continuing education for pharmacists Volume XXXV, No. 2 2016 AACE/ACE Guidelines on Type 2 Diabetes Management and New Glycemic Control Agents

Amanda R. Kriesen, R.Ph., PharmD, and Erin Bastick, R.Ph., PharmD

Drs. Amanda Kriesen and Erin Bastick to subsequent increased blood tively communicating results and/ have no relevant financial relationships to glucose. It is a principal cause of or drug therapy-related concerns disclose. morbidity and mortality worldwide. with prescribers. An interdisciplin- Type I diabetes (T1D) is character- ary approach to patient care is a Goal. The goals of this lesson are ized by a lack of insulin production, vital component of comprehensive to provide an overview of the 2016 whereas type II diabetes (T2D) is care. American Association of Clini- characterized by the body’s ineffec- cal Endocrinologists (AACE) and tive use of endogenous insulin. Overview of 2016 AACE/ American College of Endocrinology In 2014, an estimated 29.1 ACE Type II Diabetes (ACE) consensus statement regard- million Americans had diabetes; Management Algorithm ing the management of hyperglyce- with approximately one in four Founding principles of the AACE/ mia associated with type II diabe- of these Americans unknowingly ACE type II diabetes algorithm in- tes, and to discuss empagliflozin/ suffering from the condition. The clude recommendations pertaining ® metformin (Synjardy ), insulin de- implications of serious health to lifestyle optimization, patient- ® gludec (Tresiba ), insulin degludec/ complications arising from diabetes specific pharmacologic therapy, ® insulin aspart (Ryzodeg 70/30 ), are extensive. Comorbidities such combination therapy, and medica- ® insulin glargine (Basaglar ) and as blindness, renal failure, heart tion therapy for comorbid disease ® lixisenatide (Adlyxin ). disease, stroke, and neuropathy states commonly associated with significantly increase healthcare T2D. It is important to note that Objectives. At the completion of expenditures and reduce quality of the AACE/ACE guidelines are not this activity, the participant will be life. Diabetes is associated with a the only set of diabetes guidelines able to: high incidence of depression, and available. The American Diabetes 1. recognize the 2016 AACE/ adversely impacts employment Association (ADA) has also pub- ACE consensus statement regard- with increased absenteeism, and lished guidelines. For the purposes ing treatment of hyperglycemia decreased productivity. Further- of this lesson, only the AACE/ACE associated with diabetes mellitus; more, individuals with diabetes are guidelines will be reviewed. 2. list lifestyle modifications at a 50 percent higher risk of death Both genetic and environmen- that contribute to improved glyce- than those without diabetes. tal factors contribute to develop- mic control; Due to the increasing frequency ment of T2D. Physical inactivity, 3. demonstrate an understand- of T2D diagnoses in the general excessive weight gain, and obesity ing of various classes of antihyper- population, pharmacists are in a are all contributors to endogenous glycemic agents; unique position to help guide pa- insulin resistance. Lifestyle modi- 4. recognize the mechanism tients with diabetes. Pharmacists’ fications such as medical nutrition of action of the new antihypergly- in-depth knowledge of various anti- therapy, regular physical activity, cemic agents and their respective hyperglycemic medication profiles, sufficient sleep, and avoidance of roles in treating diabetes; and proficient communication skills, all tobacco products are key com- 5. identify pertinent prescrib- and accessibility in the community ponents in management of T2D. ing and counseling points associ- allow opportunities for effective Medical nutrition therapy involves ated with the new drugs. patient communication and edu- a specifically tailored diet that is cation. Furthermore, community designed and monitored by a reg- Background pharmacists who see patients with istered dietitian or a professional Diabetes mellitus is a chronic diabetes on a regular basis may be nutritionist. An optimal weight condition caused by endogenous able to assist in evaluating efficacy should be attained and maintained insulin impairment, which leads of pharmacologic therapy and effec- by a primarily plant-based diet ics such as socioeconomic status, Table 1 health literacy, comorbid disease Goals for glycemic control in nonpregnant adults states, tolerability, and affordabil- with diabetes ity. In addition to selecting therapy Hemoglobin A1C ≤6.5 percent specific to patient dynamics, creat- Patients without concurrent serious illness and low ing an individualized medication hypoglycemic risk (e.g., recent-onset T2D, no clinically regimen may further encourage significant cardiovascular disease) compliance. The AACE/ACE algorithm rec- Patients with concurrent serious illness and high >6.5-8.0 percent ommends a combination of lifestyle hypoglycemic risk (e.g., history of severe hypoglycemia, therapy plus antihyperglycemic limited life expectancy, advanced renal disease or macro- monotherapy (preferably metfor- vascular complications, extensive comorbid conditions, or min) in newly-diagnosed diabetes long-standing T2D with inability to attain target A1C) or mild hyperglycemia (A1C <7.5 Preprandial capillary plasma glucose 80-130 mg/dL percent). Metformin should remain the cornerstone of all antihyper- Peak postprandial capillary plasma glucose <180 mg/dL glycemic pharmacotherapy, if not (1-2 hours after beginning of meal) contraindicated. Acceptable alter- natives to metformin monotherapy include GLP-1 agonists, SGLT-2 high in polyunsaturated and mono- AACE/ACE supports an A1C goal inhibitors, DPP-4 inhibitors, and unsaturated fats, limiting intake of of ≤6.5 percent for most patients; TZDs. Combination therapy is saturated fatty acid, and avoidance however, A1Cs up to 8 percent are considered in patients unable to of trans fats. Physical activity, both often upheld if the ideal target attain glycemic targets after three aerobic and strength-training, has cannot be reached without adverse months of monotherapy or patients been shown to improve glycemic outcomes. A preprandial capillary presenting with A1C >7.5 per- control, lipid levels, and blood pres- plasma glucose of 80 to 130 mg/ cent. Dual therapy often includes sure. Patients should be advised to dL and a postprandial capillary metformin plus a GLP-1 agonist, engage in at least 150 minutes per plasma glucose of <180 mg/dL may SGLT-2 inhibitor, DPP-4 inhibi- week of moderate physical activity. further aid in reducing A1C. Again, tor, or a TZD. Patients intolerant Sleep deprivation is known to ag- treatment goals should be tailored to metformin should be given dual gravate insulin resistance, hyper- per individual patient needs and therapy with two medications from tension, hyperglycemia, and dyslip- demographics. Several clinical other classes that have complemen- idemia. Patients should be advised studies have published evidence tary mechanisms of action. If dual to sleep approximately seven hours supporting individualization of therapy fails to provide appropriate per night, as adequate rest is im- glycemic targets. Table 1 provides glycemic targets, the addition of a perative in maintaining energy lev- an overview of glycemic control third agent may be considered. It els and well-being. Lastly, patients goals for nonpregnant adults with is important to note, however, that should be advised to avoid use of diabetes. any third-line agent may be less all tobacco products. Structured effective in comparison to the same smoking cessation programs are Pharmacotherapy medication when used as first- or recommended for patients unable The 2016 AACE/ACE algorithm second-line therapy. Patients with to quit on their own. provides an aid in selecting ther- A1C >9 percent receive greater apy. In the algorithm, antihyper- benefit from insulin; however, in Goals for Glycemic Control glycemic drug classes are listed in the absence of significant symp- In patients with T2D, achieving the order of preference. Several classes toms, these patients may be initi- hemoglobin A1C (A1C) goal and of antihyperglycemic agents exist; ated on maximum doses of combi- glucose target require a multifac- however, therapeutic selection nation therapy. torial approach which balances should be individualized. Classes Biguanides. Metformin is age, comorbid disease states, and include biguanides, glucagon-like considered first-line therapy in hypoglycemia risk. Hemoglobin peptide-1 (GLP-1) agonists (in- treating T2D. The sole agent of A1C is a measurement of how cretin mimetics), sodium-glucose the biguanide class, metformin, much glucose binds to circulating cotransporter-2 (SGLT-2) inhibi- acts by decreasing hepatic glucose hemoglobin in the blood; it serves tors, dipeptidyl peptidase-4 (DPP- production, decreasing intestinal as a reflection of glycemic control 4) inhibitors, thiazolidinediones glucose absorption, and improv- over the past six to eight weeks. (TZDs), bile acid sequestrants, ing insulin sensitivity. It offers A glucose target, in contrast, is alpha-glucosidase inhibitors, sul- low risk of hypoglycemia, and a measurement which reflects a fonylureas, and dopamine recep- doses between 2,000 to 2,500 mg/ patient’s blood glucose concentra- tor agonists. Interventions should day have shown good antihyper- tion at one particular point in time. integrate patient-specific dynam- glycemic efficacy. Due to risk of AACE/ACE recommends GLP-1 (Onglyza), and sitagliptin (Janu- acidosis, U.S. prescribing infor- receptor agonists be used cau- via). DPP-4 inhibitors enhance mation states that metformin is tiously, if at all, in patients with a circulating incretin levels, thereby contraindicated in men and women history of pancreatitis and should stimulating glucose-dependent with serum creatinine >1.5 mg/ be discontinued upon development insulin synthesis and suppressing dL and >1.4 mg/dL, respectively, of acute pancreatitis. Because of glucagon secretion. DPP-4 in- or if the creatinine clearance is their ability to delay gastric emp- hibitors offer a modest reduction in “abnormal.” FDA, however, does