Case Study: Practical Strategies for Choosing among Incretin-Based Agents in Type 2 Diabetes, PART 3

For Parts 1 and 2 of this Case Study, please follow these links:

Case Study: Practical Strategies for Choosing among Incretin-Based Agents in Type 2 Diabetes, PART 1

Case Study: Practical Strategies for Choosing among Incretin-Based Agents in Type 2 Diabetes, PART 2

In assessing Mark's suitability for a GLP-1 receptor agonist, which of the following is an important consideration?

1. Hepatic steatosis because liver function may be adversely affected by treatment
2. Gastrointestinal motility because this may be affected by treatment
3. Mild renal impairment because it is a contraindication to treatment
4. History of gallstones because it is a contraindication to treatment

Correct Answer is 2

GLP-1 receptor agonists delay gastric emptying and commonly cause gastrointestinal AEs (e.g., nausea, vomiting, and diarrhea). According to the product labels for exenatide and liraglutide, they should not be used in patients with a history of gastroparesis or severe gastrointestinal disease. Mild renal impairment is not a contraindication to GLP-1 receptor agonist treatment. GLP-1 receptor agonists do not have hepatic side effects. Liver function has the potential to improve with weight loss. Product labeling for exenatide and liraglutide recommends that patients with a history of pancreatitis use alternative therapies for T2DM.

The most frequent AEs with GLP-1 receptor agonists are mild or moderate gastrointestinal symptoms (eg, nausea, vomiting, and diarrhea). Nausea occurs commonly on initiation of therapy but subsides over time in most patients. In general, gastrointestinal AEs with exenatide and liraglutide are transient but dose-related. Therefore, the lowest recommended dose should be initiated, then the dose can be increased as necessary, to achieve glycemic control. According to their respective product labels, liraglutide slows gastric emptying and therefore should not be used in patients with a history of gastric paresis, and exenatide should not be used in patients with severe gastrointestinal disease, including gastroparesis, because of its propensity to cause gastrointestinal AEs.

Mild renal impairment is not a contraindication to GLP-1 receptor agonist treatment. Exenatide is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease because it is renally excreted. Caution should be used when initiating or escalating doses from 5 μg to 10 μg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min). In product labeling for liraglutide once daily, general caution is urged for use in patients with renal impairment.

 

 

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GLP-1 receptor agonists do not cause hepatic AEs, but may improve biomarkers of hepatic injury (e.g., alanine aminotransferase [ALT]) with potential significance for diabetic patients with comorbid nonalcoholic fatty liver disease. In patients with 2 years' exposure to exenatide (and elevated ALT levels at baseline), exenatide significantly improved ALT levels. Of these patients, 39% achieved normal ALT levels after 2 years of exenatide treatment. Patients with elevated ALT at baseline lost significantly more weight as compared with patients with normal ALT at baseline (P = .04), although weight change was not correlated with ALT levels or change. Whether exenatide can improve nonalcoholic fatty liver disease, a condition comorbid in patients with obesity, requires further research.

Acute pancreatitis is a potentially serious safety issue with GLP-1 receptor agonists. The product labeling for both liraglutide and exenatide describe pancreatitis in their "Warning and Precautions" sections and recommend stopping treatment if pancreatitis is suspected and using alternative therapies in patients with a history of pancreatitis. These warnings reflect clinical trial data (for liraglutide) as well as post-marketing reports (for exenatide). In clinical trials of liraglutide, more patients taking liraglutide developed acute or chronic pancreatitis than comparator patients. However, some patients taking liraglutide in clinical trials had other risk factors for pancreatitis (e.g., history of cholelithiasis, alcohol abuse). The small number of events precludes definitive conclusions about causation, but the imbalance in events, along with postmarketing concerns about exenatide, led the US Food and Drug Administration (FDA) to require the sponsor of liraglutide to perform postapproval mechanistic studies in animals, as well as an epidemiologic evaluation using a large insurance claims database.

