Advances in technology and therapeutics have led to more people with diabetes living into older age and others developing it later in life. According to the Centers for Disease Control and Prevention, over 10.5% of the U.S. population has been diagnosed with diabetes, and 26.8% of adults over 65 years old have diabetes.

Advanced practice RNs (APRNs) face challenges when managing type 2 diabetes in older adults, who are at high risk for acute and chronic complications of diabetes, as well as adverse treatment reactions. In addition, older adults frequently have comorbidities that affect how APRNs prescribe, monitor, and adjust medications. Adding to that complexity is the presence of geriatric syndromes. (See Geriatric syndromes.)

This article explores the latest American Diabetes Association (ADA) guidelines for pharmacotherapeutic management of type 2 diabetes and considerations for using these guidelines in older adults.

ADA guideline review

The 2019 ADA guidelines for medication management of type 2 diabetes provide specific, stepwise recommendations. For most patients, first-line therapy continues to be metformin. If glycemic targets aren’t met, second- and third-line therapies typically depend on the presence of complications or comorbidities (atherosclerotic cardiovascular disease [ASCVD], heart failure, or chronic kidney disease [CKD]), medication affordability, or the potential for hypoglycemia.

Second-line therapies include glucagon-like peptide (GLP-1) receptor agonists, sodium-glucose cotransporter-2 (SGLT-2) inhibi­tors, thiazolidinediones, sulfonylureas, and dipeptidyl peptidase 4 (DPP-4) inhibitors. Third-line therapies include adding any of the second-line drugs not already prescribed or insulin therapy.

Metformin

Metformin has long been the mainstay of pharmacotherapy for type 2 diabetes. It works by improving insulin sensitivity and reducing hepatic glucose production, without promoting weight gain or hypoglycemia when used as monotherapy. Although no specific recommendations exist for metformin use in older adults, caution is recommended in people over age 80 because of higher risk for lactic acidosis, which can occur with kidney, liver, or heart failure.

Sulfonylureas

Sulfonylureas, the oldest class of oral hypoglycemic medications, trigger insulin secretion from pancreas beta cells, regardless of carbohydrate intake or blood glucose levels. The trade-offs for glucose lowering are risks for hypoglycemia and weight gain.

The generic status of sulfonylureas means they’re inexpensive, making them attractive options for patients with financial constraints. In the 2019 guidelines, the ADA recommends sulfonylureas as second-line therapy for patients who have financial concerns. However, older-generation and long-acting sulfonylureas have long been included on the American Geriatrics Society Beers Criteria, a catalog of medications potentially harmful to older adults. Sulfonylureas in older adults are associated with falls, hospitalization for hypogly­ce­mia, higher rates of cardiovascular illness, and mortality.

Despite these established risks, 70% of prescriptions for long-acting sulfonylureas are written for adults 65 years or older. In 2015, glimepiride, the newest sulfonylurea, was added to the Beers Criteria because of its unpredictability and propensity to cause hypoglycemia in older adults. Glimepiride and other longer-acting sulfonylureas should be avoided in older adults.

GLP-1 receptor agonists

GLP-1 receptor agonists have been shown to improve cardiovascular outcomes and are a preferred second-line therapy in adults with existing ASCVD. These injectable agents, which require either intact patient neuromotor ability or caregiver support, promote satiety by working in the gut’s incretin pathway to enhance pancreas glucose-dependent insulin production, decrease liver glucagon production, and delay gastric emptying. Used alone or in combination with metformin, GLP-1 receptor agonists are less likely to promote hypo­glycemia than insulin or sulfonylureas.

GLP-1 receptor agonists are considered safe for older adults and may be particularly helpful for those who would benefit from weight loss or who have ASCVD. Despite their safety and known benefit in older adults, GLP-1 receptor agonists commonly are prescribed in younger patients, whereas older adults are more likely to receive insulin or sulfonylureas.

Because GLP-1 receptor agonists induce satiety and decrease appetite, they can be harmful in older adults who are frail, underweight, or have poor appetites.

SGLT-2 inhibitors

SGLT-2 inhibitors act in the kidney by inhibiting the reabsorption of glucose in the proximal tubule. In patients with type 2 diabetes, the threshold for glucose reabsorption is increased, contributing to hyperglycemia. SGLT-2 inhibitors lower this reabsorption threshold, leading to increased excretion of glucose in the urine.

