Drug Injury Watch

Januvia, Onglyza, And Certain Other Diabetes Drugs Linked To Inflammatory Bowel Disease (IBD)

New Study Finds Overall 75% Increase In Risk Of IBD, And Association Peaked Between 3 And 4 Years Of Use

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

According to an observational study published on March 21, 2018 by The BMJ -- formerly known as British Medical Journal -- the use of dipeptidyl peptidase-4 (DPP-4) inhibitors for treatment of type 2 diabetes is associated with increased risk for inflammatory bowel disease (IBD).

The following diabetes medicines are in the dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs:

Januvia (sitagliptin)
Janumet (sitagliptin / metformin HCl)
Janumet XR (sitagliptin / metformin HCl)
Tradjenta (linagliptin)
Jentadueto (linagliptin / metformin HCl)
Glyxambi (empagliflozin / linagliptin)
Onglyza (saxagliptin)
Kombiglyze XR (saxagliptin and metformin)
Qtern (dapagliflozin and saxagliptin)
Nesina (alogliptin)
Kazano (alogliptin and metformin)
Oseni (alogliptin and pioglitazone)

 

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From the Discussion part of this March 2018 BMJ article, "Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study":

To our knowledge, this is the first observational study to specifically investigate the association between the use of dipeptidyl peptidase-4 inhibitors and the incidence of inflammatory bowel disease. Use of dipeptidyl peptidase-4 inhibitors was associated with an overall 75% increase in risk of inflammatory bowel disease. In secondary analyses, the association was particularly elevated between three and four years of use and between two and four years after the start of dipeptidyl peptidase-4 inhibitor treatment. This gradual increase in the risk is consistent with the hypothesis of a possible delayed effect of the use of dipeptidyl peptidase-4 inhibitors on the incidence of inflammatory bowel disease. This association remained highly consistent across a variety of sensitivity analyses.

Later in the same part of that March 2018 BMJ medical journal article, we get these details:

Finally, our results indicate that an increased risk with dipeptidyl peptidase-4 inhibitors may be associated with ulcerative colitis and not Crohn’s disease. However, this finding should be interpreted with caution as this stratified analysis was based on few events, generating a wide confidence interval with an upper 95% confidence limit of 2.09. Thus, our results do not rule out a possible association with Crohn’s disease as well. In summary, although our findings need to be replicated, additional studies are also needed to understand the possible mechanism through which dipeptidyl peptidase-4 inhibitors may increase the risk of inflammatory bowel disease.

As background, we point out that this is not the first time there have been safety concerns about the dipeptidyl peptidase-4 (DPP-4) inhibitors: 

• In April 2016 the FDA took regulatory action by mandating label changes with new warnings about an increased risk of heart failure for some of these DPP-4 inhibitor diabetes medicines, including Onglyza and Kombiglyze.
• In March 2016 the FDA said it was evaluating the need for possible regulatory action as regards all of the DPP-4 diabetes drugs due to the side effects of renal failure or kidney failure.
• In August 2015 the FDA announced that it had received drug adverse event reports of arthralgia, or severe pain in one or more joints. for the DPP-4 inhibitor class of diabetes medications.

We will continue to monitor the safety profile of Januvia, Onglyza, and the other DPP-4 diabetes drugs.

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Uloric Drug Safety Update: A Significantly Higher Risk Of Death Among Patients Using Gout Drug Uloric As Opposed To Allopurinol

Recent Findings Come From The CARES Trial, A Postmarketing Safety Study Requested By FDA Back When Uloric Was Approved In 2009

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

At the recent American College of Cardiology (ACC) 2018 Annual Scientific Session meeting, the gout drug Uloric (febuxostat) was the subject of some safety concerns due to findings about a higher risk of death when compared to an alternative gout drug, allopurinol.  However, the mechanism behind this difference was not readily apparent.

Allopurinol, approved by the FDA in 1966, and Uloric, approved in 2009, are two commonly prescribed medicines for gout. Takeda Pharmaceuticals is the drug company responsible for Uloric.

The findings presented at this 2018 ACC meeting came from the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Comorbidities (CARES) trial, or drug study, sponsored by Takeda Pharmaceuticals as an FDA postmarketing requirement.

From this March 12, 2018 MedPageToday news article, "Gout Drug Raises Safety Concerns With Death Excess in Trial", we get some commentary about this emerging drug safety issue for Uloric:

At this point, there is no known explanation for the mortality risk seen with [Uloric (febuxostat)], William White, MD, of the University of Connecticut in Farmington, reported here at the American College of Cardiology meeting late-breaking clinical trial session....

Despite the unclear mechanism, the consistency of the finding across the intent-to-treat and on-treatment analysis made the excess mortality risk "relatively robust" such that it "likely should be used to inform policy," said Noel Bairey Merz, MD, of Cedars-Sinai Hospital in Los Angeles and a member of the discussion panel at the session.

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The Uloric CARES findings presented on March 12, 2018 at the recent ACC meeting were simultaneously published online by the New England Journal of Medicine (NEJM) in this article, "Cardiovascular safety of febuxostat or allopurinol in patients with gout" (subscription required). From the "Conclusions" part of the Abstract for that NEJM article:

In patients with gout and major cardiovascular coexisting conditions, [Uloric (febuxostat)] was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with [Uloric (febuxostat)] than with allopurinol.

Just last fall, in November 2017, the FDA issued a safety communication based on preliminary results from CARES. For more information, see this earlier piece: "Gout Medicine Uloric Safety Trial Shows Increased Risk Of Heart-Related Deaths According To November 2017 FDA Alert".

