Pharmacological management of diabetes in older adults

Metformin

Metformin is the recommended first-line therapy for type 2 diabetes mellitus, including in older adults [1]. It effectively lowers blood glucose levels and carries a low risk of hypoglycemia. Common side effects include appetite loss, nausea, diarrhea, and a metallic taste. Given that gastrointestinal symptoms such as loss of appetite can significantly diminish quality of life in older adults, it is crucial to monitor them closely for these symptoms. Extended-release formulations are often better tolerated due to fewer gastrointestinal symptoms. Since gastrointestinal side effects are more common at higher doses, it is advisable to start with a low dose and gradually increase every 2 to 3 weeks based on glucose monitoring.

Metformin may also impair the absorption of vitamin B12 and folic acid. It is suggested that 5.8% to 33% of people taking metformin may develop a vitamin B12 deficiency [10,11]. Close monitoring of vitamin B12 deficiency is advised in older adults, especially in patients with atrophic gastritis or unexplained anemia [12].

Lactic acidosis is a very rare but potentially life-threatening side effect of metformin. Therefore, metformin should not be used in conditions where lactic acid production is increased, or its excretion is decreased including kidney disease, liver disease, alcoholism, congestive heart failure, peripheral vascular disease, and obstructive pulmonary disease. Special caution is warranted in older adults, who are more likely to have these conditions. Metformin can be used in patients with stable heart failure but should be avoided in those who are hospitalized for heart failure or have uncontrolled heart failure. Metformin is contraindicated in cases of severe liver dysfunction or kidney dysfunction. It should be used with caution if the estimated glomerular filtration rate (eGFR) is less than 45 mL/min/1.73 m² and is contraindicated if the eGFR is less than 30 mL/min/1.73 m². Metformin administration should be stopped immediately in the event of dehydration, hypoxia, or sepsis.

Thiazolidinediones

TZDs (e.g., pioglitazone, lobeglitazone) are insulin sensitizers that are liver-metabolized and excreted via bile allowing for unchanged dosages in patients with impaired kidney function. They are contraindicated in individuals with active liver disease or those whose liver enzyme levels are elevated to 2.5 times above the normal range. TZDs offer the benefits of once-daily dosing and carry no risk of hypoglycemia. Despite these advantages, their use in older patients is limited due to potential risks such as weight gain, edema, exacerbation of heart failure, fractures, and concerns regarding bladder cancer stability [13]. TZDs are specifically contraindicated in patients with New York Heart Association class III and IV congestive heart failure [1]. Additionally, TZDs have been shown to increase bone loss and raise the risk of fractures in older women [14,15]. Given that the risk of fractures is already heightened in individuals with type 2 diabetes mellitus due to increased fall risks, localized bone loss, and impaired bone quality, TZDs should be prescribed cautiously in patients who are at risk for osteoporosis.

Sulfonylureas

Sulfonylureas are cost-effective and potent but are associated with a higher risk of hypoglycemia and weight gain. In older patients with diabetes mellitus, sulfonylureas should be prescribed with caution, starting at the lowest effective dose to minimize the risk of hypoglycemia. In patients with stage 3 or higher chronic kidney disease, glyburide (glibenclamide) is contraindicated, glimepiride should be initiated at a low dose, and glipizide and gliclazide can generally be used without dose adjustments. These medications should only be considered if the patient consistently consumes regular meals, can recognize the symptoms of hypoglycemia, and can manage hypoglycemia appropriately. Short-acting sulfonylureas are preferred in this population. Among sulfonylureas, gliclazide is noted for its lower risk of hypoglycemia in older patients [16].

Meglitinides

Although meglitinides have a lower risk of hypoglycemia compared to sulfonylureas [17,18], they can still cause hypoglycemia and weight gain. The requirement to take these medications 2 to 3 times daily with meals may be inconvenient; however, their administration can be skipped if a meal is missed, reducing the risk of hypoglycemia. This feature makes meglitinides particularly beneficial for older patients with diabetes mellitus who have irregular meal schedules.

Repaglinide is a suitable option for patients with severely reduced kidney function, as it does not require significant dose adjustments. Nateglinide, on the other hand, is appropriate for patients with an eGFR of 30 mL/min/1.73 m² or higher, but dose adjustments are necessary in this population.

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 (DPP4) inhibitors are effective for glycemic control, especially managing postprandial blood glucose levels and have a very low risk of hypoglycemia [19–22]. When used as monotherapy, they rarely cause hypoglycemia; however, the risk increases when combined with insulin or sulfonylureas. Therefore, it is recommended to reduce the dosage of insulin or sulfonylureas in advance or provide patient education on recognizing and managing hypoglycemia when it is added to insulin or sulfonylureas.

Unlike other insulin secretagogues, DPP4 inhibitors do not cause weight gain and are associated with minimal side effects, making them increasingly popular and widely used in recent years. They are considered safe and effective for older patients with diabetes mellitus. Although DPP4 inhibitors can be used safely in patients with reduced kidney function, dosage adjustments may be necessary for some medications. While these drugs are generally considered safe for patients with cardiovascular diseases, a prospective study assessing cardiovascular safety in high-risk patients revealed that saxagliptin might increase the risk of hospitalization for heart failure [23]. Consequently, saxagliptin is not recommended for people with a history of heart failure. Given the high prevalence of heart failure among older patients with diabetes mellitus, additional vigilance is necessary when prescribing saxagliptin in this population.