The 2019 ADA guidelines recommend SGLT-2 inhibitors as second-line therapy for patients with heart failure or ASCVD. These drugs act as mild diuretics, so they have some benefit in fluid and blood pressure reduction, and they’re associated with an overall reduction in diabetic nephropathy progression.

SGLT-2 inhibitors can be safe to prescribe for older adults; however, they haven’t been extensively studied in this population, so some caution is warranted. Noteworthy SGLT-2 inhibitor side effects include increased risk of genital mycotic infections related to glucosuria and a transient decline in estimated glomerular filtration rate (eGFR).

Dehydration and orthostasis from volume reduction and genital infections are common. APRNs should provide education about orthostasis symptoms and how to reduce them, including rising slowly from a supine position, adequate fluid intake, perineal hygiene, and falls prevention. SGLT-2 inhibitors are associated with higher rates of fracture and amputation in older adults with low baseline eGFR or a history of ASCVD and those who are on high doses of diuretics. For patients who are at high risk of fracture (such as those with low bone mass density or falls history) or amputation (such as those with vascular disease, diabetic foot ulcer, or previous amputation), SGLT-2 inhibitors should be used with caution.

SGLT-2 inhibitors are the newest oral agents, so no generic options are available; their cost may be prohibitive for some patients.

DPP-4 inhibitors

DPP-4 inhibitors work in the incretin pathway by blocking the enzyme that inhibits the effects of GLP-1, thus enhancing insulin secretion. These medications are well tolerated, with low rates of hypoglycemia and no weight gain because they work when GLP-1 is secreted normally during a meal. DPP-4 inhibitors are recommended as second-line therapy for people for whom hypoglycemia is a concern. They are less likely than sulfonylureas to contribute to frailty.

In clinical trials, some drugs in this class (saxagliptin and alogliptin) increased hospitalization rates for heart failure. Despite these findings, DPP-4 inhibitors don’t carry any warnings specific to older adults; however, they should be used with caution in patients with heart failure.

Thiazolidinediones

Thiazolidinediones continue to have a role in adjuvant management of type 2 diabetes. They improve insulin sensitivity and can be added to metformin in patients for whom hypo­glycemia or cost are concerns. However, thia­zolidinediones have been linked to fluid retention, heart failure, and increased fracture rates not associated with osteoporosis. While this drug class can be safe and effective, they should be avoided in older adults with heart failure or who are at high risk for falls.

Insulin

Because of newer diabetes medications that control blood sugar and also promote weight loss and have lower rates of hypoglycemia, insulin has fallen to third- or fourth-line treatment for most patients with type 2 diabetes.

Insulin replaces or augments insulin produced by beta cells, and several types exist to mimic a physiologic response to hyperglycemia. Despite the side effects of low blood sugar and weight gain, insulin is warranted for some patients, such as those with severe kidney disease or extremely elevated glucose levels, or patients who can’t meet glycemic targets despite multiple therapies.

Rapid- and short-acting insulin can prevent hyperglycemia after meals and also treat acutely elevated blood glucose. Intermediate and long-acting insulin can maintain glycemic targets between meals and overnight, and combinations of insulin can nearly mimic the body’s natural response to glucose loads.

Before prescribing insulin to older adults, APRNs should assess patients’ cognitive, motor, and sensory abilities. In addition, family or caregiver support is crucial. Simplified insulin regimens, such as pre-mixed insulins, can be safely used by older adults, but can increase the risk of hypoglycemia.

Special considerations

For most people over age 65, type 2 diabetes treatment should follow guidelines for the general population. However, some older adults may have comorbidities—including those that affect kidney function, limit life expectancy, or make tight glycemic control dangerous—that will impact treatment decisions. (See Glycemic control in older adults.)

Declining kidney function

Nearly half of all people with diabetes will develop CKD, and incidence increases with age. CKD can cause physical changes—including decreased drug excretion—that warrant caution with any medication. Other CKD-related changes that can alter glucose levels include depression, increased infection risk, and decreased appetite. In the United States, diabetes and hypertension are leading causes of CKD and resulting treatment with dialysis and kidney transplant. APRNs must assess kidney function (including estimated eGFR, serum creatinine, and albumin-to-creatinine ratio) in all patients before initiating therapy and periodically for the duration of treatment. Most medications used to treat type 2 diabetes require dose adjustments for kidney disease, and others carry eGFR limitations for use.

