in the risk of urinary bladder tumors, however there is insufficient data to determine whether this drug is a tumor promoter for urinary bladder tumors.

Metformin-pioglitazone

Uncommon (0.1% to 1%): Bladder cancer

Pioglitazone:

Uncommon (0.1% to 1%): Bladder cancer

Renal

Common (1% to 10%): Hematuria

Hypersensitivity

Metformin-pioglitazone:

Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)

Pioglitazone:

Postmarketing reports: Hypersensitivity and allergic reactions (anaphylaxis, angioedema, and urticaria)

1. Cerner Multum, Inc. “UK Summary of Product Characteristics.” O 0

2. “Product Information. Actoplus Met (metformin-pioglitazone).” Takeda Pharmaceuticals America, Lincolnshire, IL.

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.

Medical Disclaimer

More about metformin / pioglitazone

  • During Pregnancy
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  • Pricing & Coupons
  • En Español
  • 6 Reviews
  • Drug class: antidiabetic combinations
  • FDA Alerts (3)

Consumer resources

  • Metformin and pioglitazone
  • Pioglitazone and Metformin Extended-Release Tablets
  • Pioglitazone and Metformin Tablets
  • Pioglitazone and metformin (Advanced Reading)

Other brands: ActoPlus Met, ActoPlus Met XR

Professional resources

  • Pioglitazone and Metformin (Wolters Kluwer)
  • … +1 more

Related treatment guides

  • Diabetes, Type 2

Metformin is a common first-line treatment for type 2 diabetes. It helps reduce your blood sugar levels, can lower your risk of cardiovascular events like heart attack, and has a low risk of causing harmful drug interactions and severe side effects. The American Diabetes Association (ADA) also recommends metformin for some patients with prediabetes.

Generally, if you are prescribed metformin, you will be on it long term. That could be many decades, unless you experience complications or changes to your health that require you to stop taking it.

However, metformin does have some side effects, and patients often have questions about the safety of long-term use. Here we’ll address some popular myths around metformin’s long-term side effects and explain some potential safety concerns.

Can long-term metformin use causes memory loss and dementia?

Researchers have been investigating the connection between metformin and memory loss for over a decade. Several studies have highlighted a possible link between metformin use and an increased risk of developing dementia. Other studies have found the opposite: a decrease in risk of developing dementia in patients using metformin.

Regardless of metformin use, research seems to show that diabetes itself more than doubles your risk of dementia. So if you’re taking metformin and experience memory loss, it could be your diabetes (and not the drug) that’s causing it.

Overall, the research on metformin and dementia is mixed and not definitive yet. Many clinicians would recommend the continued use of metformin at this time. Its protective role and benefits currently outweigh the unknown risk of dementia.

Can long-term metformin use cause kidney damage?

Metformin does not cause kidney damage. The kidneys process and clear the drug out of your system via urine. If your kidneys are not functioning properly, metformin can build up in your system and cause a condition called lactic acidosis. Lactic acidosis is when there is a dangerous amount of lactic acid in the body. It can be life-threatening and is the main reason why your healthcare provider must monitor your kidney function.

Keep in mind that long-term, uncontrolled diabetes increases your risk of developing kidney problems. The use of medications like metformin can help keep your kidneys and other organs healthy over time.

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Can long-term metformin use make PCOS worse?

Polycystic ovarian syndrome (PCOS) is one of the most common causes of female infertility. It causes ovarian cysts, which make it difficult for an egg to be released and fertilized. The ADA recommends that doctors check for PCOS in people with diabetes, since it’s common to have both conditions at the same time.

Metformin is considered a second-line treatment for PCOS, after hormonal contraceptives (birth control) and lifestyle modifications. PCOS can cause insulin resistance, which can lead to high blood sugar and insulin levels, and metformin combats this. Metformin can also help treat irregular periods, and can be a good option for women with PCOS and type 2 diabetes who cannot tolerate hormonal contraceptives.