tying, patients with gastroparesis A1C with low risk of hypoglycemia not define a specific cutoff for or severe gastroesophageal reflux and are considered weight-neutral. creatinine clearance. AACE/ACE disease (GERD) require close moni- All agents except linagliptin are proposes discontinuation of metfor- toring and dosage adjustments. renally eliminated; therefore, pa- min in patients with an estimated Incretin mimetics may be used as tients with renal dysfunction will glomerular filtration rate (eGFR) monotherapy in patients with con- require dosage adjustments. DPP-4 <30 mL/min/1.73 m2. Furthermore, traindications to metformin. They inhibitors should be used with AACE/ACE recommends against may also be used in conjunction caution in patients with a history metformin use in patients with with metformin as dual therapy in of pancreatitis. DPP-4 inhibitors stage 3B, 4, or 5 chronic kidney cases where glycemic targets are may be initiated as monotherapy in disease (CKD). A small percentage not met after three months. cases of contraindication or intoler- of metformin users may experience SGLT-2 Inhibitors. Sodium ance to metformin, GLP-1 analogs dysfunction in vitamin B12 absorp- glucose cotransporter-2 (SGLT-2) or SGLT-2 inhibitors. tion, which often leads to anemia inhibitors are another option in In April 2016, FDA released a and/or development of peripheral treatment of T2D. Agents such as safety communication warning that neuropathy. Vitamin B12 levels canagliflozin (Invokana), dapa- T2D medications containing saxa- should be monitored in all patients gliflozin (Farxiga), and empa- gliptin and alogliptin may increase taking metformin; patients affected gliflozin (Jardiance) remove glucose the risk of heart failure, particu- by malabsorption should receive by inhibiting the cotransporter larly in patients who already have vitamin B12 supplementation. responsible for filtered glucose heart or kidney disease. The FDA Metformin should be at the base resorption and decreasing the warning is based on two large of any T2D regimen, whether used renal glucose threshold. Excess clinical trials conducted in patients as monotherapy or in combination, glucose is then excreted in the with heart disease. Each trial unless contraindicated. urine. SGLT-2 inhibitors have been showed that more patients who GLP-1 Agonists. AACE/ observed to decrease A1C, weight, received saxagliptin- or alogliptin- ACE recommends GLP-1 receptor and systolic blood pressure. Agents containing medications were hospi- agonists, or incretin mimetics, as in this class carry an FDA black talized for heart failure compared appropriate treatment options for box warning regarding increased to patients who received placebo. T2D. Agents in this class include risk of diabetic ketoacidosis (DKA) In light of the new warning, albiglutide (Tanzeum), dulaglutide and serious urinary tract infec- patients taking these medications (Trulicity), exenatide (Byetta), tion (UTI). DKA has been reported should contact a healthcare profes- and liraglutide (Saxenda, Victoza). in both type 1 and type 2 diabetic sional right away if they develop GLP-1 receptor agonists exert their patients with slight hyperglycemia; signs or symptoms of heart fail- effect by mimicking the action of investigations into post-marketing ure, such as unusual shortness incretin hormone, which increases reports are ongoing. Despite the of breath, tiredness, fatigue, or glucose-dependent insulin secre- FDA black box warning, AACE/ unexplained weight gain. Patients tion, decreases inappropriate ACE supports SGLT-2 inhibitors as should not stop taking their medi- glucagon secretion, increases beta- third-line therapy for T2D after an cations without first talking to a cell growth and replication, delays expert consensus group found the healthcare professional, but provid- gastric emptying, and increases incidence of DKA to be infrequent. ers may consider stopping these satiety. GLP-1 receptor agonists of- SGLT-2 inhibitors may be used as agents in patients who develop fer strong A1C-lowering properties, monotherapy in patients in need of heart failure. are available in various formula- an alternative agent for metformin This is not the first issue tions, and are often associated with or GLP-1 receptor agonists. They addressed in the Warnings and weight loss and blood pressure may also be used in combination Precautions labeling of the DPP-4 reduction. In addition to a low risk therapy. inhibitors. Most recently in Au- of hypoglycemia, GLP-1 receptor DPP-4 Inhibitors. Dipepti- gust 2015, FDA warned that this agonists also decrease fluctuations dyl peptidase 4 (DPP-4) inhibitors class of antihyperglycemic agents in both preprandial and postpran- are the next therapeutic option may cause severe and disabling dial glucose levels. Although no for T2D treatment. Agents in this joint pain. In a search of the FDA studies have confirmed that in- class include alogliptin (Nesina), Adverse Event Reporting System cretin agents cause pancreatitis, linagliptin (Tradjenta), saxagliptin (FAERS) database, researchers Table 2 Selected insulin products

