Drug Safety Developments

Diabetes Drugs Invokana, Jardiance and Farxiga Associated with Fournier's Gangrene

Necrotizing Faciitis of the Perineum Linked as Side Effect of SGLT2 Inhibitor Drugs

 

Written by: Lauren Schwab, Legal Assistant

Law Offices of Thomas J. Lamb, P.A.

 

Diabetes drugs in the sodium-glucose cotransporter 2 (SGLT2) inhibitors class are associated with Fournier's Gangrene, or necrotizing fasciitis of the perineum. Drugs within this class include, but are not limited to, Invokana (canaglifozin), Jardiance (empaglifozin), and Farxiga (dapagliflozin).

 

History of SGLT2 Drugs and Fournier's Gangrene

According to an August 29, 2018, Drug Safety Communication, "FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes”:

Fournier’s gangrene is an extremely rare but life-threatening bacterial infection of the tissue under the skin that surrounds muscles, nerves, fat, and blood vessels of the perineum....

In the five years from March 2013 to May 2018, we identified 12 cases of Fournier’s gangrene in patients taking an SGLT2 inhibitor...All 12 patients were hospitalized and required surgery. Some patients required multiple disfiguring surgeries, some developed complications, and one patient died. In comparison, only six cases of Fournier’s gangrene (all in men) were identified in review of other antidiabetic drug classes over a period of more than 30 years.

Similarly, a May 2019 FDA analysis article provides more evidence of Fournier's gangrene in association with SGLT2 Inhibitor diabetes drugs. The article, published by the medical journal Annals of Internal Medicine, entitled "Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors" states:

The FDA identified 55 unique cases of FG in patients receiving SGLT2 inhibitors between 1 March 2013 and 31 January 2019... Time to onset after initiation of SGLT2-inhibitor therapy ranged from 5 days to 49 months. All patients had surgical debridement and were severely ill...

FG is a newly identified safety concern in patients receiving SGLT2 inhibitors. Physicians prescribing these agents should be aware of this possible complication and have a high index of suspicion to recognize it in its early stages.

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Moving Forward and Potential Legal Action

The FDA is currently advising patients to seek immediate medical attention if they are experiencing symptoms of Fournier's gangrene. According to the August 29, 2018, Drug Safety Communication, "FDA warns about rare occurrences of a serious infection of the genital area with SGLT2 inhibitors for diabetes”:

Patients should seek medical attention immediately if you experience any symptoms of tenderness, redness, or swelling of the genitals or the area from the genitals back to the rectum, and have a fever above 100.4 F or a general feeling of being unwell. These symptoms can worsen quickly, so it is important to seek treatment right away.

Health care professionals should assess patients for Fournier’s gangrene if they present with the symptoms described above. If suspected, start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary. Discontinue the SGLT2 inhibitor, closely monitor blood glucose levels, and provide appropriate alternative therapy for glycemic control.

 

We will continue to monitor the current drug safety issue of Fournier's gangrene in relation to patients using SGLT2 inhibitor drugs such as Invokana, Jardiance and Farxiga. We are currently evaluating Fournier's Gangrene cases and possible drug injury lawsuits against the responsible pharmaceutical companies.

 

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Invokana / Jardiance / Farxiga: Increased Risk Of Pancreatitis, According To Health Canada Safety Review

 

Health Canada's safety review of sodium-glucose cotransporter-2 (SGLT2) inhibitors -- e.g., Invokana (canagliflozin), Farxiga (dapagliflozin), and Jardiance (empagliflozin) -- concluded in July 2018 with the finding that there may be a link between the use of SGLT2 inhibitors and acute pancreatitis. However there was limited evidence to suggest a link with chronic pancreatitis. Health Canada is working with the manufacturers to update the Canadian product monographs, or drug labels, for SGLT2 inhibitors to include this increased risk of pancreatitis.

 

• Summary of Safety Review by Health Canada

 

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Only Two out of Three Classes of Diabetes Drugs Help Reduce the Risk of Death

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P. A.

