Basal Insulin Use with GLP-1 Receptor Agonists Sarah L
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FROM RESEARCH TO PRACTICE / THE USE OF INSULIN IN DIABETES MANAGEMENT Basal Insulin Use With GLP-1 Receptor Agonists Sarah L. Anderson and Jennifer M. Trujillo ■ IN BRIEF The combination of basal insulin and a glucagon-like peptide 1 receptor agonist is becoming increasingly common and offers several potential benefits to patients with type 2 diabetes. Clinical studies have demonstrated improved glycemic control and low risks of hypoglycemia and weight gain with the combination, which provides a safe and effective alternative to basal- bolus insulin with less treatment burden. Fixed-ratio combination products that administer both agents in a single injection are in the pipeline and will University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, offer additional options for clinicians and patients. This review focuses on the Aurora, CO rationale for, clinical evidence on, and implications of using this combination of Corresponding author: Jennifer M. Trujillo, therapies in the treatment of type 2 diabetes. [email protected] ype 2 diabetes is a chronic, pro- abetes achieved a goal A1C <7% in DOI: 10.2337/diaspect.29.3.152 gressive disease that remains the 2007–2010 period, indicating the ©2016 by the American Diabetes Association. Tdifficult to control despite a continued need for effective and du- Readers may use this article as long as the work is properly cited, the use is educational and not growing armamentarium of treat- rable treatment approaches (1). for profit, and the work is not altered. See http:// ment options. National data show The typical clinical course of creativecommons.org/licenses/by-nc-nd/3.0 for details. that only 52.5% of people with di- type 2 diabetes involves periods 152 SPECTRUM.DIABETESJOURNALS.ORG ANDERSON AND TRUJILLO TABLE 1. Complementary Characteristics of Basal Insulin and GLP-1 Receptor Agonists Basal Insulin GLP-1 Receptor Agonists Mechanism of action • Augments basal insulin • Increases glucose-dependent insulin secretion from the pancreas • Increases glucose disposal • Decreases glucose-dependent secretion of • Decreases hepatic glucose glucagon production • Slows gastric emptying • Increased satiety Glucose profile • Primarily lowers FPG • Short-acting agents primarily lower PPG effects excursions • Longer-acting agents lower PPG and FPG Effect on weight • Increases weight • Decreases weight FROM RESEARCH TO PRACTICE FROM RESEARCH TO Main adverse effect • Hypoglycemia • GI issues (nausea, vomiting, diarrhea) • Low risk of hypoglycemia Administration • Subcutaneous injection once or • Subcutaneous injection once or twice daily or requirements twice daily once weekly of adequate glycemic control fol- Rationale for Combining Basal (Table 2). The pharmacokinetics, lowed by glycemic deterioration and Insulin with GLP-1 Receptor pharmacodynamics, dosing, and the need for additional treatment. Agonists clinical effects differ among these Ideally, add-on therapies should pro- Several considerations make the agents. The shorter-acting agents vide significant glucose reduction combination of basal insulin and a (exenatide and lixisenatide) are asso- with a complementary mechanism GLP-1 receptor agonist appealing ciated with more significant delays in of action, without adding signifi- (Table 1). First, the combination gastric emptying and more targeted cant side effects. Basal insulin (e.g., provides complementary effects on reductions in PPG. Compared to detemir, glargine, or degludec) is a the glucose profile. Basal insulin de- short-acting GLP-1 receptor agonists, recommended option at many stages livers sustained insulin throughout the longer-acting agents (albiglu- of type 2 diabetes and is often added the day, and therapy can be individ- tide, dulaglutide, exenatide XR, and to oral antidiabetic agents (OADs) to ualized by titrating the dose to the liraglutide) have less of an effect on achieve target fasting plasma glucose patient’s target FPG levels. However, gastric emptying and rely more on the (FPG) levels. However, it increases barriers such as fear of hypoglyce- insulin secretion mechanism, which the risk of hypoglycemia and weight mia and weight gain may limit the leads to reductions in both FPG initiation and adequate titration of gain, and its dosage must be titrated and PPG (4,12). Of note, although effectively to achieve glycemic tar- basal insulin (5,6). In addition, basal liraglutide and lixisenatide are both gets (2,3). Glucagon-like peptide 1 insulin does not target postprandial dosed once daily, lixisenatide has a (GLP-1) receptor agonists are also glucose (PPG); thus, more than half shorter half-life and primarily lowers reasonable options at many stages of of patients treated with