Tag Archives: Invokana

Diabetes Drug Lowers CV Events, but at Serious Cost: Amputation Risk

A new study demonstrates that a relatively new and popular diabetes drug, Invokana (canagliflozin), also has cardiovascular benefits, such as reducing the risk of heart attacks, but at a serious cost – an increased risk of leg and foot amputation.

Conducted by Invokana’s manufacturer, Janssen Pharmaceutical, results showed that patients on Invokana saw the risk of cardiovascular events decline by 14% compared to those on placebo. The drug also lowered the risk of kidney decline by 40%. Results were presented at both the American Diabetes Association annual meeting and in the New England Journal of Medicine.

But the research also showed that patients taking Invokana had nearly twice the risk of amputation – primarily in the foot and toes – compared with those on placebo. The FDA was already aware of this and mandated a “black box” warning – the most stringent the agency can require – on the drug’s labeling about the amputation risk last month.

Invokana is part of the newest class of diabetes medications known as SGLT-2 inhibitors. A trial published in 2015 showed that Jardiance (empagliflozin) also had cardiovascular benefits. However, unlike Jardiance, Invokana did not demonstrate a reduction in cardiovascular death in the newest study.

New Diabetes Drugs May Boost Ketoacidosis Risk

The newest class of diabetes drugs on the market may increase a patient’s risk for developing a serious complication of the disease that can potentially be fatal.

Researchers found that type 2 diabetes patients taking SGLT2 inhibitors – which include Farxiga (dapagliflozin), Invokana (canagliflozin) and Jardiance (empagliflozin) – were twice as likely to experience diabetic ketoacidosis compared to people who were taking another type of diabetes medication. In diabetic ketoacidosis, a patient has high levels of acids known as ketones in the blood. Symptoms include vomiting, abdominal pain, shortness of breath and brain swelling.

Researchers came to their conclusion after looking at 40,000 people taking an SGLT2 inhibitor, and then comparing results to those on a DPP-4 inhibitor. Drugs in the latter group include Januvia (sitagliptin), Onglyza (saxagliptin) and Tradjenta (linagliptin).

After 180 days, 26 patients taking a DPP-4 inhibitor were diagnosed with diabetic ketoacidosis compared to 55 individuals taking SGLT2 inhibitors, they reported in the New England Journal of Medicine. Study authors, however, noted that the rate of ketoacidosis is still very small with SGLT2 inhibitors.

“This is a side effect that’s usually seen in patients with type 1 diabetes mellitus – not type 2 – so doctors are not ‘on the lookout’ for it,” lead author Michael Fralick, MD, of Boston’s Brigham and Women’s Hospital, said in a statement. “That means that the risk of this side effect might actually be even higher than what we found due to misdiagnosis/under recording.”

Quick Hits: Invokana and Amputations, Nonprescription Ritalin Side Effects, & a Postmarket Studies Lag

Patients Taking Invokana Have an Increased Risk of Leg and Foot Amputations
The FDA reports that the type 2 diabetes medicine Invokana (canagliflozin) causes an increased risk of leg and foot amputations. Two large clinical trials showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo. Amputations of the toe and middle of the foot were the most common. Some patients had more than one amputation, some involving both limbs. Based on the clinical trial findings, the FDA is now requiring the most prominent Boxed Warning to be added to canagliflozin drug labels. Via FDA. Posted May 16, 2017.

Nonprescription use of Ritalin linked to adverse side effects, UB study finds
A University of Buffalo study found that the nonprescription use of the stimulant drug Ritalin was linked to unwanted side effects. Researchers examined changes in the brains of rats that received regular doses of Ritalin during what would be equivalent to adolescence in humans, a time of significant brain growth and development. Results found changes in brain chemistry associated with risk-taking behaviors, disruptions in the sleep/wake cycle and problematic weight loss. Via University of Buffalo. Posted May 17, 2017.