Type of Insulin Brand Name Generic Name Onset† Peak Action† Duration of Action† Rapid-Acting Apidra glulisine 20-30 mins 60-90 mins 3-5 hrs HumaLOG lispro 5-20 mins 60-180 mins 3-5 hrs NovoLOG aspart 10 mins 60-180 mins 3-5 hrs

Short-Acting Humulin R regular 30-60 mins 2-5 hrs 4-12 hrs Novolin R regular 30-60 mins 2-5 hrs 4-12 hrs

Intermediate- Humulin N NPH 1-5 hrs 4-12 hrs 14-24 hrs Acting Novolin N NPH 1-5 hrs 4-12 hrs 14-24 hrs

Long-Acting Basaglar‡ glargine 2-4 hrs no peak 22-24 hrs Lantus glargine 2-4 hrs no peak 22-24 hrs Levemir detemir 2-4 hrs 2-9 hrs up to 24 hrs

Ultra-Long- Tresiba‡ degludec 30-90 mins no peak up to 40 hrs Acting

Mixtures Humulin 70/30 NPH + reg 30-60 mins 2-12 hrs 18-24 hrs Novolin 70/30 NPH + reg 30-60 mins 2-12 hrs 18-24 hrs

Humalog Mix 50% lispro 15-30 mins 0.8-4.8 hrs 14-24 hrs 50/50 protamine + 50% lispro

Humalog Mix 75% lispro 10-30 mins 1-6.5 hrs 14-24 hrs 75/25 protamine + 25% lispro

