US Pharm. 2015;40(10)(Diabetes suppl):8-11.
ABSTRACT: The therapeutic management options for type 2 diabetes mellitus have expanded notably over the last decade with the development of three new classes of medications. These classes are the glucagon-like peptide-1 receptor agonists, the dipeptidyl peptidase-4 inhibitors, and the sodium-glucose cotransporter 2 inhibitors. The promising therapeutic benefits of these agents have led to their widespread use; however, the possibility of adverse effects ranging from pancreatitis to genitourinary infections warrants judicious selection based on considerations of patient-specific parameters. Pharmacists must work alongside other healthcare providers to mitigate adverse effects of these agents and to optimize the use of these medications in patients with type 2 diabetes mellitus.
Therapeutic advances in the management of diabetes mellitus have provided clinicians with a host of medications to optimize patient therapy. Despite significant progress in treatment, diabetes continues to be a leading cause of kidney failure, blindness, and nontraumatic amputation in the United States.1 Approximately 29.1 million people in the U.S. have diabetes, with type 2 diabetes mellitus (T2DM) accounting for 90% to 95% of all cases diagnosed in adults.1,2
The American Diabetes Association (ADA) emphasizes the importance of individualized care in clinical decision making for T2DM; therefore, it is crucial to analyze the safety profile of each agent. According to guidelines issued by the ADA and the American Association of Clinical Endocrinologists, metformin is considered first-line therapy3,4; however, its use may be limited by adverse effects (AEs) such as gastrointestinal (GI) manifestations and (rarely) lactic acidosis.5 Insulin secretagogues such as sulfonylureas have been widely used to manage T2DM for more than 50 years, but weight gain and hypoglycemia are problematic AEs that prompt the use of other options.6 Thiazolidinediones are another popular class of agents in the management of T2DM; however, reports of fluid retention, weight gain, and bone fractures curtail their use in several patient populations.7
T2DM management has expanded in the last decade with the introduction of three new classes of medications. Despite the wide array of therapeutic choices, it is critical to recognize the AEs associated with these agents in order to determine their appropriate use. This article will review the safety profile of newer T2DM agents and provide mitigation strategies (TABLE 1) to assist healthcare providers in choosing the optimal therapy for each patient.
Glucagon-Like Peptide-1 Receptor Agonists
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) mimic the action of GLP-1 in order to stimulate the glucose-dependent release of insulin, inhibit glucagon, slow gastric emptying, and decrease appetite. These agents improve glycemic control, enable weight loss (~2-3 kg), and help reduce A1C levels approximately 1% to 1.5%.8-12 Exenatide (Byetta), the first drug in this class, was approved in 2005, followed by liraglutide (Victoza) in 2010, exenatide extended-release (Bydureon) in 2012, and albiglutide (Tanzeum) and dulaglutide (Trulicity) in 2014.8-12 Common AEs (occurring in up to 44% of patients) associated with this class of drugs include nausea, vomiting, diarrhea, and headache, which can be reduced by slowly titrating the dose or by decreasing the frequency of administration.8-12 The long-acting form of exenatide (Bydureon) is associated with fewer GI disturbances.13 In clinical trials, serious adverse drug events (ADEs) occurring in patients taking GLP-1 receptor agonists were acute pancreatitis and pancreatic cancer.8-10 Although the overall data are conflicting, patients with severe persistent abdominal pain (which may radiate to the back) should discontinue the agent immediately.14 Exenatide should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease.8,15
The other GLP-1 RAs are not excreted renally; therefore, renal dosage adjustments are not needed. Thyroid C-cell tumors have been associated with clinically relevant dosages of GLP-1 RAs in rodents, but it is unknown whether GLP-1 RAs cause tumors in humans.10,16 Patients being treated with a GLP-1 RA should be counseled on the risk of thyroid C-cell tumors and advised to immediately report symptoms, which include lump in the neck, hoarseness, or dysphagia, to their prescriber.11,13,17
Dipeptidyl Peptidase-4 Inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors currently available in the U.S. include sitagliptin (Januvia), which was approved in 2006, followed by saxagliptin (Onglyza) in 2009, linagliptin (Tradjenta) in 2011, and alogliptin (Nesina) in 2013.18-22 DPP-4 inhibitors are indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2DM either as monotherapy or in combination with other hypoglycemic agents.18 DPP-4 inhibitors prolong the activity of physiological incretin hormones by inhibiting the DPP-4 enzyme, leading to an increase of glucose-dependent insulin secretion and the suppression of glucagon, which can result in an A1C reduction of 0.4% to 1.0%.18,22
The most common ADEs observed with most of these agents include nasopharyngitis (4.4%-7%), upper respiratory infection (4.2%-7.7%), and headache (4.2%-5.9%).19-22 The risk of hypoglycemia associated with DPP-4 inhibitor use is very low for monotherapy regimens (0.6%-6.6%); however, a much higher prevalence is seen with combination therapy regimens that include other hypoglycemic agents (2.7%-22.9%).19-21 Linagliptin is the only agent in this class that does not require renal dosage adjustments.21
Pancreatitis and pancreatic cancer are among the more serious ADEs reported across most agents in this class. The FDA Adverse Event Reporting System revealed that over a 1-year period (2012), 831 of 1,723 cases of pancreatitis and 105 of 1,723 cases of pancreatic cancer were reported with the use of DPP-4 inhibitors, including saxagliptin, sitagliptin, and linagliptin.23 Given the voluntary nature of these reports, no causal relationship has been established for pancreatitis and pancreatic cancer with the use of DPP-4 inhibitors.