Too many postmarketing studies are never published
The FDA requires postmarket studies, including submission of status reports, for certain drugs. FDA researchers queried an internal database to identify all reportable postmarket drug studies classified as having been “fulfilled” by the FDA between 2009 and 2013. As of July 2016, 183 of the 288 postmarket studies (63.5%) meeting inclusion criteria were published in either the scientific literature or on the ClinicalTrials.gov website. More studies were published in journals than in the trial registry. Although there have been calls for more data sharing, publication rates for completed postmarket studies required by FDA remain low. Via JAMA. Posted May 15, 2017.

Feeling Anxious? Depressed? Check Your Meds

If you find yourself feeling on edge for no apparent reason while taking a cold medicine or diuretic, you most likely wouldn’t connect the two. However, anxiety happens to be just one of many mood-altering symptoms that can be brought on by certain meds.

“Many medications, whether prescribed or found over the counter, can cause psychiatric symptoms,” says Shiyun Kim, PharmD, BCACP, BCPP, CDE, a clinical pharmacist and clinical assistant professor at the University of Illinois Hospital & Health Sciences System, and a spokesperson for the American Pharmacists Association.

She explains that a wide range of factors influence the way a drug affects each person, including things like metabolism, underlying illness, and interactions with other drugs. “Any variations that occur, such as with improper doses or individual reactions, can result in undesirable psychiatric symptoms,” though they are relatively uncommon.

If you feel that you may be suffering from these side effects, notify your providers immediately. “Keep in mind that some medications can be stopped abruptly, while others need to be tapered to prevent further adverse effects,” Dr. Kim emphasizes. “Your provider can make the best decision with you.”

Take note of the following medications that can have these kinds of effects, and read on to find out how to minimize the risks.

Oxycontin and Similar Pain Medications

“Most prescription pain medication, such as oxycodone (OxyContin) or hydrocodone, can cause drowsiness, which can make one feel ‘cloudy’ and lack motivation — and these symptoms closely mimic depression,” according to Bree Meinzer, PharmD, CTTS, a pharmacy practice resident at Ohio Northern University. Opioids can also lead to more severe symptoms like paranoia, hallucinations, psychosis and dementia, especially at high doses. Signs that you may have taken too much of an opioid include trouble breathing and unconsciousness. People with opioid dependence and those who suffer from HIV, liver or lung disease or suffer from depression may be more susceptible to these effects, according to the World Health Organization. If you are on a pain medication that makes you drowsy or “cloudy” and you do not like how it makes you feel, you should talk to your doctor about other ways to adequately manage your pain.

Lasix, Microzide and Other Diuretics

Medications that reduce fluid retention and swelling, including furosemide (Lasix) and hydrochlorothiazide (Microzide), increase urination. This can lead to dehydration, especially in the elderly, and can result in hallucinations and dizziness, says Dr. Meinzer. SGLT2 inhibitors such as canagliflozin (Invokana) and empagliflozin (Jardiance), which are drugs used to treat diabetes, can also increase urination and cause dehydration. If you are taking these types of medication, be sure to drink plenty of water to stay sufficiently hydrated. The amount of water to drink should be discussed with your doctor and is dependent on your weight. “These medications should also be taken in the morning or early afternoon to avoid frequent urination at night,” which could disrupt sleep, she advises.

Ask your doctor to take a look at your current medication regimen to rule out potential drug-drug interactions that could cause psychiatric side effects.

Requip and Other Dopamine Agonists. Medications like ropinirole (Requip), often prescribed for restless leg syndrome and Parkinson’s disease, increase the brain chemical dopamine, which helps regulate mood and behavior. Too much dopamine can cause hallucinations, notes Dr. Meinzer, and more extreme potential side effects include confusion, mania, depression and impulse control disorders like compulsive gambling or eating. “There are other options for restless leg syndrome that don’t increase dopamine, though medications like ropinirole typically work best.” There are also different medications for Parkinson’s, though you and your doctor should carefully consider your particular treatment needs. If you experience these kinds of symptoms while taking this type of medication, it may be that your dose is too high.