 

Class Comparisons

Three popular types of diabetes drugs include sodium-glucose cotransporter (SGLT-2) inhibitors, dipeptidyl peptidase (DPP-4) inhibitors, and incretin mimetics (also referred to as glucagon-like peptide (GLP-1) agonists).

The following table provides a list of some of these types of drugs:

SGLT-2 Inhibitors	SGLT-2 / DPP-4 Inhibitors	DPP-4 Inhibitors / Incretin Mimetics	Incretin Mimetics
Invokana	Glyxambi	Onglyza	Byetta
Invokamet (XR)	Qtern	Januvia	Bydureon
Farxiga		Janumet (XR)	Victoza
Xigduo XR		Kazano	Juvisync
Jardiance		Oseni
Synjardy (XR)		Tradjenta
Steglatro		Jentadueto
Steglujan		Nesina
Segluromet		Kombiglyze XR

 

Study Results

A recent study compared these three types of diabetes drugs in order to determine their effect on "all-cause mortality" in patients with type 2 diabetes.  While all three classes lowered blood sugar levels, only two reduced the risk of death.  

The researchers found the use of SGLT-2 inhibitors and incretin mimetics was associated with lower mortality rates than DPP-4 inhibitors.  More specifically, SGLT-2 inhibitors were associated with a 21% reduction in cardiovascular-related death, and incretin mimetics were associated with a 15% reduction.

However, DPP-4 inhibitors did not reduce the risk of death when compared to a placebo or no treatment at all.

One of the researchers acknowledged that further studies are needed to confirm their findings, and tracking participants for a longer period of time would be beneficial.

 

Side Effects

While the study did not aim to identify any particular harmful side effects directly caused by the drugs, numerous side effects have been associated with these classes of drugs in other studies.  As such, one must wonder how the benefits of these drugs weigh against their potentially-fatal side effects.

For example, users of SGLT-2 inhibitors have experienced the following side effects:

• Diabetic Ketoacidosis (DKA)
• Ketoacidosis
• Ketosis
• Leg Amputation
• Foot or Toe(s) Amputation
• Acute Kidney Injury

• Kidney Failure / Renal Failure
• Kidney Damage
• Pyelonephritis (kidney infection)
• Urosepsis (blood infection)
• Urinary Tract Infection (UTI)
• Bladder Cancer

As for DPP-4 inhibitors, these side effects have been observed:

• Heart Failure
• Kidney Failure / Renal Failure
• Kidney Problems
• Decreased Renal Function 
• Cerebral Infarction / CVA / Stroke
• Myocardial Infarction (MI) / Heart Attack

• Acute Pancreatitis
• Severe Joint Pain
• Inflammatory Bowel Disease (IBD)
• Ulcerative Colitis
• Crohn's Disease
• Rhabdomyolysis

Lastly, incretin mimetics carry a potential risk of pancreatic cancer.

Going forward, we will continue to monitor the medical literature concerning the side effects associated with these three classes of diabetes drugs.

In the meantime, we encourage you to fill out one of our free case evaluations concerning SGLT-2 inhibitors, DPP-4 inhibitors, and incretin mimetics.

 

 

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New SGLT2 Diabetes Drug, Steglatro, to Hit the Market in January 2018

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

Approval

On December 19, 2017, the FDA approved Merck & Co. and Pfizer's new diabetes drug, Steglatro, and its two combination versions, Steglujan and Segluromet.  These drugs are classified as sodium/glucose cotransporter 2 (SGLT2) inhibitors, and will be available this coming January.

Steglatro consists of ertugliflozin, while Steglujan combines it with Januvia (sitagliptin), and Segluromet combines it with metformin.

According to the drug label (for Steglatro, accessed 12/28/17), these drugs are "indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus."

A recent MedScape article provides the following information:

The new drug applications were accepted for review in March 2017 and were supported by studies from the VERTIS clinical development program for ertugliflozin, which consists of nine phase 3 trials in approximately 12,600 adults with type 2 diabetes.