Specific DPP-4 inhibitors can lead to specific ADEs. Except for saxagliptin, DPP-4 inhibitors share the ability to cause hypersensitivity reactions (e.g., anaphylaxis, angioedema, Stevens-Johnson syndrome [SJS]).19,20,22 In patients with hypersensitivity reactions, including SJS, the drug regimen should be discontinued and alternative options sought by the clinician.20
Saxagliptin can cause heart failure (HF); during clinical trials, hospitalization for HF occurred in 3.5% of saxagliptin patients, compared with 2.8% of placebo patients. Patients with a history of HF, chronic kidney disease, or elevated natriuretic peptide levels are at higher risk for this ADE.24 Postmarketing surveillance also revealed fulminant hepatic failure to be an ADE associated with alogliptin. Patients who develop symptoms indicative of liver injury should be monitored, and alogliptin should be discontinued if symptoms persist.22
Sodium-Glucose Cotransporter 2 Inhibitors
The introduction of a new class of oral agents (sodium-glucose cotransporter 2 [SGLT2] inhibitors) that target the kidney and increase urinary glucose output heralded a novel approach to therapy for T2DM. The first approved agent in this class was canagliflozin (Invokana) in 2013, followed by dapagliflozin (Farxiga) and empagliflozin (Jardiance) in 2014.25 To clinicians, excess urinary glucose often signifies a diagnostic marker of uncontrolled T2DM; however, SGLT2 inhibitors operate by that same mode of action. By inhibiting SGLT2 in the proximal tubules, these agents prevent glucose reabsorption and promote renal excretion, resulting in an A1C reduction of 0.5% to 0.7%.25 SGLT2 inhibitors work adjunctively with nutrition and physical activity to improve glycemic control in T2DM patients.25
Owing to the excretion of glucose via the urinary tract, patients taking SGLT2 inhibitors may be predisposed to urinary tract infections (UTIs). In clinical trials, UTIs were a common AE observed with this class of agents, with an incidence as high as 9.3% (for empagliflozin).26 With dapagliflozin, clinical trial data noted a small increase in the number of UTIs; however, this was not a consistent finding and did not result in any serious ADEs.27
Female genital mycotic infections were another common classwide AE in clinical trials.26 Canagliflozin conferred the highest incidence (10.4%-11.4%), followed by dapagliflozin (6.9%-8.4%) and empagliflozin (5.4%-6.4%).26-28 Male genital mycotic infections occurred at a lower rate (1.6%-4.7%) in trials.26-28 Infections typically resolve spontaneously or with standard antimicrobial therapy.26-28
SGLT2 inhibitors have the potential to cause volume depletion and orthostatic hypotension as a result of their modest diuretic effects.25 Owing to the increased urination resulting from this class of agents, patients may be at risk for dehydration, which can impact renal function. There was a higher incidence of volume depletion for dapagliflozin compared with placebo, and a similar trend was observed with the other agents in this class.26-29 However, these renal changes are often transient and more likely to occur in patients with poor renal perfusion. Additionally, since these agents are effective only in the presence of adequate renal function, they are generally not recommended in patients with renal impairment (epidermal growth factor <45 mL/min/1.73 m2 for empagliflozin and canagliflozin; <60 mL/min/1.73 m2 for dapagliflozin).25
It is important to educate patients on symptoms of dehydration and to advise them to consume adequate fluids while taking SGLT2s. Certain populations that are at risk for dehydration or may need appropriate electrolyte regulation (i.e., advanced age, moderate-to-severe renal impairment, cardiac disease) may not be good candidates for SGLT2 therapy. It is important to recognize added diuretic effects and hypotension if the patient is taking other commonly employed agents, such as diuretics and renin-angiotensin-aldosterone inhibitors.
Other AEs associated with SGLT2 inhibitors include dyslipidemia, nausea, constipation, and abdominal pain.26-28 Across 22 clinical studies, newly diagnosed bladder cancer was reported in 0.17% of dapagliflozin patients versus 0.03% of placebo patients. Given the small number of cases, it is difficult to determine whether this emergence was related to dapagliflozin.29
In May 2015, the FDA issued a warning regarding the potential for SGLT2 inhibitors to cause ketoacidosis. This warning was based on 20 identified cases in patients treated with SGLT2 inhibitors between March 2013 and June 2014.30 Although a causal relationship has not been established, patients should be instructed to pay close attention for symptoms of ketoacidosis (e.g., difficulty breathing, vomiting, confusion, unusual fatigue or sleepiness) and to seek immediate medical attention if any of these occur.30
Role of the Pharmacist
The increasing prevalence of T2DM, coupled with poor patient outcomes, has served to drive the development of newer antihypertensive medications over the last decade. Unlike older diabetes medications, the newer medications are not associated weight gain or hypoglycemia. However, the newer agents can result in other potential AEs, including medullary thyroid cancer, pancreatitis, and genitourinary infections, that providers, pharmacists, and patients should be aware of.
It is of critical importance that pharmacists be conversant with these AEs in order to properly counsel and educate patients prior to initiation of newer antihyperglycemic agents. The pharmacist should work collaboratively with other healthcare providers in the proper selection of agents for patients on an individualized basis. Once a patient has begun using a newer agent, the pharmacist should be vigilant in monitoring and resolving AEs. Overall, the pharmacist’s role centers on empowering the patient with sufficient knowledge to recognize potential AEs and on concurrently working with the patient’s provider to prevent and/or mitigate any AEs that arise from the use of these newer antihyperglycemic agents.
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