Novolog Mix 70% aspart 10-20 mins 1-4 hrs 18-24 hrs 70/30 protamine + 30% aspart

Ryzodeg 70% degludec + 14 mins 72 mins ≥ 24 hrs 70/30‡ 30% aspart

†Onset, peak, and duration of action may vary between products for each patient. ‡Newly-approved insulin product noted several cases of severe joint medications to the FDA MedWatch of bone fracture in postmenopausal pain associated with the use of program. women and elderly men, and DPP-4 inhibitors. Patients devel- Thiazolidinediones. Thia- increased risk of chronic edema or oped symptoms from one day to zolidinediones (TZDs) are the fifth heart failure. Adverse effects may years after initiating the drugs. option and the only antihypergly- be managed by prescribing moder- After the agents were discontinued, cemic agents that directly reduce ate doses. their symptoms were relieved, usu- insulin resistance. Agents such as Other Agents. Alpha-glucosi- ally in less than a month. pioglitazone (Actos) and rosigli- dase inhibitors (AGIs) and sulfo- Again, patients should not stop tazone (Avandia) offer relatively nylureas (SFUs) have largely fallen taking DPP-4 inhibitors without potent A1C-lowering effects, carry out of favor due to unfavorable first talking to their healthcare a low risk of hypoglycemia, and adverse effects. AGIs, such as acar- professionals, but are advised to confer robust glycemic effects. bose (Precose) and miglitol (Gly- contact a provider right away if Pioglitazone may confer additional set), offer modest A1C reduction they experience severe and per- benefits in cardiovascular disease. and have low risk of hypoglycemia; sistent joint pain. These agents Although TZDs may be considered however, adverse effects such as should be considered as possible as monotherapy in certain patient bloating, flatulence, and diarrhea causes of joint pain and discontin- populations, their general use is have limited their use in the Unit- ued if appropriate. Healthcare pro- limited due to dose-related adverse ed States. Conversely, SFUs, such fessionals and patients are urged to effects associated with the class, in- as glipizide (Glucotrol), glimepiride report side effects involving these cluding weight gain, increased risk (Amaryl), and glyburide (Glynase), are relatively potent A1C reduc- along with their onset, peak, and same as the previous product. ers, but are associated with weight duration of action. Tresiba (insulin degludec). gain and carry the highest risk of The first ultra-long-acting insulin serious hypoglycemia. Colesevelam New Antihyperglycemic analog, insulin degludec (Tresiba), (Welchol), a bile acid sequestrant, Agents was approved in September 2015. modestly lowers glucose and does Basaglar (insulin glargine). Similar to previously-approved not cause hypoglycemia; however, A new insulin glargine 100 units/ basal insulins, insulin degludec its use is limited due to a high inci- mL (U-100) injection, Basaglar, is indicated to improve glycemic dence (>10 percent) of gastrointes- was approved in December 2015 control in adults with T1D or T2D. tinal intolerance and its ability to to improve glycemic control in Insulin degludec is available in exacerbate serum triglyceride (TG) adults and pediatric patients with both 100 units/mL (U-100) and 200 levels in patients with pre-existing T1D and adults with T2D. Basa- units/mL (U-200) prefilled pen de- TG elevations. Bromocriptine (Cy- glar contains the same amino acid vices, and is to be administered as closet, Parlodel) has minor glucose- sequence as Lantus, a previously- a once daily subcutaneous injection lowering properties and low risk approved insulin glargine U-100 at the same time each day. Start- of hypoglycemia but may cause product, and is considered a follow- ing doses for patients with T1D or nausea and orthostasis, limiting its on biologic product in the United T2D are the same as other long- use. States. Basaglar has been available acting insulin products and dosing Insulin. Patients with long- in the U.S. since December 2016. should be individualized based on standing T2D or patients who take Basaglar is the first insulin type of diabetes, metabolic needs, more than two antihyperglycemic product approved through an blood glucose monitoring results agents are unlikely to meet and abbreviated approval pathway and glycemic control. No conver- maintain their A1C goals with- under the Federal Food, Drug, and sion is needed when using the out eventually requiring insulin. Cosmetic Act. In its application for insulin degludec U-100 or U-200 In these cases, a once daily dose approval, it was demonstrated that pens, as their dose windows show of basal insulin should be added. Basaglar was sufficiently similar the number of insulin units to be Insulin is the most potent glucose- to previously approved insulin administered. lowering agent. Initiating insulin glargine products. Data included To evaluate its efficacy in pa- therapy must be patient-specific, two clinical trials enrolling 535 and tients with T1D, insulin degludec taking into consideration the 759 patients with T1D and T2D, re- was evaluated in three random- patient’s motivation, comorbidi- spectively, in which Basaglar was ized, controlled trials, in which the ties, age, general health, and cost compared to previously approved long-acting insulin was given once effectiveness. Insulin regimens insulin glargine U-100 products. daily in combination with rapid- should be reassessed frequently to At trial completion for both stud- acting insulin at mealtimes. Two reach the target glucose level while ies, Basaglar provided a mean of the studies compared the drug avoiding hypoglycemia. Adjust- reduction in A1C that was non- to insulin glargine, and the third ments in insulin regimens should inferior to that achieved with the compared it to insulin detemir. be made based on individual pa- comparator insulin glargine U-100 To evaluate its efficacy in T2D, tient response. products. Basaglar is provided as a six clinical trials were conducted Common dual insulin regimens prefilled 3 mL delivery device and to compare insulin degludec to include concomitant administration is to be administered as a subcu- previously-approved long-acting of rapid-acting insulin plus basal taneous injection once daily at the insulins as an add-on to oral anti- insulin. Patients whose insulin same time each day. The recom- hyperglycemic drug regimens and/ regimens fail to provide adequate mended starting dose of Basaglar or in combination with rapid-acting coverage may need combination in patients with T1D should be ap- insulins at mealtime. Results of the therapy