Ritalin, Adderall and Other Stimulants

Drugs that are commonly used for the treatment of attention-deficit hyperactivity disorder (ADHD) include those sold under the brand names Ritalin and Adderall. Although these stimulant medications “help children and adolescents focus and stay on task, side effects include increased heart rate and insomnia, which can often cause anxiety and restlessness,” says Dr. Meinzer. Stimulants “excite the central nervous system and can disrupt normal communication between cells in the brain,” adds Dr. Kim. “This class of drugs may also cause bizarre behavior, agitation, mania, paranoia and nightmares.” Dr. Meinzer suggests talking to your healthcare provider if you feel extremely restless and anxious while taking this type of medication. Again, it is possible that your dose is simply too high.

Corticosteroids

Medications like prednisone, cortisone and methylprednisolone are often prescribed “to help respiratory symptoms and decrease inflammation with chronic diseases,” Dr Meinzer explains. They are typically only “used for a short term to help alleviate symptoms, but if you are on these medications for a long time, they can cause some unwanted side effects.” Use of these drugs for more than a few months can increase the chances of experiencing mania, anxiety, depression, paranoia and psychosis, which have mostly been reported by patients using high doses or abusing the medication, says Dr Kim. Though experts are unclear about the exact reasons for such side effects with these drugs, research suggests that it may have to do with the way steroids work in the area of the brain that influences memory and emotion. It is also possible that “high levels of steroids result in brain damage and cause cognitive dysfunction.”

Zarontin and Other Anticonvulsants

Medications such as ethosuximide (Zarontin), which are used to control seizures in people with epilepsy, can cause symptoms resembling depression. These drugs have also been found to increase suicidal thoughts and behavior. “If you start to experience these symptoms on an anticonvulsant, you should talk to your doctor about other regimens,” Dr. Meinzer recommends. “There are other medications in the same class that are less likely to cause this side effect,” though your doctor may want you to stay on the medication because it may be the one that is most effective for you. “Anticonvulsants are usually tricky to dose and may need lab monitoring to make sure they are in the proper range.”

Dr. Kim offers the following general tips to help prevent or deal with these side effects:

  • When you are prescribed a drug, ask your provider about potential side effects that are commonly noted and reported.
  • Ask your provider to take a look at your current medication regimen to rule out potential drug-drug interactions that could cause psychiatric side effects.
  • Withdrawal of some drugs can cause symptoms such as anxiety, agitation or depression. Therefore, call your doctor before stopping medications on your own.
  • When purchasing an over-the-counter (OTC) medication, take the time to read the instructions on the package. If anything is unclear, ask the pharmacist for guidance.

Need to Know: Diabetes Drugs

If you’ve been diagnosed with type 2 diabetes, losing weight, exercising and changes in diet or exercise might be enough to keep your blood sugar in check. If it is not, your doctor is likely to prescribe a medication. While insulin is among one of the first treatments a medical professional will choose, it’s become more and more common to also prescribe an oral or injectable medicine. But with many different diabetes drug classes out there, which ones are the most effective and what are the side effects associated with them?

Common Names

Oral Medications: Meglitinides: Prandin and Starlix; Sulfonylureas: Amaryl and Glucotrol; Biguanides: metformin, Glumetza and Glucophage; Thiazolidinediones: Actos and Avandia; SGLT-2 Inhibitors: Invokana, Farxiga and Jardiance; DPP-4 Inhibitors: Januvia (sitagliptin), Onglyza (saxagliptin) Tradjenta (linagliptin), Nesina (alogliptin)

Injectable Medications: GLP-1 Receptor Agonists: Byetta/Bydureon, Victoza and Trulicity; Amylin Mimetics: Symlin.

Insulins: Rapid Acting: NuvoLog, Apidra and Humalog; Long Acting: Tresiba, Levemir, Lantus, Toujeo

Side Effects and What to Do About Them

Since there are so many types of diabetes meds, it’s best to discuss side effects for each drug classification.

Prandin and Starlix (Meglitinides) tend to work quickly and don’t stay in the body long, which is why they are usually taken right before or during meals. However, they can lead to low blood sugar (hypoglycemia), weight gain, nausea, back pain and headache.

Drug interactions: Meglitinides may interact with antifungals as well as some antibiotics such as erythromycin, which can result in hypoglycemia. Calcium channel blockers (a class of high blood pressure drugs), corticosteroids, diuretics and thyroid drugs may cause hyperglycemia.

