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    FDA Advisers Narrowly Okay Empagliflozin CV Mortality Claim

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    graham64
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    FDA Advisers Narrowly Okay Empagliflozin CV Mortality Claim

    Post by graham64 on Thu Jun 30 2016, 23:05

    A US Food and Drug Administration advisory committee has hesitantly given its backing to a new labeling claim, that of reduced cardiovascular mortality for the sodium-glucose cotransporter-2 (SGLT-2) inhibitor empagliflozin (Jardiance, Boehringer Ingelheim/Lilly), a drug used to treat type 2 diabetes.

    The Endocrinologic and Metabolic Drugs Advisory Committee voted 12-11 on June 28 that the data in the EMPA-REG OUTCOME study provided substantial evidence to establish that empagliflozin reduced cardiovascular mortality in the population studied, those with type 2 diabetes and established CV disease.

    Empagliflozin would be the first diabetes drug to claim that it can cut death — if the FDA follows the panel's advice. But the advice wasn't exactly clear-cut.

    "Good luck on figuring out what to do," committee member Marvin A Konstam, MD, professor of medicine, Tufts University, Boston, Massachusetts, told agency officials.

    Most panelists said they were impressed with the reduction in cardiovascular and all-cause mortality, but a majority also said they had reservations about using a single study to support a new labeling claim, especially for the first drug in a relatively new class of agents. A few expressed concern that the mechanism for the mortality reduction has not been determined.

    "I don't think we have to understand a mechanism to accept a benefit," said David W Cooke, MD, interim director of pediatric endocrinology at Johns Hopkins University School of Medicine, Baltimore, Maryland. But it is necessary to have an understanding of which patients might receive the greatest benefit from empagliflozin, said Dr Cooke, who voted against approving the new claim.

    Just how empagliflozin is reducing mortality was a widely discussed topic at the recent American Diabetes Association Scientific Sessions in New Orleans, as reported by Medscape Medical News. Answers are still unclear.

    "We haven't been presented with a plausible mechanism for the effects of this drug on cardiovascular mortality," said FDA panel chair Robert J Smith, MD, professor of medicine and an endocrinologist at the Warren Alpert School of Medicine, Brown University, Providence, Rhode Island.

    Dr Smith voted against allowing a new labeling claim. "As one trial goes, this is a convincing set of data," he said, referring to EMPA-REG. But he added that he was uncertain whether a second trial could produce the same results.

    Nonassessable Deaths Questioned

    EMPA-REG was first reported at the EASD meeting last September and simultaneously published in the New England Journal of Medicine. This was the first time that a diabetes drug had been shown to offer cardiovascular benefits in addition to lowering blood glucose.

    EMPA-REG was initially designed to answer safety concerns, but, with early data indicating a mortality benefit, it underwent multiple modifications in consultation with the FDA. The prespecified primary end point was the time to first occurrence of an adjudicated major adverse CV event (MACE), defined as CV death, nonfatal myocardial infarction (MI), or nonfatal stroke (three-point MACE). The trial was to stop after 691 participants had experienced an adjudicated MACE event.

    The prespecified secondary end point was the time to first occurrence of adjudicated CV death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina (MACE+, or four-point MACE). The company was to conduct four analyses comparing pooled results of two different doses of empagliflozin with placebo with appropriate control of type-1 error.

    According to the FDA, empagliflozin was found to be both noninferior and superior to placebo on MACE (hazard ratio


    , 0.86; 95% CI, 0.74–0.99; P = .04 for superiority). The drug was also found to be noninferior but not superior to placebo on MACE+ (HR, 0.89; 95% CI 0.78–1.01; P = .08 for superiority).

    The risk of MACE appeared to diverge early — about 3 months in — and was almost exclusively accounted for by the CV-death component (HR, 0.62; 95% CI, 0.49–0.77). Empagliflozin did not reduce nonfatal stroke (HR 1.24; 95% CI, 0.92–1.67) or nonfatal MI (HR 0.87; 95% CI, 0.70–1.09).

    Seventy-one empagliflozin deaths and 53 placebo deaths were categorized as "nonassessable" and adjudicated as presumed CV deaths. Those presumed CV deaths made up 40% of the total CV deaths and 27% of overall deaths.

    In a sensitivity analysis that removed all "nonassessable" deaths, empagliflozin was no longer superior to placebo (HR 0.90; 95% CI, 0.77–1.06).

    Some panelists therefore questioned whether the mortality reduction was a true finding.

    But Michael Proschan, PhD, a statistician in the biostatistics research branch at the National Institute of Allergy and Infectious Diseases, said the mortality benefit was real. "I think that's substantiated," he told his colleagues on the panel.

    Boehringer Ingelheim also reported a reduction in hospitalization for heart failure, but most committee members said the company had not given enough proof. This finding is "not nearly as compelling" as the mortality data, said Dr Proschan, who voted for the mortality claim.