Results from VERTIS MONO, VERTIS FACTORIAL, and VERTIS SITA2 were presented at medical congresses in 2016, and findings from VERTIS SU and VERTIS SITA2 were presented at the European Association for the Study of Diabetes (EASD) 2017 Annual Meeting in September 2017.

 

New Drug, Same Side Effects

Like other SGLT2 inhibitors -- such as Invokana, Farxiga, Jardiance, Synjardy, Glyxambi, and Qtern -- these new type 2 diabetes drugs also carry warnings of the following serious side effects:

• Ketoacidosis
• Acute Kidney Injury
• Impairment in Renal Function

There is also a lower-limb amputation warning for Steglatro and its counterparts.  This is particularly interesting, given that Invokana is the only other SGLT2 inhibitor at this time whose drug label also mentions this warning. 

However, unlike Invokana, Steglatro (and its combinations) do not include amputations in a so-called "Black Box" warning.  This is probably due to the label's claim that "A causal association between STEGLATRO and lower limb amputation has not been definitively established."

Perhaps the drug companies responsible for Steglatro, Steglujan, and Segluromet added this warning so as to protect themselves from lawsuits in the event that a causal relationship between these drugs and lower-limb amputations is definitively established in the future.

 

Class Effects

While other SGLT2 inhibitors are quick to distance themselves from the lower-limb amputation side effect, further clinical data may prove it to be a class effect.

The first three side effects mentioned above have been shown to apply to the entire class of SGLT2 inhibitors diabetes drugs, and as such, are mentioned in every single drug label for these drugs.

We will continue to monitor the medical literature on SGLT2 inhibitors and their relationship to lower-limb amputations and other serious side effects.  In the meantime, we encourage you to visit our website and complete a free case evaluation if you or someone you know has taken an SGLT2 inhibitor and suffered one of the serious side effects mentioned in this article.

 

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SGLT2 Inhibitors May Have an Increased Risk of Acute Renal Failure

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

SGLT2 Inhibitors: A New Side Effect 

In previous articles, I have discussed SGLT2 inhibitor diabetes drugs such as Invokana, Farxiga, and Jardiance and the adverse events associated with them.  Such side effects include diabetic ketoacidosis (DKA) and lower-limb amputations.

A recent study identified a new possible side effect of these drugs through an analysis of the FDA Adverse Event Report System database (FAERS).  The researchers found that SGLT2 inhibitors were associated with an increased risk of acute renal failure.

Acute Renal Failure: The Statistics

According to the study, out of the 1,224 reported cases of acute renal failure that involved SGLT2 inhibitors, the drugs were defined as the "primary" or "secondary" causes of acute renal failure in 96.8% of the cases.

Furthermore, the number of acute renal failure reports for these drugs was significantly greater than those involving patients with Type 2 diabetes who were not treated with SGLT2 inhibitors.

Interpreting Results

Researcher Amichai Perlman, PharmD provides her input on the study's findings:

Our results should be interpreted with caution as this is an observational study with limited control of potential confounding factors...However, we believe that clinicians should consider simple measures to minimize this potential risk, including instructing patients to keep hydrated and avoid volume depletion; consider closer monitoring of kidney function in patients with concomitant ACE inhibitors and diuretics, especially in patients with impaired baseline renal function; and avoiding administration of SGLT2 inhibitors with nephrotoxic agents, such as NSAIDs, as well as to consider temporary withholding of SGLT2 inhibitors prior to radio-contrast studies.

We are currently investigating possible drug injury lawsuits concerning Type 2 diabetes patients who have been diagnosed with acute renal failure, DKA, or lower-limb amputations as a result of their use of SGLT2 inhibitors such as Invokana, Farxiga, or Jardiance.

For more information, please visit our website and complete a free case evaluation.

 

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Could Invokana have been the cause of my lower-limb amputation?