Amaryl and Glucotrol (Sulfonylureas) work by stimulating the production of insulin. They have been around for a while, so they are relatively inexpensive. However, hypoglycemia, anemia, dizziness, drowsiness, weight gain, nausea, skin rash and headache are all possible side effects.

Metformin, Glumetza and Glucophage (Biguanides) are not associated with a risk of hypoglycemia, unlike other types of oral meds. However, they can lead to nausea, diarrhea, buildup of lactic acid, weight loss and may leave a metallic taste in the mouth.

Drug interactions: With biguanides, patients should avoid certain antibiotics (trimethoprim or vancomycin), diuretics (amiloride and furosemide), gastrointestinal/acid reflux medications (cimetidine and ranitidine), and heart medications (digoxin). Morphine, the antimalaria drug quinine and the blood thinner warfarin, a blood thinner, should be avoided. Limiting alcohol consumption is also a must.

Avandia and Actos (Thiazolidinediones) have had a troubled history due to a risk of heart failure or heart attacks associated with them. In 2007, the FDA slapped a “black box” warning –- the most stringent it can require –- about the increased risk for heart attacks on the drugs and later put limitations on their sale. However, in 2013, citing new evidence, the FDA reversed course and had the warning removed from labeling of Avandia. The labeling on Actos still contains the warning. Other side effects are respiratory problems, stroke, liver disease, bone fractures, fluid retention, abdominal pain, blurred vision, dry mouth, increased urination. Actos may also increase the risk for bladder cancer.

Drug interactions: Beta blockers (used for people at risk of heart failure) should be avoided in people taking thiazolidinediones. The drug class may also interfere with the effectiveness of ibuprofen and anticoagulants such as warfarin, and can also raise side effects. Those with asthma or COPD (chronic obstructive pulmonary disease) should also avoid thiazolidinediones. For SGLT-2s, they should be avoided in people with ketoacidosis.

Invokana, Farxiga and Jardiance (SGLT-2 Inhibitors) are among the newer oral diabetes meds on the market. This group of drugs work to lower blood sugar by using the kidneys to remove sugar from the body through urine. They can be taken alone or with metformin, and are only approved for type 2 diabetes.

Drug interactions: While patients on these medications may benefit from declines in blood pressure, body weight, and body mass, the FDA has warned that these medications may lead to ketoacidosis, a condition in which the body doesn’t produce insulin resulting in high levels of blood acids called ketones. This can quickly affect your liver and kidneys and needs emergency attention. Symptoms of ketoacidosis include difficulty breathing, nausea, vomiting, abdominal pain, confusion, and unusual fatigue or sleepiness. For obvious reasons, SGLT-2s are not recommended for those with kidney disease. Also, pregnant women or nursing mothers should weigh risks and benefits of taking these relatively new oral drugs.

Januvia, Onglyza, Tradjenta, Nesina (DPP-4 Inhibitors). Last year, the FDA mandated the manufacturers of DPP-4 inhibitors update labeling amid reports of people experiencing severe joint pain after taking the drugs. Those patients started experiencing joint pain anywhere from a day after to several years after starting therapy. And in April of this year, the FDA updated the labeling of Onglyza and Nesina to reflect an increased risk of heart failure, especially those with heart or kidney disease. Several DPP-4s (Janumet, Jentadueto, Kazano) are sold as combination pills with metformin, so note the side effects of metformin as well if you take one of these.

Byetta/Bydureon, Victoza and Trulicity (GLP-1 Receptor Agonists) have been popular due to claims that they also lead to weight loss. However, they have been associated with nausea or vomiting, headache, dizziness, kidney damage or failure (in rare cases), and thyroid tumors in animal studies. Those with a personal or family history of thyroid cancer should avoid this class.

Drug interactions: Taking GLP-1s with other oral diabetic meds may lead to hypoglycemia. This class may also inhibit absorption of other drugs such as lithium, some seizure medication and the hypertension drug dioxin.