Upon approval of liraglutide, the FDA mandated a black-box warning addressing the risk for thyroid C-cell tumors based on thyroid C-cell hyperplasia and neoplasia seen in preclinical animal studies. However, it is difficult to extrapolate findings from studies in animals to humans. In addition, in liraglutide clinical trials, there have been 5 reported cases of thyroid C-cell hyperplasia, and in comparator groups, there was 1 case of thyroid C-cell hyperplasia and 1 case of medullary thyroid cancer (MTC). This comparator patient with MTC, had a pretreatment calcitonin level > 1000 ng/L, suggesting pre-existing disease. Calcitonin, which is secreted by thyroid C cells and is a biomarker for MTC, was monitored in clinical trials of liraglutide. Patients with MTC usually have calcitonin values > 50 ng/L. Increases in calcitonin levels occurred in a slightly higher percentage of liraglutide-treated patients than controls, but levels were within normal limits. Long-term data did not show any notable difference in mean calcitonin levels between liraglutide and control groups over 2 years of follow-up (Figure 4). Routine monitoring with serum calcitonin or thyroid ultrasound is not currently recommended because it is not known whether doing so will mitigate the risk for thyroid C-cell tumors in humans taking liraglutide. However, according to the liraglutide product label, patients taking liraglutide should be counseled regarding the risk and symptoms of thyroid tumors.

Figure 4. Geometric mean calcitonin values in a 2-year trial of 1079 patients treated with liraglutide, glimepiride, or placebo as add-on therapy to metformin. Data from weeks 0-52 are from the randomized, double-blind treatment period. Data after week 52 are from an open-label, voluntary extension period. From Parks M, et al. N Engl J Med. 2010;362:774-777. Republished with permission.

You recommend that Mark should start taking a GLP-1 receptor agonist and describe to him the 2 available GLP-1 receptor agonists. Mark expressed concern about the inconvenience of taking injectable medications.

Which is likely to be the most important consideration in choosing between available GLP-1 receptor agonists in this patient?

1.    Patient's tolerability to previous antidiabetic agents

2.    Patient's insurance coverage

3.    Patient's preference

4.    Patient's desire for weight loss

While there are some potential differences between exenatide and liraglutide in terms of efficacy, safety, and tolerability, dosing frequency may be one of the most important considerations when selecting between these 2 treatments, particularly when treatment convenience is a patient's concern. It is important that physicians and patients develop a partnership to achieve therapeutic goals. In this context, patient preference is likely to be one of the most important considerations when selecting treatment in T2DM.

In clinical trials of exenatide twice daily and liraglutide once daily, given as monotherapy or in combination with oral antidiabetic therapies, both agents decreased mean A1c levels by approximately 1.0%-1.5% and resulted in significant reductions in both FPG levels and PPG levels. The only direct comparison of exenatide and liraglutide to date is described in the randomized, open-label LEAD-6 (Liraglutide Once Daily Compared with Exenatide Twice Daily) trial -- a comparison of liraglutide 1.8 mg once-daily and exenatide 10 μg twice daily (both in addition to treatment with metformin and/or sulfonylurea). Regarding A1c-lowering efficacy, results from LEAD-6 suggested that liraglutide has a more potent effect on lowering A1c levels at 26 weeks (Figure 5). Liraglutide reduced mean A1c levels significantly more than exenatide (-1.12% vs. -0.79%; P < .0001) and more patients achieved an A1c level < 7% (54% vs. 43%; odds ratio, 2.02; P = .0015). Liraglutide reduced mean FPG more than exenatide (-1.61 mmol/L [-29.01 mg/dL] vs. -0.60 mmol/L [-10.81 mg/dL]); P < .0001), but PPG control was less effective after breakfast and dinner with liraglutide as compared with exenatide. The clinical significance of these relative differences in a more generalized population, or patients using other antidiabetic medications, is unclear.

Figure 5. Efficacy of treatment with liraglutide 1.8 mg once a day or exenatide 10 μg twice a day: A1c values from baseline to week 26. A1c = glycosylated hemoglobin
From Buse JB, et al. Lancet. 2009;374:39-47.