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

The FDA is investigating a connection between diabetes drugs belonging to the Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitors class of drugs and the following side effects:

• Diabetic Ketoacidosis (DKA)
• Ketoacidosis
• Ketosis
• Acute Kidney Injury
• Kidney Failure / Renal Failure
• Kidney Damage
• Pyelonephritis (kidney infection)
• Urosepsis (blood infection)
• Urinary Tract Infection (UTI)
• Leg Amputation
• Foot or Toe(s) Amputation

Some of the popular drugs in this SGLT2 inhibitors class are Invokana, Farxiga, Jardiance, Invokamet, Xigduo, Glyxambi, Synjardy, and Qtern.

While DKA seems to be the most frequently discussed side effect of these drugs, discussion of amputations relating to the lower limbs seems to be gaining popularity in the medical literature.

At least one lawsuit has been filed against the drug manufacturer of Invokana concerning a patient who had a lower limb amputation after using the drug.  

Additionally, the drug label for Invokana has recently been updated to include the strictest possible warning for amputations:

INVOKANA may increase your risk of lower limb amputations. Amputations mainly involve removal of the toe or part of the foot, however, amputations involving the leg, below and above the knee, have also occurred. Some people had more than one amputation, some on both sides of the body.

One important step in determining whether the SGLT2 inhibitor could have caused the amputation is ruling out other risk factors for amputations.

The Invokana Medication Guide (page 45 of the PDF), revised in July 2017, provides the following information concerning possible risk factors: 

You may be at a higher risk of lower limb amputation if you:

• have a history of amputation
• have heart disease or are at risk for heart disease
• have had blocked or narrowed blood vessels, usually in your leg
• have damage to the nerves (neuropathy) in your leg
• have had diabetic foot ulcers or sores 

On a related note, the study titled "SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System," provides the following information regarding adverse effects that were also observed in study participants:

Based on indications...concomitant adverse events included wound, necrosis, gangrene, or ischaemia in 14 cases, and osteomyelitis or other infections in 15 cases.

We are currently investigating possible drug injury lawsuits against the responsible pharmaceutical companies for who have developed any of the medical conditions listed at the beginning of this article after using an SGLT2 inhibitor.  We encourage you to complete a free case evaluation, and visit our website for more information.

 

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Can SGLT-2 Inhibitor Diabetes Drugs Increase Your Risk of Stroke?

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

While we have frequently discussed DKA, kidney damage, and amputations as possible side effects of diabetes drugs in the SGLT-2 inhibitors class -- such as Farxiga, Invokana, Jardiance -- strokes and thromboembolic events are also considered potential harmful effects of these drugs.

Based on FAERS reports received during the second quarter of 2015, posted in early 2016, the FDA identified both strokes and thromboembolic events as a "potential signal of a serious risk" for SGLT-2 inhibitors, and stated that they are "evaluating the need for regulatory action."

This warning applies to the following SGLT-2 inhibitors:

• Farxiga (dapagliflozin)
• Invokana (canagliflozin)
• Jardiance (empagliflozin)
• Glyxambi (empagliflozin/linagliptin)
• Invokamet (canagliflozin/metformin HCl)
• Synjardy (empagliflozin/metformin HCl)
• Xigduo XR (dapagliflozin/metformin HCl) 

Though this information was provided back in January 2016, hardly any new information on these possible side effects has been provided.

The CANagliflozin cardioVascular Assessment Study (CANVAS) studied the effects of Invokana "compared to placebo on CV events including CV death, heart attack, and stroke in patients with T2DM."  While this study has recently been completed, the actual study results have yet to be posted.

Additionally, a similar study concerning Jardiance has already been completed, and there is also an ongoing study concerning Farxiga, which will be completed in approximately 2020.

The Abstract of a recent article, titled "Impact of glucose-lowering therapies on risk of stroke in type 2 diabetes," provides the following information:

As for DPP-4 inhibitors, there was a non-significant trend towards benefit for stroke, whereas a possible increased risk of stroke with SGLT2 inhibitors—and in particular, [Jardiance (empagliflozin)] in the EMPA-REG OUTCOME trial—has been suggested and requires clarification...

