New safety warnings for two classes of diabetes drugs: What pharmacists should know

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DPP-4 inhibitors/gliptins and SGLT-2 inhibitors

This spring, FDA called attention to two classes of diabetes drugs and potential serious risks associated with them. In April, the Endocrinologic and Metabolic Drugs Advisory Committee advised FDA to add a heart failure warning to labels on dipeptidyl peptidase–4 (DPP-4) inhibitors, also known as gliptins. A month later, FDA issued a drug safety communication warning that another diabetes drug, sodium–glucose linked transporter–2 (SGLT-2) inhibitors, could cause euglycemic diabetic ketoacidosis. 


When FDA has new information on the safety of a drug, the agency may issue a drug safety communication, or it could deem a label change necessary. In some but not all cases, these warnings warrant a change in the way pharmacists advise prescribers and counsel patients. 


“All medications come with benefits and risks, and every decision for type 2 diabetes should be based on the patient-specific advantages and disadvantages of the different options available. The potential risks with these two medication classes are something we must consider,” said Jennifer Trujillo, PharmD, BCPS, CDE, Associate Professor of Clinical Pharmacy at University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences.


New drug safety information


FDA has issued 15 drug safety communications this year. There were 16 in 2014 and twice that many in each of the two preceding years. Health care providers learn about these warnings on FDA’s website or through MedWatch Safety Alerts, the Drug Information Listserv, e-mail newsletters, podcasts, and social and traditional media. The communications are distributed to about 573,000 subscribers to e-mail distribution listservs and 451,000 followers to FDA social media accounts. (APhA’s DrugInfoLine at www.aphadruginfoline.com also publishes FDA alerts and recalls.)


FDA gathers new drug safety information from a number of sources, including the voluntary Adverse Event Reporting System and ongoing clinical trials. Drug safety communications address new and emerging postmarket drug safety issues or adverse events. 


These could include potentially serious or life-threatening risks or adverse events discovered after a drug is on the market; an issue affecting a large number of patients due to widespread use of a drug; new, clinically relevant information about a known adverse event; a new contraindication; previously unknown interactions; or a medication error that may result in a serious or life-threatening adverse reaction. 


In some cases, new safety information warrants a label change. 


DPP-4 inhibitors/gliptins


Last April, an FDA advisory committee voted in favor of new labeling to warn of heart failure risk with saxagliptin and as-yet-undetermined risks with alogliptin. Gliptins or DPP-4 inhibitors—sitagliptin (Januvia—Merck), saxagliptin (Onglyza—AstraZeneca), linagliptin (Tradjenta—Boehringer Ingelheim), alogliptin (Nesina—Takeda)—are oral medications for blood glucose control in type 2 diabetes. 


Three recently published large randomized controlled clinical trials examined adverse cardiovascular events in people taking drugs of this class. The results led to the committee’s recommendations.


Concerns arose after the SAVOR (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trial revealed a difference between saxagliptin and placebo in one of the study’s major secondary outcomes. Over the 2-year follow-up, among nearly 16,500 people with type 2 diabetes and risk factors for cardiovascular events, more were hospitalized with heart failure in the saxagliptin group (3.5%) than in the placebo group (2.8%). No difference was found between saxagliptin and placebo in the study’s primary outcome: a composite of cardiovascular death, myocardial infarction, or ischemic stroke.


“Increased risk of hospitalizations due to heart failure is certainly a serious adverse effect that we want to pay attention to, but the problem is that not all of the evidence indicates that this risk is real,” said Trujillo. 


Neither of the two other large randomized controlled trials revealed similar risks associated with gliptins. In the EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) trial, more people taking alogliptin had incidents of heart failure than those taking placebo, but the difference was not statistically significant. EXAMINE enrolled people after acute coronary syndrome. 


In TECOS (Trial to Evaluate Cardio-vascular Outcomes after Treatment with Sitagliptin), sitagliptin did not increase risk for major adverse cardiovascular events, hospitalization for heart failure, or other adverse events.


“Though there will be labeling changes to address the cardiovascular risks with these drugs, for the vast majority of patients who have good renal function and otherwise no past history of heart failure, gliptins are very safe,” said Charles Ponte, PharmD, DPNAP, Professor of Clinical Pharmacy and Family Medicine at West Virginia University Robert C. Byrd Health Sciences Center. 


DPP-4 inhibitors: What should pharmacists know?


The potential risks revealed in the SAVOR trial are not grounds to recommend that patients switch to another medication, Trujillo and Ponte agreed. “Not if you’re doing well on that particular medication and you don’t have any evidence that might suggest heart failure,” Ponte said.