More and more, patients seem to be concerned that metformin can make PCOS worse or cause infertility, but there isn’t enough research to prove this. Although metformin is not for every woman with PCOS and the evidence supporting metformin use in women with PCOS is mixed, it is recommended for women and female adolescents with both type 2 diabetes and PCOS. Some clinicians may even recommend that these women continue using metformin through pregnancy.

Can metformin cause anemia?

Yes. Metformin can interfere with the absorption of vitamin B12, a vitamin you need to maintain healthy blood levels. Low vitamin B12 levels can lead to anemia and iron deficiency.

Your blood work should be monitored by your doctor to make sure that you are not seeing a significant decrease in B12. If this happens, taking a B12 supplement may help. If you and your healthcare provider decide it’s necessary, stopping metformin should bring your vitamin B12 levels back to normal.

Can metformin can cause nerve damage?

Along with increasing your risk for anemia, low vitamin B12 levels may also contribute to nerve damage (or neuropathy), which can cause chronic nerve pain. However, uncontrolled diabetes can also lead to neuropathy. If you’re taking metformin to treat type 2 diabetes and experience neuropathy, it could be a symptom of your diabetes rather than a side effect of the drug.

Research on metformin causing nerve damage is mixed overall and suggests that while the neuropathy concern is relevant, it’s unlikely that it’s a side effect of metformin.

Can metformin extend life expectancy?

A number of news articles have recently addressed the rise in popularity of metformin and other drugs that might extend the length of your life. In the early 2000s, research showed that metformin extended life expectancy in mice, but its impact on human life expectancy is currently unknown. Some researchers believe that metformin may be effective in anti-aging, though research is ongoing and nothing is definitive at this time.

Can metformin lower the risk of cancer?

Patients with diabetes may have a 1.5- to 2-fold increase in cancer risk, according to a report from 2010. However, recent research has shown that metformin may be effective in treating and preventing cancer. Studies published in 2018 and 2015 suggest that people taking metformin may have a lower risk for cancer, with some studies suggesting a reduced risk of 30% to 50%.

How does this work? Some researchers have suggested that metformin slows or stops tumor cell growth. However, this research is still limited. It’s also hard to tell if metformin itself lowered cancer risk in the supporting studies because other treatments and interventions may have been involved. It’s unlikely that metformin will be prescribed to treat cancer at this time based on the currently available data.

– – –

The bottom line

Most of the “myths” regarding long-term, negative side effects of metformin are not cause for concern. However, some side effects, like anemia, are worth being aware of. Metformin can also cause short-term side effects like stomach discomfort.

Generally, though, metformin is considered to be a safe and effective treatment for type 2 diabetes and prediabetes. Metformin has been shown to lower the risk of cardiovascular events like heart attack and help reduce the risk of type 2 diabetes complications like poor vision, impaired kidney function, and chronic nerve pain. These issues can appear after years of untreated diabetes, but metformin can help slow or prevent them. If you have diabetes and your provider prescribes metformin, discuss the benefits, side effects, and any concerns you have.

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  • Some diabetes complications are more dangerous, but few are more annoying than diabetic bladder. You can’t pee when you want to, or you go when you don’t want to, or both. What causes diabetes bladder symptoms, and what can we do to prevent and manage them?

    Advertisement

    Bladder problems are among the most common and least talked about diabetes symptoms. Maybe they’re embarrassing to talk about, but they can make you miserable and cause worse problems, such as kidney infections.

    A study by Saeid Golbidi and Ismail Laher of the University of British Columbia found that 55% of people with diabetes have hyperactive “detrusor” muscles, the muscles that push urine out, while 23% have underactive detrusors that won’t empty the bladder completely. Either way, you are set up for incontinence and for urinary tract infection.

    Many of these problems come from nerve damage. You need a lot of healthy nerves for normal bladder function. Nerves to sense fullness, nerves to tell muscles to start pushing, nerves to close sphincters and to open sphincters. All these nerves need to be working and working together. This is difficult, which is one of the reasons toilet training is such a big project for kids.