In summary, the effects of antidiabetic drugs on risk of stroke appear to be heterogeneous, with some therapies (pioglitazone, GLP-1 receptor agonists) conferring possible protection against ischaemic stroke, other classes showing a neutral impact (DPP-4 inhibitors, insulin) and some glucose-lowering agents being associated with an increased risk of stroke (sulphonylureas, possibly SGLT2 inhibitors, high-dose insulin in the presence of insulin resistance).

Regardless of the studies that have been completed, the FDA does not appear to have made a definitive decision regarding the relationship between SGLT-2 inhibitors and strokes or thromboembolic events such as pulmonary embolism (PE) and deep vein thrombosis (DVT).

We will continue to monitor the medical literature and news concerning the FDA's determination regarding the SGLT-2 inhibitors class of diabetes drugs and the possible increased risk of stroke and thromboembolic events.

In the meantime, we invite you visit our website, and to submit a free case evaluation if you or someone you know has experienced one of the following side effects after using a brand-name SGLT-2 inhibitor (see earlier list):

• Acute Kidney Injury
• Kidney Failure or damage
• Diabetic Ketoacidosis (DKA)
• Ketoacidosis
• Ketosis
• Ischemic Stroke / Cerebrovascular Accident (CVA)
• Deep Vein Thrombosis (DVT)
• Pulmonary Embolism (PE)
• Leg Amputation
• Foot or Toe(s) Amputation

 

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Risk of Lower Limb Amputations Doubled with Invokana and Invokamet Use

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A.

 

As of yesterday, May 16, 2017, the FDA issued a Drug Safety Communication regarding an increased risk of leg and foot amputations due to use of popular diabetes drugs Invokana, Invokamet, and Invokamet XR, which contain canagliflozin.  

These drugs belong to the sodium glucose cotransporter 2 (SGLT2) inhibitor class, and are the subjects of the Canagliflozin Cardiovascular Assessment Study (CANVAS) and CANVAS-R (a study of the effects of canagliflozin on renal endpoints in adult participants with Type 2 diabetes mellitus).

We have been monitoring the medical literature concerning the risk of lower-limb amputations and drugs in the SGLT2 inhibitors class, such as canagliflozin (Invokana / Invokamet), empagliflozin (Jardiance / Glyxambi / Synjardy), and dapagliflozin (Farxiga / Xigduo / Qtern). 

The timeline below provides detailed information concerning previous warnings involving these drugs:

April 2016	The European Medicines Agency (EMA) warned that Invokana and Invokamet were linked to an increased risk of amputations, especially of the toes.
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May 2016	The FDA issued a Drug Safety Communication with the same warning for Invokana and Invokamet, but stated, "We have not determined whether canagliflozin increases the risk of leg and foot amputations. We are currently investigating this new safety issue and will update the public when we have more information."
|
July 2016	The EMA stated that the Pharmacovigilance Risk Assessment Committee (PRAC) will now review all drugs in the SGLT2 inhibitors class in order to determine whether the increased risk of lower-limb amputations is possible for more than just Invokana and Invokamet.
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Feb. 2017	The EMA stated that warnings of amputations "should be included in the prescribing information for these medicines" in the SGLT2 inhibitor class.

 

The latest warning states the following:

Based on new data from two large clinical trials, the U.S. Food and Drug Administration (FDA) has concluded that the type 2 diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR) causes an increased risk of leg and foot amputations. We are requiring new warnings, including our most prominent Boxed Warning, to be added to the canagliflozin drug labels to describe this risk.

Adding this boxed warning, commonly referred to as a "black-box warning," is significant given that such warnings are designed to call attention to serious or life-threatening risks that are common enough to warrant the most prominent and serious warning a drug can have.