“DPP-4 inhibitors have been in use for some time,” Trujillo said. “We have experience with them, and the cardiovascular outcome studies are very large. We’re looking at years of data in thousands of patients.”


For patients who express concern about taking this medication, pharmacists should mitigate their fears with the best, most recent evidence available. Pharmacists and other health care providers can teach patients to recognize signs and symptoms of heart failure, which include shortness of breath with exertion or when lying down; fatigue; weakness; swelling in the legs, ankles, or feet; and rapid or irregular heartbeat, among other symptoms.


“In patients that don’t already have heart failure or risk factors for heart failure, I think that the likely benefits would outweigh the risks in most patients,” Trujillo said. 


SGLT-2 inhibitors


Last May, FDA issued a Drug Safety Communication warning that SGLT-2 inhibitors could increase risk for diabetic ketoacidosis (DKA), a dangerous accumulation of acid in the blood. 


SGLT-2 inhibitors, a newer oral medication than DPP-4 inhibitors, also control blood glucose in people with type 2 diabetes. They include canagliflozin (Invokana—Janssen), empagliflozin (Jardiance—Boehringer Ingelheim), and dapagliflozin (Farxiga—AstraZeneca). 


From March 2013 to June 2014, the FDA Adverse Event Reporting System received notifications of 20 cases of DKA in people taking drugs in this class. In each case, patients required emergency department visits or hospitalization. FDA continues to receive similar reports since then.


Also in May, Diabetes Care published an article on 13 cases of DKA in nine patients—seven with type 1 diabetes and two with type 2. The European Medicines Agency has reported 101 such cases worldwide.


“DKA is a serious and possibly life-threatening complication of the treatment of diabetes, and the information we have right now indicates that this is a risk that we’re seeing in both patients with type 1 and type 2 diabetes,” Trujillo said. 


These reports raise serious concerns for several other reasons. First, SGLT-2 inhibitors are indicated for the treatment of type 2 diabetes, but physicians prescribe them off-label for people with type 1 diabetes, a population that is far more susceptible to DKA. Second, these medications appear to bring about euglycemic DKA, a rare form of acidosis that does not come with the telltale blood glucose spike. 


“The DKA is likely going undiagnosed or diagnosed late. For one thing, because it’s happening when glucose levels are relatively normal, so a provider would likely not think about DKA, and secondly, because we’re also seeing it in the type 2 diabetes population, where we see DKA much less frequently,” Trujillo said.


The reports, however, do not prove a causal relationship between the medications and DKA. According to FDA, several of the reports cited factors that could have triggered the condition, such as major illness, reduced food and fluid intake, and reduced insulin dose. Many of the cases reported in Diabetes Care also included triggering incidents.


“It appears that there were extenuating circumstances in about half the cases,” Ponte said. “In the others, there was no trigger, so you have no clue what caused it.” Ponte noted that the lack of trigger in some cases could be a flaw in the reporting and not necessarily a fact of the case. 


“So this is only an association with the medications,” he said. “We don’t have enough evidence to suggest that drug X caused the DKA.”


SGLT-2 inhibitors: What should pharmacists know?


While the data don’t suggest that people with type 2 diabetes should necessarily discontinue use of SGLT-2 inhibitors, health care providers should consider the risks. That advice is different for people with type 1 diabetes whose health care provider prescribed the drug off-label. FDA’s drug safety communication reminds prescribers that safety and efficacy of SGLT-2 inhibitors have not been established in patients with type 1 diabetes, and FDA has not approved them for use in these patients. 


“For patients with type 1 diabetes, this information warrants a change in the way we educate patients and the way we talk to providers,” Trujillo said. 


Pharmacists should encourage providers to reevaluate their decision to prescribe this medication to patients with type 1 diabetes, she said. Providers should ensure that the likely benefits continue to outweigh the risks for these patients. Providers who keep patients in this population on SGLT-2 inhibitors should educate them on the signs and symptoms of euglycemic ketoacidosis, which include headache, nausea, vomiting, malaise, and abdominal pain. Patients also need education on frequent ketone monitoring when they are not feeling well. Pharmacists should reinforce this education.


“It’s incumbent on physicians, other primary care providers, and pharmacists to educate patients,” Ponte said. “They need to be aware of sick-day rules, fluid intake, insulin dosing, and blood glucose monitoring.”


Patients should know that DKA is serious and that they should contact their doctor or go to the emergency department or urgent care if they have signs and symptoms. “Pharmacists have a very important role in triage,” Ponte said. “If they suspect a symptom complex that’s associated with some of these potential adverse effects, they should triage [patients] to the most appropriate person or place for that.”


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