    Writing in Diabetes Self-Management, urologist Bradley W. Anderson, MD, said, “Common include frequent urination, incontinence, difficulty starting a urinary stream, urinary tract infections, and sensations of needing to urinate urgently. The underlying problem is that neuropathy (nerve damage) causes the bladder to lose the ability to sense when it is full, just as neuropathy in the feet can interfere with a person’s ability to sense pressure or pain.”

    At first, that feels good. You don’t have to go to the bathroom as much. A healthy bladder usually signals “full” with about 300 cubic centimeters (cc), or roughly 10 ounces, of urine. Diabetic nerve damage may let bladders swell to 600 cc or more without feeling full.

    So there’s a honeymoon effect with that, but the bladder stretching weakens the detrusor muscles. Over time, it becomes harder to urinate at all. People with diabetic (or “neurogenic,” meaning caused by nerve damage) bladder often end up spending hours a day trying to urinate.

    According to Dr. Anderson, because the bladder doesn’t empty well, it fills up again quickly, causing frequent urination. “If a bladder is not emptying regularly, it can become so full that it overcomes the sphincter muscle and just ‘overflows,’ resulting in incontinence.” This is called “overflow incontinence.” Incontinence caused by an overactive bladder is called “urge incontinence.”

    I have had both kinds. I’ve been living with a neurogenic bladder for 30 years because of multiple sclerosis (MS). On a good day, I might urinate every hour in the day and every three hours at night.

    What can you do?
    There are ways to prevent diabetic bladder and to manage it, often the same ways. Here are some:

    • Urinate regularly, whether you feel a need or not. Every two hours is often suggested. According to an , this helps keep the bladder from stretching too far. “Sometimes it is helpful to push against the bladder to determine whether it is full as well as to start the flow of urine.”

    • Drink a proper amount of fluids. Six to eight glasses of water a day are often suggested. According to Medscape, “Trying to prevent incontinence by restricting fluids excessively may lead to bladder irritation and actually worsen urge incontinence.”

    • Avoid constipation. The rectum and the bladder are right next to each other. Having hard stool in the rectum can press on the bladder, making it hard to hold urine and hard to push it out. Eat more fiber, do more walking, and take a laxative if necessary.

    • Watch for infection. Diabetic bladders can easily be infected, because urine sits there stagnant instead of flowing through. Watch for cloudy or bloody urine, increased burning, and fever. If you get any of those symptoms, call your doctor. Taking cranberry capsules every day can reduce the risk of infection.

    • If you have an overactive bladder, stay away from spicy foods; orange, grapefruit, and other citrus fruits; and caffeine.

    • Other ways to push urine out: Cross one foot over the other knee to squeeze the bladder. Dip your hand in water or run water to relax the sphincter muscles.

    • Some drugs may help. Bethanechol strengthens detrusor muscles. Terazosin (Hytrin) and doxazosin (Cardura) can relax the urinary sphincter to allow it to open.

    • Maintain good glucose control. Since all these problems come from sugar damage to nerves, the better your glucose control, the fewer problems you are likely to have.

    • Self-catheterizing. If you can’t urinate adequately, sometimes it’s worth inserting a catheter when your bladder needs to be emptied, and removing it afterward. “This may seem intimidating,” says Dr. Anderson, “but it is usually easier than feared… People new to self-catheterization may also worry about contracting an infection, but there is less risk of infection with self-catheterization than there is with a full-time Foley catheter.”

    Dr. Anderson says to catheterize every 3–4 hours during the day to train the bladder. Then you may be able to cut back. “As your bladder recovers,” he says, “you may be able to self-catheterize less frequently…you may be able to get down to a single catheterization at bedtime, then perhaps every other day, then once a week. In most people, the bladder eventually recovers, and catheterization can be eliminated entirely.”

    Read his article for details.

    You don’t need sterile technique, just clean technique. If you can’t do it yourself, you may have a family member or caregiver who can help you. Catheters can be reused, but that slightly increases the risk of infection. Insurance will usually pay for catheters if a doctor orders them and documents their necessity.