basal insulin type 2 diabetes. These agents effec- do not achieve A1C targets (7–9). PPG, whereas liraglutide has a longer tively lower A1C, show favorable GLP-1 receptor agonists stimulate half-life, thus lowering both PPG and effects on weight, and have a low risk glucose-dependent insulin secretion, FPG (13). These distinctions should of hypoglycemia (4). Their use may inhibit glucose-dependent glucagon be considered when selecting a spe- be limited by gastrointestinal (GI) secretion, slow gastric emptying, and cific GLP-1 receptor agonist to use in adverse effects (AEs), administration increase satiety. Some evidence also combination with basal insulin. requirements, and cost. The combi- suggests that GLP-1 receptor ago- Combining therapy may also nation of basal insulin and a GLP-1 nists may preserve β-cell function potentially lower the risk of AEs. receptor agonist offers several poten- (10,11). Through these mechanisms, Basal insulin may cause weight gain tial benefits to patients with type 2 GLP-1 receptor agonists provide im- and hypoglycemia. GLP-1 receptor diabetes. This review focuses on the provements in both PPG and FPG agonists usually cause weight loss and rationale for, clinical evidence on, levels, complementing the effects of have a low risk of hypoglycemia but and implications of the combination basal insulin. do cause GI AEs. Combining the two of basal insulin and GLP-1 receptor There are currently six GLP-1 classes may allow patients to achieve agonists in the treatment of type receptor agonists approved for use glycemic control with lower doses, 2 diabetes. in either the United States or Europe which could potentially result in VOLUME 29, NUMBER 3, SUMMER 2016 153 FROM RESEARCH TO PRACTICE / THE USE OF INSULIN IN DIABETES MANAGEMENT TABLE 2. GLP-1 Receptor Agonists Approved for Use in the United States or Europe Short-Acting Long-Acting Generic name Exenatide Lixisenatide Liraglutide Exenatide XR Albiglutide Dulaglutide (trade name) (Byetta) (Lyxumia) (Victoza) (Bydureon) (Tanzeum, (Trulicity) Eperzan) Year of FDA 2005 Pending 2010 2012 2014 2014 approval Year of EMA 2006 2013 2009 2011 2014 2014 approval Dose 5–10 μg 10–20 μg 0.6–1.8 mg 2 mg 30–50 mg 0.75–1.5 mg Administration* Twice daily Once daily Once daily Once weekly Once weekly Once weekly Delivery Multi-use pen Multi-use pen Multi-use pen Single-use Single-use Single-use pen pen# pen# Renal dosing Not recom- None None Not recom- None None mended if mended if CrCl is <30 CrCl is <30 mL/min; mL/min; use caution if use caution if CrCl is 30–50 CrCl is 30–50 mL/min mL/min *Delivered via subcutaneous injection. #Requires reconstitution. CrCl, creatinine clearance; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration. fewer AEs than when the individual determined that combination thera- receptor agonist–treated patients; the drugs are used independently. py yielded a mean reduction in A1C most common AEs were predictably Finally, adding a GLP-1 receptor of 0.44% (95% CI –0.60 to –0.29, GI related. agonist to basal insulin offers a poten- P <0.0001) and weight of 3.22 kg Diamant et al. randomized 627 tially safer and easier approach to (95% CI –4.90 to –1.54, P <0.0001). patients with insufficient glycemic achieving glycemic control compared Combination therapy did not increase control despite 12 weeks of intensive to prandial insulin. Initiation of the relative risk of hypoglycemia (rel- protocol-driven glargine titration to prandial insulin increases treatment ative risk 0.99, 95% CI 0.76–1.29, add twice-daily exenatide or thrice- burden for patients and management P <0.0001). Although these findings daily lispro to their regimen (15). burden for providers. It requires one were favorable, only 4 of the 15 stud- Patients receiving exenatide reduced to three injections per day in addi- ies in the meta-analysis used an active their glargine dose by 10% (or more tion to the basal insulin injection, comparator. if their A1C was ≤8%), and patients significant patient education, dose The four active comparator stud- receiving lispro reduced their glargine titration, and increased monitoring ies, plus a fifth study published dose by 33–50%. Exenatide was ini- and increases the risk of hypoglyce- after the meta-analysis was com- tiated at 5 μg twice daily for 4 weeks mia and weight gain. Alternatively, pleted, compared the addition of and then up-titrated to 10 μg initi- adding a GLP-1 receptor agonist a GLP-1 receptor agonist or pran- ated at a dose to replace the reduced involves fewer injections, simpli- dial insulin to basal insulin therapy dose of glargine, divided across three fied dose titration, less education, (15–19). Of these, two evaluated meals. After exenatide or lispro ini- reduced weight, and a lower risk of twice-daily exenatide (15,16); two tiation, glargine