The FDA goes on to describe the results of the CANVAS and CANVAS-R studies of the effects of canagliflozin:

Final results from two clinical trials – the CANVAS (Canagliflozin Cardiovascular Assessment Study) and CANVAS-R (A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants With Type 2 Diabetes Mellitus) – showed that leg and foot amputations occurred about twice as often in patients treated with canagliflozin compared to patients treated with placebo, which is an inactive treatment. The CANVAS trial showed that over a year’s time, the risk of amputation for patients in the trial were equivalent to:

• 5.9 out of every 1,000 patients treated with canagliflozin
• 2.8 out of every 1,000 patients treated with placebo

The CANVAS-R trial showed that over a year’s time, the risk of amputation for patients in the trial were equivalent to:

• 7.5 out of every 1,000 patients treated with canagliflozin
• 4.2 out of every 1,000 patients treated with placebo

These studies show an approximate doubling of the risk for lower-limb amputations among patients who used diabetes drugs containing canagliflozin in comparison to those who received a placebo.

We will continue to monitor the medical literature concerning the risk of lower-limb amputations when taking Invokana, Invokamet (XR), and all other drugs in the SGLT2 inhibitors class of drugs.

In the meantime, we invite you to visit our Invokana / Invokamet / Farxiga / Jardiance information page, and complete our free case evaluation if you or someone you know have had to undergo a lower-limb amputation -- or have had a different severe side effect -- after using a SGLT2 inhibitor.

 

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More Articles on this topic:

• EMA Warns that Some Diabetes Drugs Cause Increased Risk of Amputation
• All SGLT2 Inhibitors Now Investigated for Increased Risk of Amputation
• Are Invokana & Invokamet Linked to Increased Risk of Toe Amputations?

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EMA Warns that Some Diabetes Drugs Cause Increased Risk of Amputation

 

Written by: Heather Helmendach, Legal Assistant 
Law Offices of Thomas J. Lamb, P.A

 

Earlier today, February 10, 2017, the European Medicines Agency (EMA) released the findings of their Pharmacovigilance Risk Assessment Committee (PRAC) concerning the link between particular diabetes drugs and an increased risk of toe amputation.

These diabetes drugs are part of the sodium glucose co-transporter-2 (SGLT2) inhibitor class of drugs, and are used to treat type 2 diabetes.  They are separated by their active ingredients: canagliflozin, dapagliflozin and empagliflozin.

Diabetes drugs that contain canagliflozin -- such as Invokana and Invokamet -- were the main subject drugs included in this study.  However, it was noted that similar diabetes drugs in the SGLT-2 class, such as Jardiance, Farxiga, Glyxambi, and Xigduo XR, could also have the same increased risk of amputation.  The article notes that studies are currently being conducted on the relationship between these other drugs, and further data is needed before they can be definitively associated with an increased risk of lower-limb amputations, or not.

It has been confirmed, however, that all of the drugs in the SGLT-2 class of drugs are associated with an increased risk of diabetic ketoacidosis (DKA), as discussed in my previous article, "Health Canada Warns About Link Between DKA & Popular Diabetes Drugs."

While those with diabetes that is poorly-controlled, or with pre-existing heart and blood vessel problems are already at an increased risk of infections and sores that can lead to amputations, Invokana and Invokamet can increase that risk even further.

The article released by the EMA provides the following information:

On the basis of the available data, the PRAC recommends that a warning on the risk of lower limb amputation (mostly affecting the toes) should be included in the prescribing information for these medicines, highlighting the importance of routine preventative foot care.

For canagliflozin, lower limb amputation should be listed as an uncommon side effect (occurring in between 1 and 10 patients in 1,000). Doctors should consider stopping treatment with canagliflozin if patients develop significant foot complications such as infection or skin ulcers.

The PRAC recommendation will now be sent to EMA’s Committee for Medicinal Products for Human Use (CHMP) for the adoption of EMA’s final opinion. Further details and advice for patients and healthcare professionals will be published at the time of the CHMP opinion.

Accordingly, we will continue to monitor the medical literature on the relationship between all SGLT-2 diabetes drugs and an increased risk of lower-limb amputations.