One expects the FDA will be looking closely at these new CARES findings about all-cause and cardiovascular deaths associated with Uloric over the next several months.

Similarly, it is presumed that safety analyses by those medical researchers involved with the CARES trial are ongoing to evaluate the unexpected higher mortality rates in patients using Uloric in comparison to allopurinol.

Of course, we will be watching for significant developments regarding the safety profile of Uloric.

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Tasigna And Atherosclerosis-Related Diseases: A Snapshot Of The Medical Literature From Back In April 2013

Despite Evidence That Tasigna Accelerates Atherosclerosis, Novartis Does Little To Warn Doctors And Patients In The US

 

(Posted by Tom Lamb at DrugInjuryWatch.com)

 

In a recent article, "Tasigna Side Effects Include Ischemic Cerebrovascular Events, Ischemic Heart Disease, And Peripheral Arterial Occlusive Disease", our primary focus was on the difference between Tasigna drug safety warnings provided by Novartis in Canada (more) as opposed to the US (less).

For this article we take a closer look at what had been discussed in the medical literature about the atherosclerosis side effect associated with Tasigna (nilotinib) no later than April 2013. We are doing this review because it was during April 2013 that Novartis Pharmaceuticals Canada Inc. took these actions:

1. Sent a so-called "Dear Doctor" letter in Canada (but not the US) warning about some serious side effects associated with Tasigna; and,
2. Issued a Tasigna drug label change in Canada (but not the US) with new information concerning those Tasigna side effects.

For that purpose, we have selected a Letter to the Editor published online April 22, 2013 by the medical journal Leukemia, which was written by Ayalew Tefferi, MD, of the Mayo Clinic's Division of Hematology within its Department of Medicine at Rochester, Minnesota.

In his Letter, called "Nilotinib treatment-associated accelerated atherosclerosis: when is the risk justified?", Dr. Tefferi primarily commented on an earlier article which had been published online by Leukemia in March 2013.

That earlier article, by TD Kim and several others, was titled "Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or Imatinib." In summary, it reported the prevalence of PAOD in tyrosine kinase inhibitor (TKI)-treated patients with chronic myeloid leukemia (CML).

Dr. Tefferi sets the stage, so to speak, by starting his Letter in this manner:

Atherosclerosis is the leading cause of death and morbidity in developed countries and is the culprit behind coronary artery disease (CAD), cerebral vascular disease (CVD) and peripheral artery occlusive disease (PAOD). Atherosclerosis leads to segmental narrowing and occlusion of arteries....

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Thereafter, Dr. Tefferi begins his comments about the March 2013 article by TD Kim and several others:

In the second part of their study, Kim et al. reviewed 27 cases of TKI treatment-associated overt PAOD accrued from several collaborating centers and discovered that all but one of these patients were exposed to [Tasigna (nilotinib)] therapy, including 20 patients who were receiving [Tasigna (nilotinib)] as first- or second-line treatment of CP-CML. These events were severe enough to require percutaneous transluminal angioplasty in 33.3% of the cases, stent implantation in 22.2%, amputation in 22.2% and surgery in 18.5%. [Footnote omitted]

Next, Dr. Tefferi expands his scope of analysis to other medical journal reports about Tasigna and atherosclerosis-related diseases associated with this Novartis leukemia drug:

The observations from Kim et al. are consistent with those of earlier and more recent reports associating [Tasigna (nilotinib)] with accelerated atherosclerosis. Aichberger et al. reported a 33% incidence of PAOD, myocardial infarction, spinal infarction or subdural hematoma, among 24 CML patients treated with [Tasigna (nilotinib)]. Tefferi et al. described two patients who experienced sudden death or severe PAOD/CAD; continued [Tasigna (nilotinib)] treatment in the latter patient was associated with rapid progression of intra- and extracranial atherosclerosis leading to stroke. Most recently, Levato et al. reported their single-institution experience with 82 CML patients treated with imatinib (n=55) or [Tasigna (nilotinib)] (n=27); four (14.8%) [Tasigna (nilotinib)]-treated patients developed severe PAOD or other vascular disease. In contrast, none of the 55 imatinib-treated patients developed PAOD and only one experienced myocardial infarction, despite a longer median duration of treatment with imatinib (79.5 months) vs [Tasigna (nilotinib)] (21.5 months). [Footnotes omitted]

In turn, Dr. Tefferi makes this relatively strong statement, which probably gave rise to the caption attributed to this April 2013 Leukemia Letter to the Editor by Tefferi:

Taken together, the above observations strongly implicate [Tasigna (nilotinib)] therapy as being proatherogenic. Regardless of what the underlying mechanisms for this might be, the question is whether or not it is necessary or appropriate to subject newly diagnosed patients with CP-CML to this risk [of atherosclerosis associated with Tasigna (nilotinib)], considering the remarkable efficacy and safety of imatinib therapy.

In closing this article, I will point out that in the US there still has not been any "Dear Doctor" letter sent nor any Tasigna drug label change made by Novartis Pharmaceuticals Corporation regarding atherosclerosis, despite the actions taken by its Canadian counterpart during April 2013.

We are currently investigating Tasigna drug injury cases against Novartis for US patients who have developed atherosclerosis-related diseases such as strokes, heart attacks, and amputations, as well as certain other Tasigna side effects.

DrugInjuryLaw.com: Medical & Legal Information About Drug Side Effects  (All website content by attorney Tom Lamb)

Drug Injury Case Evaluation - Free. Confidential. No Obligation.  (Case review done by attorney Tom Lamb)