with an additional antihy- proximately one-third of the total studies in both T1D and T2D deter- perglycemic agent. In combination daily insulin requirements, and mined that patients treated with with insulin therapy, both GLP-1 rapid-acting insulin should be used insulin degludec achieved levels of receptor agonists and SGLT-2 to make up the remainder of the glycemic control similar to those inhibitors further propagate glu- daily requirements. For patients achieved with previously-approved cose reduction without the risk of with T2D, the recommended start- long-acting insulins. hypoglycemia. Incretin mimetics ing dose is 0.2 units/kg or up to 10 Ryzodeg 70/30 (insulin de- also increase endogenous insulin units once daily. Dosing and timing gludec/insulin aspart). A mixture secretion in response to meals, of other insulins and other antihy- of insulin degludec and insulin lowering postprandial hyperglyce- perglycemic agents may need to be aspart, a rapid-acting insulin, was mia. Within the last year, several adjusted when starting Basaglar. also recently approved by FDA un- new antihyperglycemic agents If changing patients from another der the brand name Ryzodeg 70/30. have been approved by FDA. Table insulin glargine U-100 product, It improves glycemic control in 2 lists available insulin products the dose of Basaglar should be the patients with T1D and T2D. Dosing of insulin degludec/insulin as- Due to limited data avail- should be discontinued and the part should be individualized and able for the use of the new insulin patient should seek immediate titrated based on each patient’s products in pregnant women and medical care. The most common specific needs and glycemic control because there are potential risks to adverse reactions associated with goals. The U-100 product is avail- both mother and fetus in the case the use of lixisenatide are nausea, able as a 3 mL prefilled pen and is of poorly controlled diabetes, these vomiting, headache, diarrhea, diz- to be administered subcutaneously agents should be used during preg- ziness, and hypoglycemia. Other once or twice daily with any main nancy only if the potential benefit reported adverse reactions (2 to meal; a rapid-acting insulin may justifies the potential risk to the 5 percent of lixisenatide-treated be administered at other meals if fetus. No dosage adjustments for patients and more frequently than needed. renal or hepatic impairment are placebo) include dyspepsia, consti- The efficacy of insulin degludec/ provided in manufacturer labeling; pation, abdominal distension, and insulin aspart used in combination however, more frequent glucose abdominal pain. with mealtime insulin in patients monitoring and dose adjustments Because lixisenatide delays with T1D was evaluated in one may be necessary in these patients. gastric emptying, it may impact 26-week controlled trial, in which When counseling patients absorption of concomitantly ad- 529 patients were randomized to on proper preparation and use of ministered oral medications. receive insulin degludec/insulin as- insulin products, it is important to Consequently, medications that are part, or insulin detemir once daily. offer guidance on how to correctly particularly dependent on thresh- Results of the trial determined that administer the injection, including old concentrations for efficacy, such insulin degludec/insulin aspart the importance of aseptic tech- as antibiotics or medications for was non-inferior to insulin detemir nique. All basal insulins should which a delay in effect is unde- in providing glycemic control in be administered subcutaneously sirable, such as acetaminophen, patients with T1D. For use in T2D, into the abdominal area, thigh, or should be administered one hour the efficacy of insulin degludec/ deltoid muscle, and patients should before lixisenatide. Oral contracep- insulin aspart administered once be instructed to rotate injection tives should also be taken at least or twice daily used in combination sites daily to reduce the risk of one hour before or 11 hours after with oral antihyperglycemic agents lipodystrophy (abnormal or de- the dose of lixisenatide. was evaluated in four randomized generative conditions of the body’s Lixisenatide is not indicated controlled trials. The studies deter- adipose tissue). Patients must also for use in patients with T1D or for mined that patients treated with be educated to recognize and man- treatment of diabetic ketoacidosis. insulin degludec/insulin aspart age episodes of hypoglycemia when Concurrent use with short-acting achieved levels of glycemic control using any insulin product. insulin has not been studied. Ad- similar to those treated with insu- Adlyxin (Lixisenatide). The ditionally, lixisenatide has not been lin glargine, insulin detemir and new GLP-1 receptor agonist, studied in patients with chronic biphasic insulin aspart. lixisenatide [Adlyxin], was ap- pancreatitis or a history of unex- Hypersensitivity reactions proved in July 2016. Lixisenatide plained pancreatitis or in patients including anaphylaxis have been is a once-daily injection indicated with gastroparesis, and thus is not reported with insulin products. to improve glycemic control, along recommended in these patients. Should symptoms of hypersensitiv- with diet and exercise, in adults Due to limited data available ity occur, treatment should be dis- with T2D. Like other GLP-1 recep- for the use of lixisenatide in preg- continued and the patient should tor agonists, lixisenatide increases nant women, the drug should be seek immediate medical care. Insu- glucose-dependent insulin release, used during pregnancy only if the lins also have the potential to cause decreases glucagon secretion, and potential benefit justifies the -po hypokalemia. Therefore, potas- slows gastric emptying. Lixisena- tential risk to the fetus. No dosage sium levels should be monitored in tide is initiated at 10 micrograms adjustment is required for patients patients at risk, including patients once daily for 14 days. On day with mild, moderate, or severe using other potassium-lowering 15, the dose is increased to the renal impairment; however, these medications. The most common ad- maintenance dose of 20 micro- patients should be closely moni- verse reaction associated with the grams once daily. It is injected tored for adverse reactions and use of all insulins is hypoglycemia. subcutaneously in the abdomen, changes in renal function as these Thus, insulin products are contra- thigh or upper arm, and is to be patients tend to have a higher inci- indicated in periods of hypoglyce- administered