    See more about how to self-catheterize here for men and in a video here for women. (Sorry, I couldn’t find a good video for men.) Your urologist may have different information in handouts.

    Please let us know what you do to maintain and improve your bladder function. People might benefit from knowing.

    Xigduo XR

    SIDE EFFECTS

    The following important adverse reactions are described below and elsewhere in the labeling:

    • Lactic Acidosis
    • Hypotension
    • Ketoacidosis
    • Acute Kidney Injury and Impairment in Renal Function
    • Urosepsis and Pyelonephritis
    • Use with Medications Known to Cause Hypoglycemia
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
    • Vitamin B12 Concentrations
    • Genital Mycotic Infections
    • Increases in Low-Density Lipoprotein Cholesterol (LDL-C)
    • Bladder Cancer

    Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    Dapagliflozin And Metformin Hydrochloride

    Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin coadministered with metformin immediate-or extended-release was used to evaluate safety. This pool included several add-on studies (metformin alone and in combination with a dipeptidyl peptidase-4 inhibitor and metformin, or insulin and metformin, 2 initial combination with metformin studies, and 2 studies of patients with cardiovascular disease and type 2 diabetes who received their usual treatment ). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool. Across these 8 studies 983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin. These 8 studies provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients.

    The overall incidence of adverse events for the 8-study, short-term, placebo-controlled pool in patients treated with dapagliflozin 10 mg and metformin was 60.3% compared to 58.2% for the placebo and metformin group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin was 4% compared to 3.3% for the placebo and metformin group. The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).

    Table 1 shows common adverse reactions associated with the use of dapagliflozin and metformin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin and metformin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

    Table 1: Adverse Reactions in Placebo-Controlled Studies Reported in ≥2% of Patients Treated with Dapagliflozin and Metformin

    Adverse Reaction % of Patients
    Pool of 8 Placebo-Controlled Studies
    Placebo and Metformin
    N=1185
    Dapagliflozin 5 mg and Metformin
    N=410
    Dapagliflozin 10 mg and Metformin
    N=983
    Female genital mycotic infections* 1.5 9.4 9.3
    Nasopharyngitis 5.9 6.3 5.2
    Urinary tract infections† 3.6 6.1 5.5
    Diarrhea 5.6 5.9 4.2
    Headache 2.8 5.4 3.3
    Male genital mycotic infections‡ 0 4.3 3.6
    Influenza 2.4 4.1 2.6
    Nausea 2.0 3.9 2.6
    Back pain 3.2 3.4 2.5
    Dizziness 2.2 3.2 1.8
    Cough 1.9 3.2 1.4
    Constipation 1.6 2.9 1.9
    Dyslipidemia 1.4 2.7 1.5
    Pharyngitis 1.1 2.7 1.5
    Increased urination§ 1.4 2.4 2.6
    Discomfort with urination 1.1 2.2 1.6
    * Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, genital infection, vulvovaginitis, fungal genital infection, vulvovaginal candidiasis, vulval abscess, genital candidiasis, and vaginitis bacterial. (N for females: Placebo and metformin=534, dapagliflozin 5 mg and metformin=223, dapagliflozin 10 mg and metformin=430).
    † Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, pyelonephritis, urethritis, and prostatitis.
    ‡ Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection, posthitis, balanoposthitis. (N for males: Placebo and metformin=651, dapagliflozin 5 mg and metformin=187, dapagliflozin 10 mg and metformin=553).
    § Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.

    Metformin Hydrochloride

    In placebo-controlled monotherapy trials of metformin extended-release, diarrhea and nausea/vomiting were reported in >5% of metformin-treated patients and more commonly than in placebo-treated patients (9.6% versus 2.6% for diarrhea and 6.5% versus 1.5% for nausea/vomiting). Diarrhea led to discontinuation of study medication in 0.6% of the patients treated with metformin extended-release.

