PHARMACY AND THERAPEUTICS

Case Study: Use of GLP-1 Receptor Agonist in a Patient on Intensive Therapy Kenneth Calvin Wiley,1 Ranti Akiyode,1 and Gail Nunlee-Bland2

urrent treatment of type 2 additional treatment options is that begins with diet and the wide range of choices may pres- Clifestyle modifications accom- ent a challenge to prescribers when panied by use of oral antihyperglyce- determining the optimal therapeutic mic medications. Despite multiple regimen. In making these decisions, therapeutic options for people with health care providers should consider , the disorder contin- patients’ disease progression state, ues to progress, resulting in the grad- comorbidities, and concomitant ual deterioration of glycemic con- treatments (5). trol over time (1). This is the result GLP-1 receptor agonists are one of insulin resistance and progressive of the newer drug classes to appear decline in β-cell function, combined on the market. These agents have with increased hepatic out- been proven to be effective without put as a result of dysregu- increased risk of or lation (2). These factors lead to ele- weight gain (6,7). They are ideal for vations in both fasting and prandial patients who have had episodes of glucose levels. hypoglycemia on large insulin doses It is well known that poor gly- and for obese patients who could cemic control is associated with benefit from the modest weight increased risk of microvascular loss associated with their use. These and macrovascular complications. agents can also be considered for Ultimately, basal insulin, premixed patients who are failing to achieve insulin, and/or prandial insulin are adequate glycemic control on one or added to the treatment regimen more oral medications. (3). The U.K. Prospective Diabetes Currently, patients on GLP-1 Study and its follow-up found that receptor agonists are either not con- patients with uncontrolled type 2 currently taking insulin or are only diabetes receiving intensive insulin taking basal insulin ( therapy had significantly lower risks or insulin detemir) per U.S. Food and 1Howard University College of Pharmacy, Washington D.C. of microvascular and macrovascular Drug Administration (FDA) guide- complications, as well as lowered lines. Several observational studies 2Howard University School of Medicine Department of Endocrinology, Washington, mortality rates compared to diabetes have shown that the combination of D.C. patients on standard therapy (1,4). basal insulin and a GLP-1 receptor Corresponding author: Kenneth Calvin However, intensive insulin therapy agonist results in improvements in Wiley, [email protected] is associated with weight gain and postprandial glucose, excess weight, DOI: 10.2337/diaspect.28.2.121 hypoglycemia (1). and A1C (a component of hemoglo- A plethora of other treatment bin in which glucose binds), with no ©2015 by the American Diabetes Association. Readers may use this article as long as the work options are available for diabetes substantial increase in hypoglycemia is properly cited, the use is educational and not patients, many of which are either (8–13). These studies also found that for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0 weight neutral or promote weight immediate-release had a for details. loss. The downside of having these more significant impact on postpran-

VOLUME 28, NUMBER 2, SPRING 2015 121 PHARMACY AND THERAPEUTICS dial glucose levels than , hydrochlorothiazide 20/25 mg for improved slightly to 10.8%, but her whereas liraglutide preferentially high blood pressure. Her compli- weight increased by 12 lb to a total targeted fasting glucose levels while ance with these medications, and of 297 lb. also having a lowering effect on post- with her insulin regimen, was poor. The medical team eventually prandial glucose. There have been She reported having periods during decided to change L.T.’s regimen to no randomized, controlled trials of which she takes her medications as 70/30 mix 45 units the use of a GLP-1 receptor agonist prescribed and other times when she twice daily, and, a month later, lira- in conjunction with premixed or does not. As a result, her blood pres- glutide was added (Table 1). The goal prandial insulin, and such use is not sure and cholesterol cycle from being of this combination was to lower the incorporated in the new American controlled to uncontrolled. L.T. has number of daily injections, lower the