In LEAD-6, weight loss was similar in the liraglutide and exenatide groups (-3.24 kg with liraglutide vs -2.87 kg with exenatide; P = .2235). Improvement in beta-cell function (measured by homeostasis model assessment index of beta-cell function) was significantly greater with liraglutide than exenatide (P < .0001). Blood pressure decreased with both treatments, with no significant differences for either systolic or diastolic blood pressures. Reductions of triglyceride (P = .0485) and free fatty acid (P = .0014) values were significantly greater in the liraglutide group than in the exenatide group.

There was a slightly lower rate of AEs with liraglutide compared with exenatide (74.9% vs. 78.9%) in LEAD-6, but the liraglutide group had more of the uncommon serious and severe AEs. The most frequent AEs were dyspepsia in the liraglutide group (n = 3) and nausea in the exenatide group (n = 4). The incidence rate of nausea was initially similar, but less persistent in the liraglutide group (estimated treatment rate ratio 0.448 for liraglutide vs. exenatide). By week 26 of the study, 3% of patients in the liraglutide group experienced nausea as compared with 9% of patients on exenatide. Minor hypoglycemia was less frequent with liraglutide than exenatide (26% vs 34%) and the event rate for minor hypoglycemia (1.932 vs. 2.600 events per participant per year; P = .0131) was lower with liraglutide than with exenatide, with greater differences between treatments during the evening.

As described, some differences in efficacy and safety profiles for exenatide and liraglutide have been acknowledged. With regard to dosing schedules, liraglutide's longer half-life translates into once-daily dosing vs. exenatide's twice-daily schedule. Liraglutide is given once daily independent of meals; exenatide is given subcutaneously twice daily up to 60 minutes before each meal (breakfast and dinner). Both exenatide and liraglutide are given via a prefilled pen.

Selection of therapies has traditionally been driven by clinician knowledge and preferences. However, given the progressive nature of diabetes and the need for long-term patient management, it is important that physicians and patients develop a partnership to achieve therapeutic goals, which includes evaluating appropriate treatment options based on therapeutic goals in addition to the patient's lifestyle, quality of life, and overall treatment needs.

Furthermore, patient adherence to treatment, which is known to be suboptimal in T2DM, needs to be maximized in order to achieve glycemic targets and improve outcomes for patients with T2DM. In this context, patient preference may be one of the key considerations in treatment selection for T2DM. Differences in dosing schedules for exenatide and liraglutide may be a factor in treatment selection for patients who may prefer once-daily vs twice-daily dosing. Estimated patient preference scores from a recent conjoint analysis of hypothetical GLP-1 profiles, representing liraglutide once daily and exenatide twice daily, revealed that among attributes studied efficacy (measured by A1c levels) is the most important attribute in patient preference, followed by less nausea, less hypoglycemia, and a once-daily dosing schedule.

Because of the convenience (preferring once-daily to twice-daily treatment), you commence Mark on liraglutide 0.6 mg for the first week followed by 1.2 mg per day. After 6 months, Mark's A1c level has decreased to 7.0% and he has lost 5 pounds of weight. However, 5 months later his A1c level is 7.5%.Top of Form

Which of the following is the most appropriate next step in treating this patient?

1.    Increase the dose of his GLP-1 receptor agonist and arrange diet and exercise review

2.    Recheck the A1c level in 3 months and add insulin to his current regimen if he has not reached his treatment target

3.    Make no change because his A1c level is acceptable and he has no known microvascular complications

4.    Stop his GLP-1 receptor agonist because he is likely not adhering to treatment

The product labeling for both exenatide and liraglutide indicate that treatment should be initiated at the lowest available dose and then titrated based on clinical response and tolerability. In patients taking GLP-1 receptor agonists at less than the maximum available or tolerated dose and who are not at their A1c treatment goal, increasing the dose and then evaluating response to the dose amplification is an appropriate therapeutic approach. In addition, patients not at goal should have their lifestyle (diet and exercise) evaluated by their healthcare provider(s) at regular intervals.

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