Diabetes Roadmap: GLP-1 Receptor Agonists

Physiological changes in elderly individuals, such as decreased physical activity, abdominal obesity, and increased inflammatory state, increase insulin resistance in peripheral tissue and reduce glucose-dependent insulin release, leading to carbohydrate intolerance and diabetes.¹ Long-term care (LTC) residents with type 2 diabetes, the most prevalent type in older age groups, are vulnerable to increased risk of hyperglycemia and hypoglycemia, which may increase the risk of diabetes-related problems. Additionally, diabetes is associated with increased risk of falls, cardiovascular disease, functional impairment, and cognitive decline, among other poor outcomes. Furthermore, this patient population is often unable to perceive or communicate symptoms of hyperglycemia and hypoglycemia. Both conditions may occur without symptoms; therefore, regularly monitoring blood glucose is important. Because many LTC residents have diabetes-related health problems and comorbidities requiring multiple medications, a protocol-driven, individualized approach is recommended.^2,3

Glycemic Goals and Treatment Guidelines

While several organizations have developed guidelines pertaining to older adults and/or those with significant comorbidities, lack of evidence makes it harder to provide concrete guidance for clinicians. This patient population has often been excluded from randomized, controlled trials of treatments—and treatment targets—for diabetes and its associated conditions, according to a 2012 consensus report on diabetes in older adults published in the Journal of the American Geriatrics Society. The report outlines a framework for considering treatment goals for blood glucose, blood pressure, and lipids.³ The American Diabetes Association (ADA) has recommended goals for fasting plasma glucose (FPG; 70-130 mg/dL), postprandial glucose (PPG; <180 mg/dL), and hemoglobin A_1c (HbA_1c; <7%) for most patients. The ADA glycemic goals are not specific to elderly patients, and glycemic goals should be tailored according to the patient’s needs.⁴ AMDA - The Society for Post-Acute and LTC Medicine has recommended goals for FPG (<140 mg/dL) and HbA_1c  (<7%).² In 2013, the American Geriatrics Society published its newly revised and updated guidelines for improving diabetes care in older adults. The guidelines call for patient-centered care and individualized goals with attention to quality of life and personal and caregiver choices related to healthcare. The updated guidelines continue to support glycemic control recommendations customized to burden of coexisting conditions, functional status, and life expectancy. A target HbA_1c level between 7% and 7.5% may be appropriate if it can be safely achieved in healthy older adults with few comorbidities and good functional status. Higher HbA_1c  targets (8%-9%) are appropriate for older adults with multiple comorbidities, poor health, and limited life expectancy. If glycemic control is too aggressive (<6.5%) in older adults, it may lead to hypoglycemia and complications, such as falls or loss of consciousness.⁵

Once the HbA_1c target is selected, the clinician then assesses the optimal medication or combination of medications to be used, keeping in mind that special care is required in prescribing and monitoring pharmacological therapy in older adults. Currently, there are more than 10 classes of antihyperglycemic medications for clinicians to consider when developing a treatment plan. The optimal treatment regimen for an individual patient is not always clear, and combinations of therapies are frequently needed to achieve glycemic control, further complicating the choice of pharmacotherapy (Figure [log in and download PDF to view]).

Glucagon-like Peptide-1 Receptor Agonists

The ultimate goal of glucose-lowering drugs is to control glucose homeostasis to prevent the development of microvascular and macrovascular complications and early death. In order to achieve glycemic targets, a treatment regimen combining several glucose-lowering drugs is often needed. Several treatment modalities, however, are associated with side effects: hypoglycemia, weight gain, gastrointestinal (GI) side effects, increased risk of genital and urinary tract infections, and increased risk of bone fractures and heart disease. Furthermore, none of these drugs target the multifaceted pathophysiology of type 2 diabetes. Incretin-based glucagon-like peptide-1 receptor agonists (GLP-1 RAs)—one of the newer classes of diabetes medications—target a broad spectrum of the multifaceted pathophysiology of type 2 diabetes.⁶