Diabetes Association recommenda- never been compliant with keeping total daily insulin dose, encourage tions (2). scheduled appointments or checking weight loss, and improve glycemic United Kingdom specialist clini- her blood glucose. She reported that control. Liraglutide was started at 0.6 cians are exploring the use of GLP-1 she had not been checking during mg daily subcutaneously for 1 week receptor agonists in combination with the 3 months before this initial visit and then increased to 1.2 mg daily. bolus and basal insulin for obese type because she had run out of test strips. At the follow-up visit 1 month 2 diabetes patients with poor glyce- L.T.’s initial complaints were later, LT denied any side effects or mic control (14). However, there is visual disturbances, burning and tin- adverse reactions with liraglutide not yet enough evidence regarding gling in her feet and legs, alterations therapy and was pleased that she had how to initiate this combination in in appetite, weight gain, edema, lost 2 lb. She also reported checking patients or what outcomes can be nausea, and irritability. She also her blood glucose more often while expected. The following case study felt depressed because she believed on liraglutide and having lower read- provides a successful account of the that diabetes-related stress had had ings than when she was on insulin use of liraglutide and insulin aspart a negative effect on her family life, therapy alone. protamine/insulin aspart 70/30 mix social activities, finances, sports and Three months later, L.T.’s A1C had in an obese patient with poorly con- exercise activities, school and work greatly improved to 7.6%. She admit- trolled type 2 diabetes. performance, and sexual relations. ted to having some low readings but Her A1C was 8.9%. Case Presentation said they were asymptomatic and Her biggest concern was her did not require medical attention. In L.T. is a 27-year-old woman with weight. At her initial visit, she total, she had 34 hypoglycemic read- type 2 diabetes who presented to the weighed 265 lb. She stated that her ings (blood glucose <70 mg/dL) and Howard University Hospital diabe- most comfortable weight is 190 lb some as low as 19 mg/dL, but none tes clinic for the first time in June and that she had experienced an required hospitalization. More than 2008. She was diagnosed with type unplanned weight gain of 35 lb in 95% of the hypoglycemic readings 2 diabetes in June 1995, at the age the past 3 months. She was given a were >50 mg/dL and were readily of 9 years, by her primary care physi- meal plan in the past but said she did treated with either three 5-mg glucose cian. ( was ruled out not adhere to it. She reported that tablets, 4 oz of fruit juice or nondiet by negative anti-islet antibody test the stress of her disease causes her to soda, or 8 oz of skim milk. Because results.) L.T. has a family history of overeat, although she does exercise of concern about continued hypogly- diabetes, high blood pressure, and el- regularly, and her exercise program cemia, her insulin dose was decreased evated cholesterol. She is a nonsmok- includes walking. Overall, however, to 30 units twice daily. er with no children and works at a she rates her personal health as poor. At follow-up 2 months later, L.T.’s fast-food chain. In the years following her initial average glucose readings were 133 She was taking NPH 20 units presentation to the clinic, L.T. missed mg/dL. While taking liraglutide, in the morning and 15 units in the several appointments and was very she had lost 20 lb, and her BMI had evening and 25 units inconsistent with her insulin regimen. decreased by 3 kg/m2 with no changes in the morning and 15 units in the Her A1C climbed to a peak of 11.1%. in diet or activity level. None of her evening for her diabetes. She was also She also developed albuminuria. Her other diabetes medications were taking atorvastatin 10 mg daily for insulin doses were intensified in an adjusted during this 6-month period, hypercholesterolemia (elevated LDL attempt to gain control of her diabe- and she did not use over-the-counter cholesterol, low HDL cholesterol, tes, but the increased dosage resulted medicines or dietary supplements. and elevated triglycerides), warfarin in only a slight improvement in her 7.5 mg daily for deep venous throm- diabetes. On a regimen of insulin Discussion bosis, ergocalciferol 50,000 units for glargine 40 units daily and insulin In individuals with diabetes, plasma vitamin D deficiency, and lisinopril/ aspart 15 units with meals, her A1C glucagon concentrations are inappro-