    Pool of 12 Placebo-Controlled Studies for Dapagliflozin 5 and 10 mg

    Dapagliflozin

    The data in Table 2 are derived from 12 placebo-controlled studies ranging from 12 to 24 weeks. In 4 studies dapagliflozin was used as monotherapy, and in 8 studies dapagliflozin was used as add-on to background antidiabetic therapy or as combination therapy with metformin .

    These data reflect exposure of 2338 patients to dapagliflozin with a mean exposure duration of 21 weeks. Patients received placebo (N=1393), dapagliflozin 5 mg (N=1145), or dapagliflozin 10 mg (N=1193) once daily. The mean age of the population was 55 years and 2% were older than 75 years of age. Fifty percent (50%) of the population were male; 81% were White, 14% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 6 years, had a mean HbA1c of 8.3%, and 21% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired in 92% of patients and moderately impaired in 8% of patients (mean eGFR 86 mL/min/1.73 m2).

    Table 2 shows common adverse reactions associated with the use of dapagliflozin. These adverse reactions were not present at baseline, occurred more commonly on dapagliflozin than on placebo, and occurred in at least 2% of patients treated with either dapagliflozin 5 mg or dapagliflozin 10 mg.

    Table 2: Adverse Reactions in Placebo-Controlled Studies Reported in ≥2% of Patients Treated with Dapagliflozin

    Adverse Reaction % of Patients
    Pool of 12 Placebo-Controlled Studies
    Placebo
    N=1393
    Dapagliflozin 5 mg
    N=1145
    Dapagliflozin 10 mg
    N=1193
    Female genital mycotic infections* 1.5 8.4 6.9
    Nasopharyngitis 6.2 6.6 6.3
    Urinary tract infections† 3.7 5.7 4.3
    Back pain 3.2 3.1 4.2
    Increased urination‡ 1.7 2.9 3.8
    Male genital mycotic infections§ 0.3 2.8 2.7
    Nausea 2.4 2.8 2.5
    Influenza 2.3 2.7 2.3
    Dyslipidemia 1.5 2.1 2.5
    Constipation 1.5 2.2 1.9
    Discomfort with urination 0.7 1.6 2.1
    Pain in extremity 1.4 2.0 1.7
    * Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for females: vulvovaginal mycotic infection, vaginal infection, vulvovaginal candidiasis, vulvovaginitis, genital infection, genital candidiasis, fungal genital infection, vulvitis, genitourinary tract infection, vulval abscess, and vaginitis bacterial. (N for females: Placebo=677, dapagliflozin 5 mg=581, dapagliflozin 10 mg=598).
    † Urinary tract infections include the following adverse reactions, listed in order of frequency reported: urinary tract infection, cystitis, Escherichia urinary tract infection, genitourinary tract infection, pyelonephritis, trigonitis, urethritis, kidney infection, and prostatitis.
    ‡Increased urination includes the following adverse reactions, listed in order of frequency reported: pollakiuria, polyuria, and urine output increased.
    § Genital mycotic infections include the following adverse reactions, listed in order of frequency reported for males: balanitis, fungal genital infection, balanitis candida, genital candidiasis, genital infection male, penile infection, balanoposthitis, balanoposthitis infective, genital infection, posthitis. (N for males: Placebo=716, dapagliflozin 5 mg=564, dapagliflozin 10 mg=595).

    Pool of 13 Placebo-Controlled Studies for Dapagliflozin 10 mg

    Dapagliflozin 10 mg was also evaluated in a larger placebo-controlled study pool. This pool combined 13 placebo-controlled studies, including 3 monotherapy studies, 9 add-on to background antidiabetic therapy studies, and an initial combination with metformin study. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg for a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population were male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, had a mean HbA1c of 8.2%, and 30% had established microvascular disease. Baseline renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients (mean eGFR 82 mL/min/1.73 m2).

    Volume Depletion

    Dapagliflozin causes an osmotic diuresis, which may lead to reductions in intravascular volume. Adverse reactions related to volume depletion (including reports of dehydration, hypovolemia, orthostatic hypotension, or hypotension) are shown in Table 3 for the 12-study and 13-study, short-term, placebo-controlled pools .