Symlin (Amylin Mimetics), which works by slowing down the movement of food through the stomach, and also prevents the liver from releasing stored glucose into the blood, may help to ease hunger and promote weight loss, but has possible side effects including hypoglycemia, nausea or vomiting, headache, redness and skin irritation at the injection site.

Drug interactions: Those on amylin mimetics should avoid certain drugs for gastrointestinal issue such as astropine as they can exacerbate side effects. Taking an oral diabetic drug, an ACE inhibitor for hypertension or certain antibiotics should consult their doctor if taking them with Symlin as the combination can increase the likelihood for hypoglycemia.

NuvoLog, Apidra and Humalog are rapid-acting insulins, typically taken just before meals, can cause hypoglycemia, low blood potassium, allergic reactions and swelling hands and feet. However, these are all rare occurrences. Some people may also experience skin irritation around the injection site. If you experience skin changes, try changing injecting the insulins around different areas of the skin.

Tresiba, Levemir, Lantus and Toujeo are long-acting insulins typically taken once per day (Tresiba is an exception as it can last up to 42 hours) and should be taken at the same time every day to avoid the absence of insulin in the blood stream, or taking them too closely together, causing hypoglycemia. Other side effects can include pain, redness or skin swelling near the injection site. Because insulin is sometimes given in combination with thiazolidinediones, this can increase the risk of fluid retention and heart failure.

Drug interactions for fast- and long-acting insulins: People taking insulins need to be careful of also taking thiazolidinediones since it may lead to hypoglycemia. Also, taking insulins in combination should be careful as it increases the risk for fluid retention and heart failure. Certain drugs may interact with insulins causing hypoglycemina. These include: ACE inhibitors and angiotensin II receptor antagonists; drugs used to lower blood pressure; the antidepressant Prozac (fluoxetine); aspirin; corticosteroids for asthma and allergies; estrogen and progesterone for hormone therapy; HIV/AIDS meds Norvir (ritonavir) and Invirase (saquinavir); and the antipsychotics Clozaril (clozapine) and Zyprexa (olanzapine).

Effectiveness and Method of Action

Meglitinides: They tend to work quickly and don’t stay for a long time in the body as they are taken right before a meal. They increase insulin production for 4 hours.

Sulfonylureas: These are among the cheapest diabetes drugs and are their efficacy is well known to bring down blood glucose level. This class stimulates the release of insulin into the bloodstream.

Biguanides: One of their major benefits is that unlike other classes of diabetes meds, they do not tend to cause hypoglycemia They work by inhibiting the release of glucose from the liver and improve sensitivity to insulin.

Thiazolidinediones: Due to the controversy surrounding heart risks of Avandia and Actos, they are avoided by many doctors. This class increases insulin sensitivity in the muscles and the liver.

SGLT-2 inhibitors: Some studies have indicated that besides lowering blood sugar, these medications may also increase HDL or “good” cholesterol. Some people also experience declines in blood pressure and weight. SGLT-2 inhibitors work by causing the kidneys to remove sugar from the body through urine.

DPP-4 Inhibitors: DPP-4s work to suppress the activity of hormones in the gut known as incretins. Incretins are beneficial since they cause they pancreas to produce more insulin and the liver to halt production of glucose. By blocking the DPP-4 enzyme that inactivates incretins, more incretins are available to keep your blood sugar in check.

Amylin Mimetics: They have the additional benefits of promoting weight loss and may also ease hunger pains. They slow down the movement of food through the stomach and help prevent the liver from releasing stored glucose into the blood.

Incretin Mimetics: These also have the benefit of modest weight loss, and are commonly used in combination with metformin and sulfonylurea. They stimulate the release of insulin.

Insulins: Because the pancreas of diabetics can’t produce enough insulin, insulin injections replace this important function. They are the standard of care for diabetes treatments. While traditional insulins are typically taken right before meals, newer, long-acting insulins provide similar effectiveness (though the take a longer time to start working in the body) and are only taken once per day. The downside of them is that they are much more expensive than traditional insulin.

Alternatives to Diabetes Meds

Type 2 diabetes progress can often be slowed or stopped with changes in diet and increases in exercise. Check in with your doctor as you improve your diet and exercise since weight loss might result in less medication needed.