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TABLE 1. L.T.’s Changes Over Time Reference Date Medication Change A1C (%) at Time of Change First day at clinic (3 years before start- NPH insulin: 20 units at breakfast, 15 units at dinner 8.9 ing liraglutide) Regular insulin: 25 units at breakfast, 15 units at dinner 14 months before starting liraglutide Insulin aspart 70/30 mix: 40 units at breakfast, 30 9.7 units at dinner 13 months before starting liraglutide Insulin aspart 70/30 mix: 35 units twice daily 11.1 10 months before starting liraglutide Insulin glargine: 40 units at bedtime 10.8 Insulin aspart: 15 units with meals 6 months before starting liraglutide Insulin glargine: 45 units at bedtime 12.2 Insulin aspart: 15 units with meals 1 month before starting liraglutide Insulin aspart 70/30 mix: 45 units twice daily 11.4 Date liraglutide was added Insulin aspart 70/30 mix: 45 units twice daily 11.4 Liraglutide: 1.2 mg 3 months after starting liraglutide Insulin aspart 70/30 mix: 35 units twice daily 7.6 Liraglutide: 1.8 mg 6 months after starting liraglutide Insulin aspart 70/30 mix: 30 units twice daily 7.7 Liraglutide: 1.8 mg priately elevated and α-cell suppres- other glucose-lowering agents such formation of C-cell tumors in the sion by hyperglycemia is blunted. as insulin, the risk for hypoglycemia thyroid gland. There have been no This results in a greater rate of hepat- increases with these agents. Other cases in humans of these agents caus- ic glucose production in the fasting effects of GLP-1 receptor agonists ing cancer; however, C-cell formation state and attenuated reduction after include slowing the rate of gastric is listed as a warning in the package meals (15). Therefore, medications emptying and improving satiety, insert. There is also a risk of pancre- such as the GLP-1 receptor agonists which likely contribute to improve- atitis with these agents. Practitioners and DPP-4 inhibitors are unique and ments in postprandial hyperglycemia, should monitor patients’ serum exciting options because they target fasting glucose, and A1C (17). amylase and lipase when patients the glucagon pathway. As mentioned earlier, GLP-1 complain of pancreatitis symptoms Currently available GLP-1 recep- receptor agonists are dosed differently while on these agents. It should be tor agonists include exenatide and depending on the drug and formu- noted that DPP-4 inhibitors such as liraglutide. Additional GLP-1 recep- lation. Immediate-release exenatide sitagliptan also carry the increased tor agonists in clinical development is dosed twice daily, whereas extend- risk of pancreatitis. Another possible include once-daily ed-release exenatide is dosed once disadvantage to GLP-1 receptor ago- and twice-weekly and weekly; liraglutide is dosed once nists is that patients who have burned (16). These agents are daily. They are all delivered subcu- out their β-cells may not respond as incretin mimetics; they bind to the taneously and are easier than insulin well to therapy with these agents. GLP-1 receptor, resulting in the to administer. In comparison to insu- The major advantages with this stimulation of insulin secretion in a lin, the volume injected is very small, drug class are the low incidence of glucose-dependent manner. GLP-1 syringes and vials are not needed, hypoglycemia (compared to agonists also normalize and doses do not vary with the size and secretagogues), potential weight hypersecretion of glucagon during of meals or activity. loss, and less stringent contraindica- the postprandial state. There is very The main side effect of GLP-1 tions based on clinical or laboratory low risk of hypoglycemia with these receptor agonists is mild to moderate assessments of organ function before agents when used alone because the nausea, which diminishes with pro- initiation of therapy (as is needed with glucose-mediated secretagogue effect longed therapy. There have also been and ) of GLP-1 receptor agonist therapy documented reports of animal studies (17). No dosage adjustment is neces- fades as glucose levels fall (unlike showing an association of extended- sary for hepatic impairment for any of with ). When used with release exenatide and liraglutide with the available GLP-1 receptor agonists.