    Table 3: Adverse Reactions of Volume Depletion* in Clinical Studies with Dapagliflozin

    Impairment of Renal Function

    Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR (see Table 4). In patients with normal or mildly impaired renal function at baseline, serum creatinine and eGFR returned to baseline values at Week 24. Renal-related adverse reactions, including renal failure and blood creatinine increase, were more frequent in patients treated with dapagliflozin (see Table 5). Elderly patients and patients with impaired renal function were more susceptible to these adverse reactions (see Table 5). Sustained decreases in eGFR were seen in patients with moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m2).

    Table 4: Changes in Serum Creatinine and eGFR Associated with Dapagliflozin in the Pool of 12 Placebo-Controlled Studies and Moderate Renal Impairment Studies

    Table 5: Proportion of Patients with at Least One Renal Impairment-Related Adverse Reaction

    In the pool of 12 clinical studies, a subgroup analysis assessed the safety of patients with eGFR between 30 to less than 60 mL/min/1.73 m2. At Week 24, the safety was similar to that seen in the overall program, although a higher proportion of patients had at least one event related to renal impairment or failure.

    Fractures

    In a study of patients with eGFR 30 to less than 60 mL/min/1.73 m2, 13 patients experienced bone fractures for treatment durations up to 104 weeks. No fractures occurred in the placebo group, 5 occurred in the dapagliflozin 5 mg group, and 8 occurred in the dapagliflozin 10 mg group. Eight of these 13 fractures were in patients who had a baseline eGFR of 30 to 45 mL/min/1.73 m2. Ten of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the anatomic site of fracture.

    Hypoglycemia

    The frequency of hypoglycemia by study is shown in Table 6. Hypoglycemia was more frequent when dapagliflozin was added to sulfonylurea or insulin .

    Table 6: Incidence of Major* and Minor† Hypoglycemia in Placebo-Controlled Studies

    Genital Mycotic Infections

    Genital mycotic infections were more frequent with dapagliflozin treatment. Genital mycotic infections were reported in 0.9% of patients on placebo, 5.7% on dapagliflozin 5 mg, and 4.8% on dapagliflozin 10 mg, in the 12-study placebo-controlled pool. Discontinuation from study due to genital infection occurred in 0% of placebo-treated patients and 0.2% of patients treated with dapagliflozin 10 mg. Infections were more frequently reported in females than in males (see Table 2). The most frequently reported genital mycotic infections were vulvovaginal mycotic infections in females and balanitis in males. Patients with a history of genital mycotic infections were more likely to have a genital mycotic infection during the study than those with no prior history (10.0%, 23.1%, and 25.0% versus 0.8%, 5.9%, and 5.0% on placebo, dapagliflozin 5 mg, and dapagliflozin 10 mg, respectively).

    Hypersensitivity Reactions

    Hypersensitivity reactions (e.g., angioedema, urticaria, hypersensitivity) were reported with dapagliflozin treatment. Across the clinical program, serious anaphylactic reactions and severe cutaneous adverse reactions and angioedema were reported in 0.2% of comparator-treated patients and 0.3% of dapagliflozin-treated patients. If hypersensitivity reactions occur, discontinue use of dapagliflozin; treat per standard of care and monitor until signs and symptoms resolve.

    Laboratory Tests

    Increase In Hematocrit

    Dapagliflozin

    In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were −0.33% in the placebo group and 2.30% in the dapagliflozin 10 mg group. By Week 24, hematocrit values >55% were reported in 0.4% of placebo-treated patients and 1.3% of dapagliflozin 10 mg–treated patients.

    Increase In Serum Inorganic Phosphorus

    Dapagliflozin

    In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10 mg–treated patients compared with placebo-treated patients (mean increases of 0.13 mg/dL versus −0.04 mg/dL, respectively). Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17-65 or ≥5.1 mg/dL if age ≥66) were reported in the dapagliflozin 10 mg group versus the placebo group at Week 24 (1.7% versus 0.9%, respectively).