Metformin. Despite its position as first-line pharmacotherapy for type 2 diabetes, metformin use is limited to people with an eGFR >45 mL/min in those who haven’t received the medication before, and >30 mL/min in patients who already take the medication. Discontinuing metformin should be considered in adults over age 80 who have persistent GI side effects or declining kidney function with an eGFR <60 mL/min.

GLP-1 receptor agonists. Most GLP-1 receptor agonists don’t require dose adjustments for moderate eGFR impairments. However, in patients with severely diminished eGFR (<15 mL/min), lixisenatide and exenatide aren’t recommended. GLP-1 receptor agonists, as a class, aren’t well studied in patients with severe CKD, so caution is recommended. Patients who experience severe GI side effects are at increased risk of kidney injury, so their kidney function should be monitored.

Insulin and sulfonylureas. Insulin and sulfonylureas increase the amount of circulating insulin, independent of meals, increasing the risk of hypoglycemia in older adults with kidney disease. Because the kidneys clear up to 80% of circulating insulin, impaired kidney function can lead to prolonged insulin exposure to any single dose of insulin or a sulfonylurea. Caution should be used when prescribing insulin or a sulfonylurea for patients with CKD who may be at risk for hypoglycemia due to prolonged action of insulin. Insulin doses should be frequently assessed and adjusted based on the patient’s needs.

Thiazolidinediones. Pioglitazone, the only thia­zolidinedione available in the United States, is metabolized entirely by the liver; no dose adjustments are recommended in patients with CKD. However, this drug class causes fluid retention, which also is a hallmark of later-stage CKD. Monitoring edema is warranted in patients with CKD who take a thiazolidinedione; edema from any cause should be a consideration for discontinuing the drug.

SGLT-2 inhibitors. Although SGLT-2 inhi­bi­tors can slow the progression of diabetic nephropathy, using these drugs is limited in patients with CKD, and most require discontinuation at an eGFR <45 mL/min. The primary rationale for these recommendations is a lack of clinical research in the use of these agents in people with moderate-to-severe CKD. However, because of SGLT-2 inhibitors’ diuretic effects, which can lower blood pressure and cause transient increases in serum creatinine, they should be used cautiously to prevent further kidney injury.

Life-limiting illness

The primary rationale for type 2 diabetes treatment is complication prevention. However, people with limited life expectancy for any reason may not receive the benefit of reduced risk of nephropathy, retinopathy, and cardiovascular diseases. In fact, they may be at increased risk of adverse reactions to intensive treatment regimens. Despite known complications of suboptimally controlled type 2 diabetes, treatment contributes to polypharmacy and can lead to hypoglycemia in older adults. Hypoglycemia, in turn, can lead to falls, injury, hospitalization, and psychological stress, which can increase patient and healthcare system burden.

In systematic reviews (by Seidue and colleagues and by Abelhafiz and colleagues) of approaches to deintensify (decrease or discontinue medication without replacing it) or deprescribe (identify and discontinue drugs in which existing or potential harm outweighs benefits) diabetes therapy among older adults, most participants didn’t experience a worsening of disease control. They did, however, experience fewer episodes of hypoglycemia. Additionally, no differences in mortality existed between comparison groups. Despite these encouraging findings, the reviewed trials were small and didn’t show long-term outcomes related to treatment deintensification in older adults. In addition, comparing long-term benefits and risks of discontinuation or continuation of specific agents was difficult.

Recommendations

Recommendations for managing any condition in older adults include treating with the lowest dose required to achieve adequate control. Although glycemic targets for type 2 diabetes are well established, intensive management can lead to adverse outcomes in older adults. For adults with limited life expectancy or severe comorbid illness such as frailty or dementia, aiming for a glycated hemoglobin of < 8.5% is reasonable. For older adults at high risk for hypoglycemia, or for whom hypoglycemia would be detrimental, choosing agents unlikely to promote hypoglycemia is warranted.

In some situations, deintensifying or deprescribing therapy in older adults is necessary. In addition to deintensifying regimens, choosing those that are less likely to cause adverse reactions is important. Specific guidelines for deintensifying or deprescribing type 2 diabetes therapy don’t exist, highlighting a gap in evidence for disease management in older adults. (See Deintensification strategies.)

