Antihyperglycemic Therapy in Elderly Diabetics

Adopting an individualized approach is the cornerstone of much of modern medicine, and nowhere is that more true than in the care of older patients with type 2 diabetes (T2DM).¹ Older patients represent a highly variable population. Some may have no health problems other than T2DM, while others may suffer from multiple health issues that complicate treatment. Longstanding diabetes increases the risk for microvascular and macrovascular complications, yet those with well controlled disease may need a different treatment approach than those whose disease has been difficult to manage. Patients who are newly diagnosed later in life with T2DM may need yet another strategy.

In recent years, guidelines have recognized the variability in this age group by emphasizing the importance of balancing the risks of hypoglycemia vs the benefits of adequate glucose control. Although guidelines differ, in general they recommend less intensive treatment and more relaxed HbA1c targets in certain circumstances, especially for frail patients and those with cardiovascular disease.

These guidelines follow on the heels of research suggesting the existence of a U-shaped curve for mortality vs HbA1c. Results from the landmark ACCORD trial showed that participants (mean age 62 years) had increased risk of mortality at A1c values around 6.0% and 9.0%, and lower risk of mortality for A1c levels intermediate between 6.0% and 9.0%.² A recent Kaiser Permanente of Northern California study confirmed this U-shaped curve in 71,000 people who were over age 60 and had T2DM. The retrospective cohort study also found that the risk of death and chronic complications rose significantly at A1C ≥8.0%.³

[[{"type":"media","view_mode":"media_crop","fid":"45325","attributes":{"alt":"","class":"media-image","height":"642","id":"media_crop_4029511766788","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"5175","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"width: 823px; height: 399px;","title":" ","typeof":"foaf:Image","width":"1209"}}]]

Despite less stringent A1c goals, experts stress the importance of continuing to strive for adequate glycemic control. Chronic hyperglycemia in older patients may increase the risk of incontinence, dehydration, hyperglycemic crisis, cognitive decline, visual disturbances, zinc loss, decreased muscle mass, and falls.⁸

While issues about efficacy, hypoglycemia, weight gain, and drug-drug interactions apply across age groups, these concerns can become more pronounced in older patients.  Additionally, some older patients have unique concerns specific to their age group. The increased incidence of renal impairment may affect management and choice of antihyperglycemic medication. While the weight loss effects of certain antihyperglycemics (GLP-1 receptor agonists and SGLT2 inhibitors) come as good news to some younger patients, frail elderly patients at risk for malnutrition may not tolerate these agents.  Cardiovascular effects of some antihyperglycemics are also an issue.  

As a general rule, older patients need a safe intensification strategy and drugs with low glycemic variability.³ Newer incretin-based therapies and long-acting insulin analogs may offer advantages in this regard.⁸ Some experts recommend metformin and dipeptidyl peptidase-4 (DPP4) inhibitors as the drugs of choice in older patients, though these drugs may be inappropriate for some.⁸

With the exception of the insulins and sulfonylureas, most antihyperglycemics today carry low risk for hypoglycemia. Other general concerns when choosing antihyperglycemics in elderly patients include:¹

• Metformin:

♦ GI side effects: May pose a problem for frail patients at risk for malnutrition

♦ Renal impairment (RI): Contraindicated

♦ Polypharmacy: May compete with other drugs for renal excretion, leading to increased blood levels and more side effects 

• DPP-4 inhibitors:

♦ Mild RI: no dose adjustments needed

♦ Moderate-Severe RI: Dose adjustments needed for alogliptin, saxagliptin, sitaglitpin

♦ Cardiovascular: Insufficient data to date. Avoid or use caution in patients with heart failure.

• Sulfonylureas:

♦ Weight increase

♦ Hypoglycemia: Increased risk; glyburide increases the risk for prolonged and severe hypoglycemia

♦ Polypharmacy: Affects CYP450 2C9, may interact with other drugs that act on this isoenzyme

• Thiazolidinediones:

♦ Weight increase

♦ Bone: Potential adverse effects

♦ RI: No dose adjustment needed

♦ Cardiovascular: Risk of edema and heart failure

• GLP-1 receptor agonists

♦ GI Side Effects: May pose a problem for frail patients at risk for malnutrition

♦ RI: May worsen renal function, use exenatide cautiously in moderate RI and renal transplant patients, not for use in severe RI and ESRD

♦ Cardiovascular: Limited data in older patients suggests no increased risk of CV events

• SGLT2 inhibitors:

♦ Hypovolemia: Potential for intravascular volume depletion and postural hypotension

♦ Weight loss

♦ Increased risk of genital mycotic infections

♦ RI: Dose adjustments needed

♦ Cardiovascular: Trials are ongoing, recent data suggests lower rates of major CV events with empagliflozin

Drug choice is only part of the story, though. Depression and cognitive dysfunction are common among older patients, and can negatively impact glycemic control by affecting self-care and adherence. The American Geriatrics Society recommends screening for and promptly treating depression in older patients with T2DM. The valuable role of caregivers and their need for support may also need to be addressed when drawing up a comprehensive diabetes management plan for older patients.

Take-home Points

• Older patients with T2DM are a highly variable population with different requirements for diabetes management.

• Guidelines vary, but in general recommend less intensive treatment and more relaxed HbA1c targets, especially for frail patients and those with cardiovascular disease.

• Some experts recommend metformin and DPP4 inhibitors as the drugs of choice in older patients, though these drugs may be inappropriate for some.

• Addressing depression, cognitive dysfunction, the role of the caregiver, and caregiver support is important in diabetes management of older patients.

References:

1. Freeman J. Considerations in the selection of antihyperglycemic therapy for older patients with type 2 diabetes mellitus: a focus on newer therapies. J Fam Pract. 2015; 64(12) Suppl:S59-S66.

2. Riddle MC, et al. Action to Control Cardiovascular Risk in Diabetes Investigators. Epidemiologic relationships between A1C and all-cause mortality during a median 3.4-year follow-up of glycemic treatment in the ACCORD trial. Diabetes Care. 2010;33:983-990.

3. Huang ES, et al. The Diabetes and Aging Study. Glycemic control, complications, and death in older diabetic patients. Diabetes Care. 2011;34: 1329-1336.

4. American Diabetes Association. Standards of medical care in diabetes 2015. Diabetes Care. 2015;38(suppl):S1-S93.

5. Handelsman Y, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for developing a diabetes mellitus comprehensive care plan. 2015. Endocr Pract. 2015;21(suppl 1):1-87.

6. Moreno G, et al. American Geriatrics Society expert panel on care of older adults with diabetes mellitus. Guidelines abstracted from the American Geriatrics Society guidelines for improving care of older adults with diabetes mellitus: 2013 update. J Am Geriatr Soc. 2013;61(11):2020-2026.

7. International Diabetes Federation. IDF Global Guidelines for Managing Older People with Type 2 Diabetes. Accessed January 26 2016 at

8. Du YF, et al. Achieving glycemic control in elderly patients with type 2 diabetes: a critical comparison of current options. Clin Interv Aging. 2014;9:1963-1980.