Currently, there are four FDA-approved injectable GLP-1 RAs: albiglutide, exenatide, dulaglutide, and liraglutide. Other drugs in this class are under development. The drugs were first introduced in clinical practice in 2005 with the approval of exenatide twice- daily. The 2012 ADA/EASD position statement recommends GLP-1 RAs as one of several choices for 2- and 3-drug combinations following initial treatment with lifestyle modification, exercise, diet, and metformin. They are also recommended if metformin is contraindicated or not tolerated.^6-8

GLP-1 is a GI hormone secreted in response to ingestion of nutrients and has beneficial effects on several of the pathophysiological features of type 2 diabetes.⁶ GLP-1 facilitates the regulation of PPG control by stimulating insulin secretion in a glucose-dependent manner and helps regulate the rate of glucose appearance by inhibiting glucagon secretion, inhibiting hepatic glucose production, regulating gastric emptying, and reducing food intake.⁹ GLP-1 RAs share the same basic mechanism, however, differences in pharmacokinetics, structure, and size of the compounds result in different clinical profiles.⁶

As with all glucose-lowering therapies, GLP-1 RAs have advantages and disadvantages that clinicians should consider before initiating therapy in elderly patients. In addition to sustained improvements in body weight and glycemic control without hypoglycemia, GLP-1 RAs have demonstrated efficacy in terms of HbA_1c  reduction and favorable effects on cardiovascular risk factors and biomarkers. Route of administration and cost are also key considerations.⁸ The most common side effects are dose-dependent and may include mild to moderate nausea, vomiting, diarrhea, and injection site reactions.^6,8

Ask the Expert

Annals of Long-Term Care: Clinical Care and Aging® (ALTC) had the opportunity to discuss prescribing considerations for GLP-1 RAs in greater depth with Joshua J. Neumiller, PharmD, CDE, FASCP, associate professor, department of pharmacotherapy, College of Pharmarcy, Washington State University (WSU), Spokane, WA. Neumiller works with WSU’s Geriatrics Pharmacy Research team, which works to improve the care of geriatric patients in the inland Northwest through research and training students and other healthcare professionals on the special pharmaceutical needs of the older adult patient. Neumiller also works with WSU’s Clinical Trials Research Team, which conducts clinical trials centered on the management of diabetes and its complications. Neumiller currently serves as the editor-in-chief of Diabetes Spectrum, a peer-reviewed journal of the American Diabetes Association. 

ALTC: Why might providers choose to prescribe a GLP-1 RA in an older adult over other available agents?

Neumiller: There are three key advantages of GLP-1 RA therapy: (1) the ability to target postprandial hyperglycemia in people experiencing after-meal spikes in blood glucose (particularly with exenatide); (2) a low intrinsic risk of hypoglycemia; and (3) the potential for weight loss with treatment. GLP-1 RAs can be a useful tool in older adults with pronounced postprandial hyperglycemia who are at risk for morbidity and mortality due to hypoglycemia with other treatments, such as insulin secretagogues (ie, sulfonylureas) and mealtime insulin. Older adults, in general, are more vulnerable to hypoglycemia due to blunted counter-regulatory responses to hypoglycemia and impairments in hypoglycemic awareness. In such individuals, use of agents with a low hypoglycemic risk can provide a safety benefit. However, weight loss associated with these agents may be problematic in frail older adults where weight loss is not desirable.

How does administration factor into the decision to prescribe a GLP-1 RA?

Administration plays a significant role in deciding on use of a GLP-1 RA. For older adults in the ambulatory setting and/or those managing their own medications in a facility, visual and dexterity limitations must be considered when assessing therapeutic appropriateness. Injectable medications can add to regimen complexity for individuals and facility staff. In the spirit of shared decision-making and patient-centered care, a discussion of whether an individual is open to the use of non-insulin injectable therapies versus other alternatives is of benefit to optimize treatment outcomes. We now have four GLP-1 RAs on the US market with variable dosing intervals; the frequency of dosing may be an important consideration for patients and staff when assessing the feasibility of use. While the addition of an injectable agent may increase regimen complexity, the trade-off of a once-weekly injection may be preferable to the addition of another oral medication for some patients.

Chronic pancreatitis is one of the major concerns associated with using GLP-1 RAs. Can you briefly explain the association between pancreatitis and GLP-1 RAs, and how this risk can be managed in older adults?