    Increase In Low-Density Lipoprotein Cholesterol Dapagliflozin

    Dapagliflozin

    In the pool of 13 placebo-controlled studies, changes from baseline in mean lipid values were reported in dapagliflozin-treated patients compared to placebo-treated patients. Mean percent change from baseline at Week 24 were 0.0% versus 2.5% for total cholesterol and -1.0% versus 2.9% for LDL cholesterol in the placebo and dapagliflozin 10 mg groups, respectively.

    Vitamin B12 Concentrations

    Metformin hydrochloride

    Metformin may lower serum vitamin B12 concentrations. Measurement of hematologic parameters on an annual basis is advised in patients on XIGDUO XR and any apparent abnormalities should be appropriately investigated and managed .

    Postmarketing Experience

    Dapagliflozin

    Additional adverse reactions have been identified during postapproval use of dapagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

    • Ketoacidosis
    • Acute Kidney Injury and Impairment in Renal Function
    • Urosepsis and Pyelonephritis
    • Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene)
    • Rash
    • Cholestatic, hepatocellular, and mixed hepatocellular liver injury

    Read the entire FDA prescribing information for Xigduo XR (Dapagliflozin and Metformin HCl Extended-release Tablets)

    Your guide to getting ON IT with JARDIANCE

    IMPORTANT SAFETY INFORMATION

    • Do not take JARDIANCE if you are allergic to empagliflozin or any of the ingredients in JARDIANCE.
    • Do not take JARDIANCE if you have severe kidney problems or are on dialysis.

    JARDIANCE can cause serious side effects, including:

    • Dehydration. JARDIANCE can cause some people to have dehydration (the loss of body water and salt). Dehydration may cause you to feel dizzy, faint, light-headed, or weak, especially when you stand up. You may be at a higher risk of dehydration if you: have low blood pressure, take medicines to lower your blood pressure, including water pills (diuretics), are on a low salt diet, have kidney problems, are 65 years of age or older.
    • Vaginal yeast infection. Women who take JARDIANCE may get vaginal yeast infections. Talk to your doctor if you experience vaginal odor, white or yellowish vaginal discharge (discharge may be lumpy or look like cottage cheese), and/or vaginal itching.
    • Yeast infection of the penis. Men who take JARDIANCE may get a yeast infection of the skin around the penis, especially uncircumcised males and those with chronic infections. Talk to your doctor if you experience redness, itching or swelling of the penis, rash of the penis, foul smelling discharge from the penis, and/or pain in the skin around the penis.
    • Ketoacidosis (increased ketones in your blood or urine). Ketoacidosis is a serious condition and may need to be treated in the hospital. Ketoacidosis may lead to death. Ketoacidosis occurs in people with type 1 diabetes and can also occur in people with type 2 diabetes taking JARDIANCE, even if blood sugar is less than 250 mg/dL. Stop taking JARDIANCE and call your doctor right away if you get any of the following symptoms, and if possible, check for ketones in your urine: nausea, vomiting, stomach-area (abdominal) pain, tiredness, or trouble breathing.
    • Kidney problems. Sudden kidney injury has happened in people taking JARDIANCE. Talk to your doctor right away if you reduce the amount you eat or drink, or if you lose liquids; for example, from vomiting, diarrhea, or being in the sun too long.
    • Serious urinary tract infections. Serious urinary tract infections can occur in people taking JARDIANCE and may lead to hospitalization. Tell your doctor if you have symptoms of a urinary tract infection, such as a burning feeling when passing urine, a need to urinate often or right away, pain in the lower part of your stomach or pelvis, or blood in the urine. Sometimes people also may have a fever, back pain, nausea or vomiting.
    • Low blood sugar (hypoglycemia). If you take JARDIANCE with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of low blood sugar is higher. The dose of your sulfonylurea or insulin may need to be lowered. Symptoms of low blood sugar may include headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heartbeat, sweating, shaking or feeling jittery.
    • Necrotizing fasciitis. A rare but serious bacterial infection that causes damage to the tissue under the skin in the area between and around your anus and genitals (perineum). This bacterial infection has happened in women and men who take JARDIANCE, and may lead to hospitalization, multiple surgeries, and death. Seek medical attention immediately if you have fever or are feeling very weak, tired or uncomfortable (malaise), and you develop any of the following symptoms in the area between and around your anus and genitals: pain or tenderness, swelling, and redness of skin (erythema).
    • Allergic (hypersensitivity) reactions. Symptoms of serious allergic reactions to JARDIANCE may include: swelling of your face, lips, throat and other areas of your skin, difficulty with swallowing or breathing, raised, red areas on your skin (hives). If you have any of these symptoms, stop taking JARDIANCE and contact your doctor or go to the nearest emergency room right away.
    • Increased fats in your blood (cholesterol).