For more information on this topic, see my previous articles:

• All SGLT2 Inhibitors Now Investigated for Increased Risk of Amputation (7/11/16)
• Are Invokana & Invokamet Linked to Increased Risk of Toe Amputations? (4/18/16)

We are currently investigating amputation cases concerning these type 2 diabetes drugs, and encourage you to complete a free case evaluation if you or someone you know, has experienced lower-limb amputation(s) while using these drugs.

 

Drug Injury Watch: Side Effects News & Reports

Drug Injury Law: Medical & Legal Information

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More Articles on this topic:

• Risk of Lower Limb Amputations Doubled with Invokana and Invokamet Use
• All SGLT2 Inhibitors Now Investigated for Increased Risk of Amputation
• Are Invokana & Invokamet Linked to Increased Risk of Toe Amputations?

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All SGLT2 Inhibitors Now Investigated for Increased Risk of Amputation

 

Written by Heather Helmendach, Legal Assistant
Law Offices of Thomas J. Lamb, P.A.

 

As discussed in my post, Are Invokana & Invokamet Linked to Increased Risk of Toe Amputations?, the European Medicines Agency (EMA) warned in April of 2016 that the popular diabetes drugs, Invokana and Invokamet (canagliflozin), were linked to an increased risk of amputations, especially of the toes.  These drugs belong to the sodium glucose cotransporter 2 (SGLT2) inhibitor class, and are the subjects of the Canagliflozin Cardiovascular Assessment Study(CANVAS) and CANVAS-R.

In May of 2016, the FDA issued a Drug Safety Communication with the same warning for Invokana and Invokamet, but stated, "We have not determined whether canagliflozin increases the risk of leg and foot amputations. We are currently investigating this new safety issue and will update the public when we have more information."

The most recent information available on the subject comes from this Medscape article from July 8, 2016.  The EMA recently stated that the Pharmacovigilance Risk Assessment Committee (PRAC) will now review all drugs in the SGLT2 inhibitors class -- such as Jardiance (empagliflozin), Farxiga and Xigduo XR (dapagliflozin) -- in order to determine whether the increased risk of lower-limb amputations is possible for more than just Invokana and Invokamet.

The aforementioned Medscape article provides the following information:

Commenting for Medscape Medical News in May, Simeon I Taylor, MD, professor of medicine, University of Maryland School of Medicine, Baltimore, said, "I am not certain this safety signal is real, but I do believe it is appropriate to take it seriously....The numbers are small, so it is premature to draw firm conclusions about whether the apparent increase in amputations represents a true risk of the drug or whether it results from random statistical variation."

But there is biological plausibility, he said, citing a case-control study of 12,240 type 2 diabetic residents of eight Dutch cities, in which it was noted that thiazide diuretics were associated with a 6.11-fold increase in the risk of lower-extremity amputation when compared with ACE inhibitors (Pharmacoepidemiol Drug Saf. 2004;13:139-146).

Thiazide diuretics and SGLT2 inhibitors "both promote natriuresis and volume contraction. So it is tempting to hypothesize that volume contraction and an associated decrease in lower-extremity perfusion might possibly contribute to pathophysiological mechanisms leading to amputation."

Dr. Taylor also goes on to say that "It is prudent for physicians and patients to…take this recent information into account when selecting therapeutic options. This particular safety concern may be most relevant for patients with peripheral neuropathy who are at increased risk for amputations."

We will continue to monitor the medical literature concerning the possible link between increased amputation risk and SGLT2 inhibitors, Invokana, Invokamet, Farxiga, Xigduo XR, and Jardiance.

 

Drug Injury Watch: Side Effects News & Reports

Drug Injury Law: Medical & Legal Information

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More Articles on this topic:

• Risk of Lower Limb Amputations Doubled with Invokana and Invokamet Use
• EMA Warns that Some Diabetes Drugs Cause Increased Risk of Amputation
• Are Invokana & Invokamet Linked to Increased Risk of Toe Amputations?

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