Post-marketing reports of pancreatitis have been reported with GLP-1 RA use as well as with dipeptidyl peptidase-4 (DPP-4) inhibitors. While this risk has been widely discussed in the literature and in the media, to date a causal relationship and/or a definitive mechanism has not been identified. People with diabetes are known to be at increased risk for pancreatitis when compared to people without diabetes. The US Food and Drug Administration and the European Medicines Agency recently reported findings on independent evaluations of the risk of pancreatitis and pancreatic cancer in patients using incretin-based therapies (GLP-1 RAs and DPP-4 inhibitors). Upon review of toxicological studies in animals and clinical trials involving humans taking incretin-based therapies, both agencies have stated that “assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer are inconsistent with the current data.”¹⁰ Nonetheless, both agencies also continue to investigate this potential safety issue and agree with current product information and labeling. Given the potential risk it may be prudent to avoid the use of GLP-1 RAs in individuals with a history of pancreatitis. People should also be warned about the signs and symptoms of pancreatitis and be asked to communicate such symptoms to their prescriber if they occur.

Older adults, especially those residing in LTC settings, are taking multiple medications to treat acute and chronic conditions. As GLP-1 RAs are potent inhibitors of gastric emptying, what do you advise to prescribers to reduce the risks associated with polypharmacy in older adults?

Because some GLP-1 RAs can cause a delay in gastric emptying, they can affect the rate and/or extent of absorption of orally administered medications. The prescribing information for exenatide notes that the drug should be used with caution in people receiving oral medications that require rapid gastrointestinal absorption. It is recommended that such oral medications be taken at least 1 hour prior to receiving an injection of exenatide, and if the medications should be taken with food they should be administered with a meal when exenatide is not given. While these strategies may be important when minimizing drug–drug interactions with extenatide, it appears that such interactions are less of a concern with longer-acting GLP-1 RAs (such as liraglutde, exenatide once-weekly, and albiglutide). Long-acting GLP-1 RAs may have an initial effect on gastric emptying, but they do not seem to have a substantial effect on gastric motility when given long term.¹¹ This difference is believed to be due to continuous activation of GLP-1 receptors by long-acting agents resulting in tachyphylaxis with continued use.

It is important to consider potential drug interactions that can stem from use of GLP-1 RAs given the multitude of agents that older adults are often receiving. Periodic evaluation of the patient’s entire medication regimen and the continuing need for each medication is important to minimize polypharmacy and associated risks.

References

1. Midgal A, Yarandi SS, Smiley D, Umpierrez GE. Update in diabetes in the elderly and in nursing home residents. J Am Med Dir Assoc. 2011;12(9):627-632.e2.

2. American Medical Directors Association. Diabetes Management in the Long-Term Care Setting: Clinical Practice Guideline.
Columbia, MD: AMDA; 2008, revised 2010.

3. Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults: a consensus report. J Am Geriatr Soc. 2012;60(12):2342-2356.

4. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14-S80.

5. American Geriatrics Society Expert Panel on the Care of Older Adults with Diabetes Mellitus, Moreno G, Mangione CM, Kimbro L, Vaisberg E. Guidelines abstracted from the American Geriatrics Society Guidelines for Improving the Care of Older Adults with Diabetes Mellitus: 2013 update. J Am Geriatr Soc. 2013;61(11):2020-2026.

6. Lund A, Knop FK, Vilsbøll T. Glucagon-like peptide-1 receptor agonists for the treatment of type 2 diabetes: differences and similarities. Eur J Intern Med. 2014;25(5):407-414.

7. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35(6):1364-1379.

8. Reid S. Practical use of glucagon-like peptide-1 receptor agonist therapy in primary care. Clin Diabetes. 2013;31(4):148-157.

9. Unger J. Incretins: clinical perspectives, relevance, and applications for the primary care physician in the treatment of patients with type 2 diabetes mellitus. Mayo Clin Proc. 2010;85(suppl 12):S38-S49.

10. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs–FDA and EMA assessment. N Engl J Med. 2014;370:794-797.

11. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728-742.