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With liraglutide, no dose adjustment is required for renal impairment, and the exenatide formulations can be used in mild to moderate chronic kidney disease (although exenatide is not recommended if creatinine clear- ance is <30 mL/min). Also, studies have found that GLP-1 receptor agonist therapy shows promise in preserving and improving markers of β-cell function and favorable changes in risk factors and markers for cardio- vascular disease (18). L.T. presented with uncon- trolled type 2 diabetes and complex ■ FIGURE 1. L.T.’s blood glucose readings 6 months before and 6 months after comorbidities, all of which required adding liraglutide. treatment. She tried several differ- ent insulin regimens, none of which often than in the previous 6-month resulted in optimal blood glucose and 4%, respectively, for placebo. period). She averaged 1.25 readings control. She had many additional It should be noted, however, that per day compared to 0.47 readings factors exacerbating her diabe- during the 12-week follow-up period tes diagnosis, including poor diet, per day before starting liraglutide. after treatment discontinuation, both morbid obesity, sedentary lifestyle, Results in her target range increased liraglutide treatment groups experi- noncompliance with medications, from 28 to 44%. Her mean blood enced a moderate weight regain. In and depression. glucose during this period was 166 general, most patients will lose a Despite repeated reminders to mg/dL, which is lower than it had moderate amount of weight (0–10 check her blood glucose at home, been during the previous 6 months lb) in the first few months of therapy L.T. did not do so consistently, which (Figure 1). However, she did have and then plateau; in rare instances, resulted in more difficult decisions more hypoglycemic readings on lira- patients can lose significant amounts when adjusting her medications. For glutide, although none resulted in a of weight while taking liraglutide. example, despite being encouraged hospital visit. Determining a medica- Other observational studies to check her blood glucose at least tion’s potential to cause hypoglycemia involving the addition of a GLP-1 three times daily (before her insulin is an important consideration when receptor agonist to prandial insulin injections and before bedtime), over altering a patient’s diabetes pharma- have been reported. Yoon et al. (20) a period from January to June 2011, cotherapy regimen. observed 188 patients taking a GLP-1 she recorded only 72 readings. L.T.’s Weight loss was a great benefit of receptor agonist and insulin over a average blood glucose reading during liraglutide therapy for this patient. 27-month period and found that the this time was 295 mg/dL, with a L.T.’s main concern with her insu- longer patients used this combina- minimum of 58 mg/dL and a max- lin regimen was its associated weight tion, the more their A1C decreased. imum of 601 mg/dL. Forty-eight of gain. A few months after initiation of Mean percentage-point decreases the readings were >200 mg/dL. Only liraglutide, the dose of the insulin was in A1C were –0.66 at 0–6 months, 28% of her readings were within her decreased, and an almost immediate –0.55 at 6–12 months, –0.54 at target range. weight loss was observed. During the 12–18 months, and –0.54 at 18–27 After multiple approaches failed to course of her liraglutide treatment, months. This study also reported that control L.T.’s blood glucose, she was she lost 20 lb, and her BMI decreased weight and total daily dose of insulin finally given liraglutide, along with from 55 to 52 kg/m2. Similarly, in the (mostly prandial insulin) decreased her aspart 70/30 mix, and this reg- second phase of the SCALE (Satiety the longer patients were on this com- imen yielded the best response. Her and Clinical Adiposity—Liraglutide bination, with a mean weight loss of A1C dropped from 10.8 to 7.6%. Evidence in Non-Diabetic and 5.5 kg. Sheffield et al. (21) performed Along with her improved diabetes Diabetic Subjects) trial (19), the a similar study with immediate- control, she also reported perform- proportions of people achieving a release exenatide and insulin in 134 ing more self-monitoring of blood weight loss ≥5% or ≥10% were 50% patients for 1 year. The study found glucose. In fact, from 30 July to and 22%, respectively, for liraglutide that exenatide use resulted in a signif- 30 December 2011, she tested her 3 mg; 35% and 13%, respectively, icant 0.87 percentage-point reduction blood glucose 193 times (121% more for liraglutide 1.8 mg; and 13% in A1C, as well as discontinuation