    "I'm not impressed with the heart-failure data," agreed panelist Paul Palevsky, MD, professor of medicine at the University of Pittsburgh School of Medicine, Pennsylvania.

    EMPA-REG also showed that empagliflozin was renoprotective, reducing the incidence of worsening nephropathy by 39%, according to Boehringer, which recently unveiled that data at the ADA meeting.

    Dr Palevsky, who voted against the new labeling claim, said the renal data were not rigorously collected or adjudicated. "There are very intriguing data here, but it's far from the level that would establish a specific renal benefit," he said.

    Decision Coming Soon?

    The FDA accepted the Lilly/Boehringer Ingelheim application for a new claim for empagliflozin in January.

    At the time, the company said it expected a decision "within the standard review time frame."

    In a statement, Thomas Seck, MD, Boehringer vice president of clinical development and medical affairs, called the panel vote a "critical step" toward securing approval. "We look forward to continuing to work with the FDA in our ongoing efforts to provide options that help reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease," he said.

    The company told Medscape Medical News it expects a decision on this additional labeling claim for empagliflozin in the second half of 2016.

    http://www.medscape.com/viewarticle/865523


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    Derek
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    Re: FDA Advisers Narrowly Okay Empagliflozin CV Mortality Claim

    Post by Derek on Fri Jul 01 2016, 09:51

    Sounds like a bodge to me getting glucose to come out in pee!
    Sort of being a modern Epicurean! Anything but the self control of low carb! D.
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    Eddie
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    Re: FDA Advisers Narrowly Okay Empagliflozin CV Mortality Claim

    Post by Eddie on Fri Jul 01 2016, 17:25

    Side effects. From here https://www.drugs.com/sfx/empagliflozin-side-effects.html

    Severity: Major
    You should check with your doctor immediately if any of these side effects occur when taking empagliflozin:

    More common:
    Bladder pain
    bloody or cloudy urine
    change in the color, amount, or odor of vaginal discharge
    difficult, burning, or painful urination
    frequent urge to urinate
    itching, stinging, or redness of the vaginal area
    lower back or side pain
    pain during sexual intercourse
    Less common:
    Discharge with a strong odor from the penis
    increased volume of pale, dilute urine
    redness, itching, swelling, or pain around the penis
    waking to urinate at night
    Rare:
    Anxiety
    blurred vision
    chills
    cold sweats
    confusion
    decreased urination
    dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
    fast heartbeat
    headache
    increased hunger
    nausea
    nightmares
    rapid breathing
    seizures
    shakiness
    slurred speech
    sweating
    unusual tiredness or weakness
    Incidence not known:
    Loss of appetite
    swelling of the face, fingers, or lower legs
    troubled breathing
    vomiting
    weight gain
    Severity: Minor
    Some of the side effects that can occur with empagliflozin may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

    Less common:
    Body aches or pain
    cough
    fever
    loss of voice
    muscle pain or stiffness
    nasal congestion
    For Healthcare Professionals
    Applies to empagliflozin: oral tablet

    Cardiovascular
    Volume depletion included decreased ambulatory blood pressure, decreased systolic blood pressure, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope.[Ref]

    Uncommon (0.1% to 1%): Volume depletion[Ref]

    Renal
    Common (1% to 10%): Increased urination
    Uncommon (0.1% to 1%): Dysuria
    Frequency not reported: Increased serum creatinine, decreased eGFR[Ref]

    Genitourinary
    Common (1% to 10%): Female and male genital mycotic infections, urinary tract infection
    Uncommon (0.1% to 1%): Phimosis[Ref]

    Metabolic
    Frequency of hypoglycemia depended on the type of background therapy used. In combination with metformin and sulfonylurea, hypoglycemia was reported in 16.1% of patients taking the 10 mg dose and 11.5% in patients taking the 25 mg dose. In combination with insulin, hypoglycemia was reported in 22.5% of patients taking the 10 mg dose and 29.7% in patients taking the 25 mg dose.

    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]

    Common (1% to 10%): Increased low-density lipoprotein cholesterol
    Frequency not reported: Hypoglycemia
    Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis[Ref]

    General
    The most common reported side effects included urinary tract infections and female genital mycotic infections.[Ref]

    Dermatologic
    Common (1% to 10%): Pruritus[Ref]

    Gastrointestinal
    Common (1% to 10%): Nausea[Ref]

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

    Musculoskeletal
    Common (1% to 10%): Arthralgia[Ref]

    Other
    Common (1% to 10%): Polydipsia[Ref]

    Respiratory
    Common (1% to 10%): Upper respiratory tract infection[Ref]


