Review Article

Adverse Effects Associated With Newer Diabetes Therapies: A Review Article

Journal of Pharmacy Practice 2017, Vol. 30(2) 238-244 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190015594732 journals.sagepub.com/home/jpp

Oluwaranti F. Akiyode, PharmD, BCPS, CDE1, and Adebola A. Adesoye, PharmD, BCPS2

Abstract The increasing number of newer type 2 diabetes therapies has allowed providers an increased armamentarium for the optimal management of patients with diabetes. In fact, these newer agents have unique benefits in the management of type 2 diabetes. However, they are also associated with certain adverse effects. This review article aims to describe the notable adverse effects of these newer antidiabetic therapies including the glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and the sodium-glucose cotransporter 2 inhibitors. The adverse effects reviewed herein include pancreatitis, medullary thyroid carcinoma, heart failure, gastrointestinal disturbances, renal impairment, and genitourinary infections. More clinical data are necessary to solidify the association of some of these adverse effects with the newer diabetes agents. However, it is important for health care practitioners to be well informed and prepared to properly monitor patients for these adverse effects. Keywords glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, new antidiabetic agents, adverse effects

Introduction Management of type 2 diabetes mellitus (T2DM) has become progressively complex with considerations for patient characteristics, disease severity, and the increasing number of available pharmacological agents on the market.1,2 Among the available therapeutic agents, insulin, metformin, sulfonylureas (SU), and thiazolidinediones (TZDs) are the most studied.1 The increasing prevalence, morbidity, and mortality associated with diabetes have contributed to the development of additional drug therapies. As new drugs are developed, new safety issues also arise. The safety concerns of the majority of the earlier agents including insulin, SU, and TZDs included hypoglycemia, negative cardiovascular (CV) outcomes, and weight gain. The risk of hypoglycemia is not of a significant concern with the newer agents, however, there are still potential adverse effects that providers should be aware of and provide patient education in an effort to monitor and prevent these adverse events. This article aims to review major adverse effects associated with the newer noninsulin antihyperglycemic agents including the glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and the sodium-glucose cotransporter 2 inhibitors (Table 1). This review will also include strategies that may be utilized in preventing and/or lessening these adverse effects in clinical practice. The adverse effects to be reviewed herein include pancreatitis, medullary thyroid carcinoma (MTC), heart failure, gastrointestinal (GI)

disturbances, renal impairment, and genitourinary infections (Table 2).

Glucagon-Like Peptide 1 Receptor Agonists The glucagon-like peptide 1 receptor agonists (GLP-1RAs) are peptide incretin mimetic agents that exert their effects by enhancing GLP-1 activity to improve glycemic control in patients with T2DM.1,2 The pharmacologic effects of these agents include (1) increased glucose-dependent insulin secretion, (2) suppression of glucagon activity under hyperglycemic conditions, and (3) delay of gastric emptying rate.1-3 Together, these effects lead to the lowering of both fasting and postprandial glucose levels as well as promoting weight loss.1-3 The first of its class, exenatide, was first approved by the US Food and Drug Administration (FDA) as its twice-daily formulation in 1 Department of Clinical and Administrative Pharmacy Sciences, Howard University College of Pharmacy, Washington, DC, USA 2 Department of Pharmacy, Howard University Hospital, Washington, DC, USA

Corresponding Author: Oluwaranti F. Akiyode, Department of Clinical and Administrative Pharmacy Sciences, Howard University College of Pharmacy, 2300 4th Street, NW, Washington, DC 20059, USA. Email: [email protected]

Akiyode and Adesoye

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Table 1. Newer Diabetes Agents. Drugs Within Class Drug Class

Generic Name

Trade Name

GLP-1RAs

Exenatide Liraglutide Albiglutide Dulaglutide Sitagliptin Saxagliptin Linagliptin Alogliptin Canagliflozin Dapagliflozin Empagliflozin

Byetta1, Bydureon1 Victoza1 TanzeumTM TrulicityTM Januvia1 Onglyza1 Tradjenta1 Nesina1 Invokana1 FarxigaTM Jardiance1

DPP-4 inhibitors

SGLT2 inhibitors

Abbreviations: GLP-1RAs, glucagon-like peptide 1 receptor agonists; DPP-4 inhibitors, dipeptidyl peptidase-4 inhibitors; SGLT2 inhibitors, sodium-glucose cotransporter 2 inhibitors.

2005 and then later approved as its longer acting once weekly formulation in 2010. The other FDA-approved agents within this class include liraglutide, albiglutide, and dulaglutide, with the former available as once-daily, and the latter 2 as onceweekly formulations. All agents within this class are administered as subcutaneous injections and have dose-related efficacy in lowering hemoglobin A1c (HbA1c) by 0.5% to 1.5%.3 The most common adverse effects, and perhaps most common reason for therapy discontinuation or nonadherence, of GLP-1RAs are related to their GI disturbances. But the other notable adverse effects associated with the use of these agents include the increased risk of acute pancreatitis and the risk of developing malignant thyroid C-cell carcinomas.