124 SPECTRUM.DIABETESJOURNALS.ORG w i l e y e t a l . of premeal insulin use in 45% of accomplished with intensive insu- of published guidelines and is not patients, a 9-unit reduction in mean lin regimens, these can result in a FDA-approved and, therefore, must premeal insulin doses, a decrease in higher risk for hypoglycemia and be used with caution. Until there the median number of daily insulin weight gain, which is burdensome is more evidence in support of this injections, and a mean weight loss of for patients (27–29). Adding a GLP-1 strategy, the combination of a GLP-1 5.2 kg. Viswanathan et al. (22) also receptor agonist is a potential solution receptor agonist and prandial insulin reported data on 38 patients who to this challenge because it comple- should be undertaken only under the completed 26 weeks of treatment ments the activity of insulin and may supervision of a diabetes specialist. with immediate-release exenatide lower the daily insulin dose required and insulin. They found that mean to maintain glycemic control. Duality of Interest A1C decreased by 0.6 ± 0.21 per- Conclusion No potential conflicts of interest relevant to centage points, insulin requirements this article were reported. decreased for mixed and rapid- The case presented here supplements the scarce available data on the utility acting , and mean body References of GLP-1 receptor agonist therapy in weight decreased by 6.46 ± 0.8 kg. 1. U.K. Prospective Diabetes Study Group. An additional study by Balena et al. combination with an intensive insu- Intensive blood-glucose control with (18) found that, over a 12-month lin regimen. The use of these agents sulphonylureas or insulin compared with with rapid-acting insulin is uncom- conventional treatment and risk of com- period, adding immediate-release plications in patients with type 2 diabetes exenatide to an insulin regimen mon, possibly because they both tar- (UKPDS 33). Lancet 1998;352:837–853 get postprandial blood glucose or be- resulted in a mean A1C reduction of 2. Inzucchi SE, Bergenstal RM, Buse JB, et 0.51 percentage points, weight loss cause the combination does not have al. Management of hyperglycemia in type 2 of 5.8 kg, insulin dose reduction of FDA approval. However, limited diabetes: a patient-centered approach: posi- published studies demonstrate that tion statement of the American Diabetes 42 units/day, and cessation of insulin Association and the European Association use in 16.6% of patients. A study in this can be an effective strategy for for the Study of Diabetes. Diabetes Care type 1 diabetes patients by Kielgast patients requiring very high doses of 2012;55:1577–1596 et al. (23) reported that the use of insulin. Indeed, many practitioners 3. Buse J, Bergenstal R, Glass L, et al. Use combination therapy with liraglu- are using this combination off-label of twice-daily exenatide in basal insu- and anticipate that the FDA will ap- lin-treated patients with type 2 diabetes: a tide and insulin reduced the insulin randomized, controlled trial. Ann Intern requirement from 0.50 ± 0.06 to 0.31 prove this use in the future. The use Med 2011;154:103–111 ± 0.08 units/kg/day in C-– of GLP-1 receptor agonists in pa- 4. Holman RR, Paul SK, Bethel MA, positive patients and from 0.72 ± tients on basal insulin alone is safe Matthews DR, Neil HA. 10-year follow-up ± and has been approved by the FDA. of intensive glucose control in type 2 diabe- 0.08 to 0.59 0.06 units/kg/day in tes. N Engl J Med 2008;359:1577–1589 C-peptide–negative patients while The potential benefits of adding GLP-1 receptor agonist therapy to 5. Nathan DM. Finding new treatments for maintaining or improving glycemic diabetes: how many, how fast … how good? control. insulin include weight loss, improved N Engl J Med 2007;356:437–440 GLP-1 receptor agonists also have glycemic control, and enhanced 6. Buse JB, Rosenstock J, Sesti G, et al. been shown to produce slight reduc- safety compared to combination sul- Liraglutide once a day versus exenatide tions in blood pressure for patients fonylurea and insulin therapy. The twice a day for type 2 diabetes: a 26 week randomized, parallel group, multina- with hypertension (reductions of 1–5 potential disadvantages are gastro- tional, open-label trial (LEAD-6) Lancet mmHg in systolic and diastolic blood intestinal side effects and the risk of 2009;274:39–47 pressure) (24). L.T.’s blood pres- hypoglycemia if the doses of concur- 7. Drucker DJ, Buse JB, Taylor K, et al. sure remained controlled (<140/90 rent hypoglycemic medications are Exenatide one weekly versus twice daily for mmHg) while taking liraglutide and not titrated down as patients’ glucose treatment of type 2 diabetes: a randomized, open-label, non-inferiority study. Lancet her blood pressure medications (lisin- levels improve on GLP-1 receptor 2008;372:1240–1250 opril 20 mg and hydrochlorothiazide agonist therapy. Also, the concerning 8. Kolterman OG, Buse JB, Fineman 25 mg). Liraglutide also has been documented reports of pancreatitis MS, et al. Synthetic exendin-4 (exenatide) found to improve the lipid panel of and thyroid C-cell tumor formation significantly reduces postprandial and should be kept in mind. fasting plasma glucose in subjects with patients with dyslipidemia (25). L.T.’s type 2 diabetes. J Clin Endocrinol Metab lipid panel has not been ordered since For motivated patients who main- 2003;88:3082–3089 she started liraglutide. tain good communication with their 9. Arnolds S, Dellweg S, Clair J, et al. Because of the progressive nature clinician, this regimen can vastly Further improvement in postprandial of type 2 diabetes, many patients improve quality of life and assist in glucose control with addition of exenatide or to combination therapy will require multiple therapeutic attaining previously unattainable gly- with insulin glargine and metformin: a strategies to maintain glycemic tar- cemic goals. All parties must respect proof-of-concept study. Diabetes Care gets (26). Although control can be that this combination falls outside 2010;33:1509–1515

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