within one hour dence of hypoglycemia, nausea and mia. Changes in insulin strength, before the first meal of each day. vomiting. No data are available manufacturer, type or method of Serious hypersensitivity reactions, for patients with acute or chronic administration may affect glycemic including anaphylaxis, angioedema hepatic impairment. Lixisenatide is control. These changes, therefore, and urticaria, have been reported primarily eliminated through glo- should be made cautiously and only in clinical trials. If symptoms of merular filtration and proteolytic under close medical supervision. hypersensitivity occur, treatment degradation with a terminal half- life of approximately three hours. burgundy maintenance pen (100 and a third agent may be added if Lixisenatide has been stud- mcg/mL) that delivers 14 doses of glycemic control continues to be un- ied as monotherapy, in combina- 20 mcg each. Prior to the first use, achievable. There are patients with tion with oral antihyperglycemic lixisenatide should be stored in the diabetes who require more than medications, and in combination refrigerator and kept in the origi- one agent to control their blood with basal insulin. Monotherapy nal package to protect it from light. glucose levels. Having several was evaluated in a 12-week double- Each new pen must be activated metformin combinations available, blind trial, in which 241 patients prior to use. After activation, it can including the newest combination with T2D, inadequately controlled be stored at room temperature and may help decrease a patient’s pill on diet and exercise, were random- should be discarded 14 days after burden and improve compliance. ized to receive lixisenatide 20 mcg first use. once daily or placebo. Treatment Synjardy (empagliflozin/met- Summary resulted in a statistically signifi- formin). FDA has approved a new The incidence of diabetes in the cant reduction of 0.83 percent in combination medication contain- United States has grown rapidly A1C from baseline to week 12, ing metformin for the treatment of and steadily. Patients with poor compared to a 0.18 percent reduc- adults with T2D. Synjardy, ap- glycemic control are at significantly tion with placebo. proved in August 2015, combines higher risk of developing complica- To evaluate its use in combina- metformin with empagliflozin, an tions such as neuropathy, blind- tion with oral antihyperglycemic SGLT-2 inhibitor. It is indicated ness, and renal failure. Therapy medications, lixisenatide was as adjunct to diet and exercise to should include a combination of investigated in four placebo-con- improve glycemic control when lifestyle modifications and medica- trolled studies as an add-on to dif- treatment with both drugs is ap- tion. Several antihyperglycemic ferent therapies, including metfor- propriate. There have been no ef- agents are available; however, min with or without a sulfonylurea, ficacy studies conducted; however, pharmacologic therapy should be a sulfonylurea with or without the bioequivalence of the combina- individualized to meet the patient’s metformin, and pioglitazone with tion product to empagliflozin and needs. Pharmacists have a unique or without metformin. In each of metformin coadministered as indi- opportunity to aid in the manage- these studies, lixisenatide dem- vidual tablets was demonstrated in ment of diabetes and the associated onstrated statistically significant healthy subjects. complications. For further details, reductions in A1C compared to pla- Empagliflozin/metformin is of the AACE/ACE diabetes guide- cebo from baseline to trial comple- supplied as a tablet for oral admin- lines, visit: https://www.aace.com/ tion. In another study, metformin istration. Dosing is based on the sites/all/files/diabetes-algorithm- plus lixisenatide was compared to patient’s current antihyperglycemic executive-summary.pdf. metformin plus exenatide, a previ- regimen. Because the drug contains ously approved GLP-1 receptor both empagliflozin and metformin, agonist. In this case, lixisenatide it may cause adverse reactions produced lower A1C reductions such as urinary tract infections, than exenatide 10 mg twice daily. diarrhea, nausea, vomiting, abdom- Lixisenatide was also compared inal discomfort, and indigestion. It The authors, the Ohio Pharmacists Founda- to basal insulin with and without also comes with a boxed warning tion and the Ohio Pharmacists Association oral antihyperglycemic agents. for the risk of lactic acidosis due disclaim any liability to you or your patients resulting from reliance solely upon the infor- Compared to placebo, lixisenatide to metformin accumulation. This mation contained herein. Bibliography for demonstrated statistically signifi- risk is increased with conditions additional reading and inquiry is available cant reductions in A1C when added such as renal impairment, sepsis, upon request. to basal insulin regimens; however, dehydration, excess alcohol intake, This lesson is a knowledge-based CPE activity and when the drug was compared to hepatic impairment, and acute is targeted to pharmacists in all practice settings. insulin glulisine three times daily congestive heart failure. Disclosure: The OPF trustees and other indi- viduals responsible for planning OPF continuing added to basal insulin, it provided The new combination adds to pharmacy education activities have no relevant significantly less A1C reduction a list of antihyperglycemic agents financial relationships to disclose. from baseline. that are already combined with When counseling patients metformin, including other SGLT2 on proper preparation and use inhibitors, SFUs, DPP-4 inhibitors, Program 0129-0000-17-002-H01-P of lixisenatide, it is important TZDs, and repaglinide. Unless con- Release date: 2-15-17 to offer guidance on how to cor- traindicated, metformin remains Expiration date: 2-15-20 rectly administer the injection, the first-line oral agent recom- CPE Hours: 1.5 (0.15 CEU) including the importance of asep- mended in T2D. If target A1C is tic technique. It is supplied in a not met after approximately three The Ohio Pharmacists Foundation Inc. is green starter pen (50 mcg/mL) that months, adding a second oral agent accredited by the Accreditation Council for Pharmacy Education as a provider of delivers 14 doses of 10 mcg, and a or insulin should be considered, continuing pharmacy education. Please print. Program 0129-0000-17-002-H01-P continuing education quiz 0.15 CEU Name______2016 AACE/ACE Guidelines on Type 2 Diabetes Address______Management and New Glycemic Control Agents City, State, Zip______