There are many supplements that have anecdotal evidence that they promote lower blood sugar, but studies on them have not conclusively proven the effectiveness of any of them. Some of them include chromium, ginseng, magnesium, vanadium and CoQ10. A 2012 review of studies on cinnamon found that it had a possible beneficial effect on reducing glycemic levels. Make sure your doctor knows if you take any supplements or herbal medicines. They could interact and either increase or decrease the effectiveness of any other medicines you are taking.

What Worked For You?

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MedShadow Coverage on Diabetes Drugs

Risks Emerge for New Class of Diabetes Drugs

A new class of diabetes drugs that has been available for a little over three years have become immensely popular with doctors and patients, even though the pills have a host of adverse events and risks.

The first SGLT2 (first sodium-glucose cotransporter-2) inhibitor to hit the market, back in 2013, was Invokana (canagliflozin). Since then, the FDA has granted approval to 2 other oral medications in this class, Farxiga (dapagliflozin) and Jardiance (empagliflozin). By the fourth quarter of 2015, the trio accounted for 2 million prescriptions, an amazing six-fold increase since the first quarter of 2014, according to IMS Health.

Despite their growing popularity, SGLT2s have been associated with many adverse event reports and other troubling side effects based on clinical trials, according to a new report from the Institute for Safe Medication Practices (ISMP). These include: life-threatening ketoacidosis; electrolyte imbalances leading to severe dehydration and other problems; acute kidney injury; frequent genital infections, primarily fungal; and increased risk of bone fracture.

For example, interim data from a cardiovascular outcomes trial for Inovkana released in January found that the drug caused a statistically significant increased risk of bone fracture (4.0% v. 2.6%) compared to a placebo group treated with other medications. There was also an increased risk of foot and toe amputation from the same trial.

ISMP also found emerging signals of three other adverse effects: possible increased risk of limb amputation; pancreatitis; and hypersensitivity. They added that the number of cases increased for other reported adverse effects, especially sepsis and urosepsis, kidney stones. and abnormal weight loss.

Last month, the FDA strengthened the warnings on SGLT2 drugs regarding acute kidney injury “based on recent reports.”

Quick Hits: Opioids Tied to Heart Problems, Diabetes Meds Linked to Kidney Injury, & More

People who take an opioid medication for pain are at a higher risk for heart problems. Patients prescribed an opioid painkiller had a 64% higher risk of early death compared to patients given an another type of pain med, researchers reported in JAMA. Much of the increased risk was connected to difficulty breathing during sleep, as well as abnormal heartbeat and other cardiovascular complications. Some of the alternatives meds examined in the study were Neurontin (gabapentin), Lyrica (pregabalin) and Tegretol (carbamazepine), and some low doses of antidepressants. The authors concluded that long-acting opioids should be in favor of other meds, especially in people with existing cardiovascular issues or diabetes. Posted June 14, 2016. Via Healthday.

The FDA is strengthening existing warnings about kidney injury risk for a popular class of type 2 diabetes drugs. The medications, Invokana and Invokamet (canagliflozin), as well as Farxiga and Xigduo XR (dapagliflozin), belong to a relatively new class of drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors. Between March 2013 and October 2015, the agency said it received word of 101 cases of acute kidney injury associated with the meds. The FDA is advising doctors to monitor a patient’s kidney function prior starting and while on therapy, and avoid prescribing the drugs to patients who may be predisposed to kidney injury. Posted June 14, 2016. Via FDA.

The FDA is calling on drugmakers to conduct long-term bone quality studies for the development of new osteoporosis treatments. The agency says in its guidance that the nonclinical studies are needed to investigate whether long-term use of osteoporosis drugs results in poorer bone quality. Because the studies are not to be conducted in humans, the FDA says companies should conduct studies in 2 animal species. In addition, the FDA is advising drugmakers that are developing anabolic drugs for osteoporosis study whether they have the potential to cause cancer. The agency says previous studies have shown potential for bone tumor growth in mice and rats when given parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) drugs. Posted June 13, 2016. Via Regulatory Affairs Professionals Society.