Gastrointestinal Disturbances The GI disturbances noted with these GLP-1RAs mainly include nausea (8%-44%), vomiting (4%-18%), diarrhea (6%20%), and constipation (6%-10%) with nausea being the most frequently reported.4-6 In a meta-analysis study, exenatide and liraglutide as compared with placebo or traditional antidiabetic agents showed an increased probability of nausea by at least 2.5- to 6-fold, with the highest incidence seen with shortacting twice-daily exenatide 10 mg.7 Additionally, a dose– response difference between the GLP-1RAs was also reported, and higher doses tend to be associated with higher incidences of nausea.7 Notably, the occurrence of nausea was found to be less persistent, that is, a quicker resolution with liraglutide as compared to exenatide.8 Even more so, the once-weekly formulation of exenatide is reported as having lesser incidence and lesser persistence of GI adverse effects, particularly nausea and vomiting, when compared to twice-daily exenatide or the once-daily liraglutide.9 In summary, shorter acting formulations and in higher doses have the greatest risk while the longer acting formulations show a lesser persistence of nausea.7-9 These GI adverse effects may be tied to their effect on gastric motor function, specifically the delay of gastric emptying. And

considering that poor glycemic control in long-standing diabetes can contribute to an autonomic dysfunction of gastric motility intrinsically causing a delayed gastric emptying that can present with GI symptoms such as early satiety, postprandial fullness, nausea, and vomiting, clinicians should be aware that GI adverse effects of GLP-1RAs can worsen any existing GI disorder and also have a poor outcome on therapy adherence, leading to poor glycemic control and a consequential vicious cycle.7,10 In an effort to manage the GI adverse effects noted with the GLP-1RA treatment option, clinicians should initiate the agent at the lowest dose and titrate according to patient’s tolerability. The nausea can usually be alleviated with gradual dose titration and should typically resolve within 6 to 8 weeks following therapy initiation.3 Additionally, the longer acting formulations including exenatide once weekly, albiglutide, liraglutide, and dulaglutide may be selected for a lesser persistence of nausea. Finally, the use of these agents is not recommended in patients with preexisting severe GI disease such as gastroparesis.

Pancreatitis and Pancreatic Cancer Although the common risk factors for acute pancreatitis include alcohol abuse, gallstones, advanced age, African American race, smoking, and obesity, approximately 2% of its cases are said to be due to the use of certain drugs.11-12 Recent literature findings suggest that patients with diabetes are more likely to develop acute pancreatitis, with an associated 50% mortality rate, compared to nondiabetic patients.11,13 Varying studies have explored whether this increased risk may be due to the disease itself or the utilization of the antidiabetic agents, specifically the GLP-1RAs and the later discussed DPP-4 inhibitors, both considered GLP-1–based therapies. Reports from postmarketing surveillance data from the FDA adverse event reporting system (FAERS) database for both exenatide and a DPP-4 inhibitor, sitagliptin, identified the possible increased risk of acute pancreatitis, thereby compelling the FDA to add a warning label about increased risk of acute pancreatitis in association with the use of these agents and similar agents within the drug class.11,12-15 A risk evaluation and mitigation strategy (REMS) was also approved for all GLP-1–based therapies requiring drug manufacturers to communicate the risk of pancreatitis and pancreatic cancer to health care professionals and the professional societies. Evaluation of animal16-20 as well as various observational and meta-analysis12-15,21,22 studies have revealed conflicting findings as to the association of GLP-1–based agents with acute pancreatitis. In 2011, Elashoff et al reported findings of their examination of the FAERS database to gain insight into the potential adverse events of GLP-1 therapies. The study reported a 10-fold increased risk of pancreatitis with the use of exenatide when compared to other therapies.14 A recent self-controlled case series analysis of a large observational database reported findings of no association,11 while a population-based case–control study of a large administrative database reported over 2-fold increased odds of hospitalization secondary to the use of GLP-1–based

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Journal of Pharmacy Practice 30(2)

Table 2. Notable Adverse Effects Implicated With the Newer Diabetes Agents. Drug Class GLP-1RAs DPP-4 Inhibitors SGLT2 Inhibitors

Pancreatitis Medullary Thyroid Carcinoma Heart Failure GI Disturbances Renal Impairment Genitourinary Infections ü ü

ü

ü a

üb c

ü

d

ü

Abbreviations: GI, gastrointestinal; GLP-1RAs, glucagon-like peptide 1 receptor agonists; DPP-4 inhibitors, dipeptidyl peptidase-4 inhibitors; SGLT2 inhibitors, sodium-glucose cotransporter 2 inhibitors; eGFR, estimated glomerular filtration rate. a Clinical findings implicate saxagliptin in association with heart failure more so than the other DPP-4 inhibitors, but this is still considered a class wide concern. b Use of exenatide is not recommended in creatinine clearance < 30 mL/min and should be used with caution in creatinine clearance 30 to 50 mL/min. Liraglutide, albiglutide, and dulaglutide do not require renal dosage adjustment. c All DPP-4 inhibitors with the exception of linagliptin require renal dosage adjustment. d Initiation of canagliflozin is not recommended in eGFR < 45 mL/min/1.73 m2 and its use is contraindicated in eGFR < 30 mL/min/1.73 m2, ESRD, or dialysis dependent. Initiation of dapagliflozin and empagliflozin is not recommended in eGFR < 60 mL/min/1.73 m2, and

Adverse Effects Associated With Newer Diabetes Therapies.

The increasing number of newer type 2 diabetes therapies has allowed providers an increased armamentarium for the optimal management of patients with ...
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