1. Which of the following types of diabetes is characterized by Email______the body’s ineffective use of endogenous insulin? a. Type 1 diabetes b. Type 2 diabetes NABP e-Profile ID______Birthdate______(MMDD)

2. Sleep deprivation has no effect on insulin resistance. Return quiz and payment (check or money order) to a. True b. False Correspondence Course, OPA, 2674 Federated Blvd, Columbus, OH 43235-4990 3. For most patients, AACE/ACE supports an A1C goal of: a. <6.5 percent. c. >7.0 percent. b. >6.5 percent. d. >8.0 percent. 9. All of the following are true for insulin glargine EXCEPT: 4. Which of the following agents is considered first-line therapy a. it should be administered once weekly. in treating type 2 diabetes? b. the recommended starting dose in patients with T1D a. Basal insulin c. GLP-1 agonists should be approximately 1/3 of the total daily insulin require- b. Empaglifozin d. Metformin ments, with rapid-acting insulin making up the remainder of the daily requirement. 5. Which of the following agents carries an FDA black box c. it improves glycemic control in pediatric patients with warning regarding increased risk of diabetic ketoacidosis? T1D. a. SGLT-2 inhibitors c. GLP-1 agonists d. the dosing and timing of other insulins may need to be b. DPP-4 inhibitors d. Thiazolidinediones adjusted when starting this agent.

6. FDA issued a safety warning that T2D medications contain- 10. Tresiba has a duration of action of up to: ing saxagliptin and alogliptin may increase the risk of: a. 4 hours. c. 24 hours. a. serious hypoglycemia. c. heart failure. b. 18 hours. d. 40 hours. b. hypokalemia. d. urinary tract infections. 11. Due to an increased risk of hypokalemia, potassium levels 7. Which of the following directly reduces insulin resistance? should be monitored in patients receiving agents from which of a. Acarbose c. Metformin the following classes of drugs? b. Glipizide d. Rosiglitazone a. Insulin c. DPP-4 inhibitors b. TZDs d. GLP-1 agonists 8. All of the following adverse effects of alpha-glucosidase in- hibitors have limited their use in the U.S. EXCEPT: 12. All of the following are appropriate to convey when counsel- a. diarrhea. c. flatulence. ing patients on the use of insulin products EXCEPT: b. nausea. d. bloating. a. the importance of aseptic technique. b. to rotate injection sites to reduce the risk of lipodystrophy. c. all basal insulins should be administered intramuscularly in the thigh or deltoid muscle. Completely fill in the lettered box corresponding to d. how to recognize and manage episodes of hypoglycemia. your answer. 13. Lixisenatide should be administered: 1. [a] [b] 6. [a] [b] [c] [d] 11. [a] [b] [c] [d] a. daily with the largest meal. 2. [a] [b] 7. [a] [b] [c] [d] 12. [a] [b] [c] [d] b. once or twice daily with any main meal. 3. [a] [b] [c] [d] 8. [a] [b] [c] [d] 13. [a] [b] [c] [d] c. at the same time every day. 4. [a] [b] [c] [d] 9. [a] [b] [c] [d] 14. [a] [b] [c] [d] d. within one hour before the first meal of the day. 5. [a] [b] [c] [d] 10. [a] [b] [c] [d] 15. [a] [b] [c] [d] 14. The most common adverse reactions associated with lix-  I am enclosing $5 for this month’s quiz made payable isenatide include all of the following EXCEPT: to: Ohio Pharmacists Association. a. headache. c. dizziness. b. bloating. d. diarrhea. 1. Rate this lesson: (Excellent) 5 4 3 2 1 (Poor) 2. Did it meet each of its objectives?  yes  no If no, list any unmet______15. Synjardy comes with a boxed warning for the risk of: 3. Was the content balanced and without commercial bias? a. liver impairment. c. heart failure.  yes  no If no, why?______b. lactic acidosis. d. urinary tract infections. 4. Did the program meet your educational/practice needs?  yes  no 5. How long did it take you to read this lesson and complete the quiz? ______6. Comments/future topics welcome. To receive CPE credit, your quiz must be received no later than February 15, 2020. A passing grade of 80% must be attained. CPE credit for successfully completed quizzes will be uploaded to the CPE Monitor. CPE statements of credit can be printed from the CPE Moni- tor website. Send inquiries to [email protected]. february 2017