Take a thoughtful approach

Type 2 diabetes management in older adults is complicated and requires a thoughtful approach. APRNs are well positioned to design safe and effective treatment plans and to equip patients and caregivers with the tools they need to safely navigate the disease process. More research in managing type 2 diabetes in this population is needed, and a significant gap exists in the literature about treatment deintensification. Until that evidence exists, APRNs must continually assess treatment safety.

Carrie Palmer is an associate professor and DNP lead faculty at the University of North Carolina Chapel Hill School of Nursing.

References

2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-94.

Abdelhafiz AH, Sinclair AJ. Deintensification of hypoglycaemic medications—Use of a systematic review approach to highlight safety concerns in older people with type 2 diabetes. J Diabetes Complications. 2018;32(4):444-50.

Aldrich S, Ashjian E. Use of GLP-1 receptor agonists in patients with T2DM and chronic kidney disease. Nurse Pract. 2019;44(3):20-8.

American Diabetes Association. Older adults: Standards of medical care in diabetes—2019. Diabetes Care. 2019;42(suppl 1):S139-47.

American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes – 2019. Diabetes Care. 2019;42(suppl 1):S90-S102.

Aspinall SL, Hanlon JT, Niznik JD, Springer SP, Thorpe CT. Deprescribing in older nursing home patients: Focus on innovative composite measures for dosage deintensification. Innov Aging. 2017;1(2):1-8.

Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2020: Estimates of Diabetes and Its Burden in the United States. cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf

Freeman J. Management of hypoglycemia in older adults with type 2 diabetes. Postgrad Med. 2019;131(4):241-50.

Hsia DS, Grove O, Cefalu WT. An update on SGLT2 inhibitors for the treatment of diabetes mellitus. Curr Opin Endocrinol Diabetes Obes. 2017;24(1):73-9.

Inouye SK, Studenski S, Tinetti ME, Kuchel GA. Geriatric syndromes: Clinical, research, and policy implications of a core geriatric concept. J Am Geriatr Soc. 2007;55(5):780-91.

Gomez-Peralta F, Abreu C, Lecube A, et al. Practical approach to initiating SGLT2 inhibitors in type 2 diabetes. Diabetes Ther. 2017;8(5):953-62.

Koye DN, Magliano DJ, Nelson RG, Pavkov ME. The global epidemiology of diabetes and kidney disease. Adv Chronic Kidney Dis. 2018;25(2):121-32.

Lewandowicz A, Skowronek P, Maksymiuk-Klos A, Piatkiewicz P. The giant geriatric syndromes are intensified by diabetic complications. Gerontol Geriatr Med. 2018;11(4):2333721418817396.

Longo M, Bellastella G, Maiorino MI, Meier JJ, Esposito K, Giugliano D. Diabetes and aging: From treatment goals to pharmacologic therapy. Front Endocrinol. 2019;10:45.

Munshi MN, Slyne C, Segal AR, Saul N, Lyons C, Weinger K. Simplification of insulin regimen in older adults and risk of hypoglycemia. JAMA Intern Med. 2016;176(7):1023-5.

Pilla SJ, Segal, JB, Alexander GC, Boyd CM, Maruther NM. Differences in national diabetes treatment patterns and trends between older and younger adults. J Am Geriatr Soc. 2019;67(5):1066-73.

Schlender L, Martinez YV, Adeniji C, et al. Efficacy and safety of metformin in the management of type 2 diabetes mellitus in older adults: A systematic review for the development of recommendations to reduce potentially inappropriate prescribing. BMC Geriat. 2017;17(suppl 1):99-117.

Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317-26.

Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: Observations the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579-88.

Seidu S, Kunutsor SK, Topsever P, Hambling CE, Cos FX, Khunti K. Deintensification in older adult patients with type 2 diabetes: A systematic review of approaches, rates, and outcomes. Diabetes Obes Metab; 2019;21(7):1668-79.

Watts NB, Bilezikian JP, Usiskin K, et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2016;101(1):157-66.

Whittaker CF, Miklich MA, Patel RS, Fink JC. Medication safety principles and practice in CKD. Clin J Am Soc Nephrol. 2018;13(11):1738-46.

Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-57.