    The most common side effects of JARDIANCE include urinary tract infections and yeast infections in females. These are not all the possible side effects of JARDIANCE. For more information, ask your doctor or pharmacist.

    Before you take JARDIANCE, tell your doctor if you have kidney problems. Your doctor may do blood tests to check your kidneys before and during your treatment with JARDIANCE. Also tell your doctor if you have liver problems; have a history of urinary tract infections or problems with urination; are going to have surgery; are eating less due to illness, surgery, or a change in your diet; have or have had problems with your pancreas, including pancreatitis or surgery on your pancreas; drink alcohol very often, or drink a lot of alcohol in the short term (“binge” drinking); have any other medical conditions; are pregnant or plan to become pregnant. JARDIANCE may harm your unborn baby. If you become pregnant while taking JARDIANCE, tell your doctor as soon as possible. Tell your doctor if you are breastfeeding or are planning to breastfeed. JARDIANCE may pass into your breast milk and may harm your baby. Do not breastfeed while taking JARDIANCE.

    Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Especially tell your doctor if you take water pills (diuretics) or medicines that can lower your blood sugar, such as insulin.

    You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1‑800‑FDA‑1088.

    For more information, please see Prescribing Information and Medication Guide.

    CL-JAR-100026 10.30.18

    Diabetes and nighttime urination, or nocturia, can be a sign of uncontrolled blood sugar levels

    This guide to nocturia explains the basics of recognising nocturia, and how to avoid it.

    What is nocturia?

    Nocturia is defined as nocturnal urination. This means the need to get up in the night to go to the toilet.

    Needing to go to the toilet up to once during the night is considered to be normal. Needing to urinate more than once during the night could indicate a temporary or longer term problem may be present.

    Causes of nocturia

    There are a number of possible causes for needing to urinate more frequently than normal at night and these may include one or more of the following:

    • Diabetes insipidus
    • High blood glucose levels
    • Autonomic neuropathy
    • Urinary tract infections
    • Cystitis
    • Prostate diseases
    • Pregnancy
    • Excessive fluid intake – particularly alcohol or caffeine intake
    • Taking diuretic medications
    • Parkinson’s disease
    • Multiple sclerosis

    Nocturia is more likely to appear as we get older.

    Diabetes and nocturia

    Having high blood glucose levels can cause the body to excrete excess glucose via the urine. In this instance, more sugar appears in the urine and simulates extra volumes of urine to be produced.

    If you regularly have high blood glucose levels, you may increase the risk of picking up a urinary tract infection which can also increase the need to urinate through the night.

    One specific form of diabetes that is not linked with abnormal blood glucose levels, diabetes insipidus, is closely linked with nocturia.

    How can nocturia be treated?

    How nocturia is treated will depend upon what the underlying cause is. If you are having than recommended blood glucose levels, bringing your levels under tighter control could help to reduce the need to urinate at night. Contact your GP or diabetes team for help in improving your blood glucose control

    If nocturia becomes troublesome or more frequent than normal, speak to your GP a sign of a condition unrelated to diabetes.

    In some cases, your doctor may prescribe medication to help reduce the frequency of urination over night. Diuretic medication may be prescribed for use earlier in the day to help you pass excess urine before going to sleep.

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