    _________________
    Type two diabetic-low carb diet (50 carbs per day) and two 500mg Metformin pills per day. Apart from diagnosis HbA1c almost 12-all HbA1c results none diabetic. For over eight years my diabetes medication has not changed. My weight has remained stable, I have suffered no ill effects from my diet whatsoever. Every blood test has proved, I took the right road to my diabetic salvation. For almost seven years, I have asked medical professionals and naysayers, how do I maintain non diabetic BG levels on two Metformin other than low carb ? The silence has been deafening !
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    Paul1976
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    Re: FDA Advisers Narrowly Okay Empagliflozin CV Mortality Claim

    Post by Paul1976 on Fri Jul 01 2016, 17:35

    @Eddie wrote:Side effects. From here https://www.drugs.com/sfx/empagliflozin-side-effects.html

    Severity: Major
    You should check with your doctor immediately if any of these side effects occur when taking empagliflozin:

    More common:
    Bladder pain
    bloody or cloudy urine
    change in the color, amount, or odor of vaginal discharge
    difficult, burning, or painful urination
    frequent urge to urinate
    itching, stinging, or redness of the vaginal area
    lower back or side pain
    pain during sexual intercourse
    Less common:
    Discharge with a strong odor from the penis
    increased volume of pale, dilute urine
    redness, itching, swelling, or pain around the penis
    waking to urinate at night
    Rare:
    Anxiety
    blurred vision
    chills
    cold sweats
    confusion
    decreased urination
    dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
    fast heartbeat
    headache
    increased hunger
    nausea
    nightmares
    rapid breathing
    seizures
    shakiness
    slurred speech
    sweating
    unusual tiredness or weakness
    Incidence not known:
    Loss of appetite
    swelling of the face, fingers, or lower legs
    troubled breathing
    vomiting
    weight gain
    Severity: Minor
    Some of the side effects that can occur with empagliflozin may not need medical attention. As your body adjusts to the medicine during treatment these side effects may go away. Your health care professional may also be able to tell you about ways to reduce or prevent some of these side effects. If any of the following side effects continue, are bothersome or if you have any questions about them, check with your health care professional:

    Less common:
    Body aches or pain
    cough
    fever
    loss of voice
    muscle pain or stiffness
    nasal congestion
    For Healthcare Professionals
    Applies to empagliflozin: oral tablet

    Cardiovascular
    Volume depletion included decreased ambulatory blood pressure, decreased systolic blood pressure, dehydration, hypotension, hypovolemia, orthostatic hypotension, and syncope.[Ref]

    Uncommon (0.1% to 1%): Volume depletion[Ref]

    Renal
    Common (1% to 10%): Increased urination
    Uncommon (0.1% to 1%): Dysuria
    Frequency not reported: Increased serum creatinine, decreased eGFR[Ref]

    Genitourinary
    Common (1% to 10%): Female and male genital mycotic infections, urinary tract infection
    Uncommon (0.1% to 1%): Phimosis[Ref]

    Metabolic
    Frequency of hypoglycemia depended on the type of background therapy used. In combination with metformin and sulfonylurea, hypoglycemia was reported in 16.1% of patients taking the 10 mg dose and 11.5% in patients taking the 25 mg dose. In combination with insulin, hypoglycemia was reported in 22.5% of patients taking the 10 mg dose and 29.7% in patients taking the 25 mg dose.

    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]

    Common (1% to 10%): Increased low-density lipoprotein cholesterol
    Frequency not reported: Hypoglycemia
    Postmarketing reports: Acidosis including diabetic ketoacidosis, ketoacidosis, or ketosis[Ref]

    General
    The most common reported side effects included urinary tract infections and female genital mycotic infections.[Ref]

    Dermatologic
    Common (1% to 10%): Pruritus[Ref]

    Gastrointestinal
    Common (1% to 10%): Nausea[Ref]

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

    Musculoskeletal
    Common (1% to 10%): Arthralgia[Ref]

    Other
    Common (1% to 10%): Polydipsia[Ref]

    Respiratory
    Common (1% to 10%): Upper respiratory tract infection[Ref]

    But apart from the above It's a good,safe and beneficial drug right?? jimlad woot facepalm rofl


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    graham64
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    Re: FDA Advisers Narrowly Okay Empagliflozin CV Mortality Claim

    Post by graham64 on Fri Jul 01 2016, 22:15

    @Paul1976 wrote:But apart from the above It's a good,safe and beneficial drug right??

    It was a close call with eleven members of the FDA panel having voted against and as Eddies post shows they were right to be concerned, those diabetics who are prescribed this drug are guinea pigs in a continuation of the study. Still preferable to the dangerous LCHF diet eh! facepalm  

    Anyway good to see you back Paul hope alls well with you and yours Very Happy


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    I'm a skinny T2 diagnosed 4/4/2008, a high calorie LCHF diet and one metformin a day A1c 6.2 and no complications.

    Proving the LowCarb sceptics wrong for over nine years,

    Not all cherubs are Angels  Wink nor all diabetics Bonkers  Rolling Eyes

      Current date/time is Thu May 25 2017, 11:41