Glucagon-like peptide-1 receptor agonists

The safety and efficacy of glucagon-like peptide-1 (GLP-1) receptor agonists have been well-established in studies involving older patients with diabetes mellitus [24–26]. These medications are associated with a low risk of hypoglycemia and offer the added benefit of promoting weight loss. In the LEADER study, which evaluated cardiovascular safety, liraglutide significantly reduced both the incidence and mortality rates of major cardiovascular events, making it the first GLP-1 receptor agonist to achieve such outcomes [27]. Similarly, the SUSTAIN-6 study demonstrated that semaglutide significantly reduced the incidence of cardiovascular events [28].

Although GLP-1 receptor agonists rarely cause hypoglycemia when used as monotherapy, the risk may increase when combined with other hypoglycemia-inducing medications. A key limitation of these drugs is that they are administered via injection (oral semaglutide is currently not available in Korea), and they may cause gastrointestinal side effects, including nausea, vomiting, and diarrhea. Before initiating treatment, it is important to ensure that the patient has adequate vision, motor skills, and cognitive capacity to manage injections safely. Short-acting GLP-1 receptor agonists are more likely to cause nausea and vomiting. Starting at the lowest dose and gradually increasing it can help mitigate gastrointestinal side effects.

Caution is advised when prescribing GLP-1 receptor agonists to older adults, as significant weight loss or persistent gastrointestinal symptoms could adversely impact their quality of life.

Αlpha-glucosidase inhibitors

Alpha-glucosidase inhibitors provide effective postprandial glycemic control and carry a very low risk of hypoglycemia. Their efficacy and safety have been validated in older adults [29,30]. However, these medications require multiple daily doses and may cause gastrointestinal side effects, such as abdominal distension, diarrhea, and frequent flatulence. Initiating treatment with a low dose and gradually increasing it in small increments can help minimize these adverse effects.

These drugs are contraindicated in patients with inflammatory bowel disease, a creatinine level of 2.0 mg/dL or higher, or liver cirrhosis. When used as monotherapy, alpha-glucosidase inhibitors do not induce hypoglycemia, weight gain, or hyperinsulinemia. However, if hypoglycemia occurs during combination therapy with sulfonylureas or insulin, recovery may be delayed despite oral carbohydrate intake. In such cases, consuming pure glucose (dextrose) is recommended to expedite recovery from hypoglycemia. Patient education on this specific aspect of treatment is essential to ensure safe and effective management.

SGLT2 inhibitors

SGLT2 inhibitors lower blood glucose levels by inhibiting glucose reabsorption in the renal tubules through SGLT2, leading to increased glucose excretion via urine. SGLT2 inhibitors are generally well tolerated and effective for glycemic control in older adults with type 2 diabetes [31–33].

Additional beneficial effects of SGLT2 inhibitors on reducing hospitalizations for heart failure and improving renal outcomes also have been shown from subsequent studies designed to evaluate cardiovascular and renal safety [34–36]. These benefits have also been observed in subanalyses focusing on individuals aged 65 years and older, suggesting a priority in their use among older patients with diabetes who have cardiovascular disease [37].

SGLT2 inhibitors operate independently of insulin and do not increase insulin secretion, thus presenting a very low risk of hypoglycemia. However, when used in conjunction with medications that have a high risk of hypoglycemia, such as insulin or insulin secretagogues, dose adjustments may be necessary to prevent hypoglycemic episodes.

The use of SGLT2 inhibitors leads to increased urinary glucose excretion, which can raise the risk of urinary tract or genital infections. Additionally, the osmotic diuresis induced by these drugs can cause fluid depletion, potentially leading to dehydration, orthostatic hypotension, electrolyte imbalances, and increased hematocrit. Despite these side effects, they are not known to adversely affect patients' quality of life in clinical practice. Nevertheless, caution is advised in individuals aged 75 years and older or those taking diuretics [38].

Euglycemic diabetic ketoacidosis, a condition that may occur at low blood glucose levels, has been reported with the use of SGLT2 inhibitors [39,40], and this risk also exists in older adults with type 2 diabetes mellitus [41]. Symptoms such as dyspnea, nausea, vomiting, and abdominal pain should be monitored closely.

SGLT2 inhibitors might lead to skeletal muscle loss alongside reductions in body weight and fat mass. The potential of SGLT2 inhibitors to cause sarcopenia remains unconfirmed; however, caution is advised in older patients with type 2 diabetes mellitus particularly at risk of exacerbated sarcopenia. Ongoing clinical studies aim to further explore this issue [42].

Insulins

Patients with type 2 diabetes mellitus often initiate insulin therapy after unsuccessful attempts with oral hypoglycemic agents, making insulin a common treatment among older individuals who have had diabetes for an extended period.

Educating elderly patients and their caregivers on insulin and injectable therapies requires tailored strategies that account for age-related challenges such as cognitive decline, visual impairments, and limited manual dexterity. Before starting insulin therapy in older patients, it is crucial to assess whether the patient or their caregiver has impairments in vision, motor skills, or cognitive function [1,43–45]. If cognitive issues such as memory loss or dementia are present, these must be taken into account when providing instructions. It is important to use short, clear sentences, avoid overwhelming the listener with too much information at once, and frequently repeat key points to reinforce understanding. Additionally, caregivers should be actively involved in the education process to ensure proper support in daily insulin administration. Elderly patients may face challenges such as hearing loss, visual impairments, or reduced hand strength. For hearing impairments, it is important to speak slowly and clearly, or use written instructions. For visual impairments, large-print materials and high-contrast designs can be helpful. If manual dexterity is an issue, teaching specific techniques or recommending devices that are easier to handle, such as pens with larger grips, can improve their ability to administer insulin.

Given that insulin therapy poses a higher risk of hypoglycemia compared to other medications, it is prudent to establish a blood glucose target that minimizes the risk of hypoglycemia. This involves simplifying the treatment regimen, starting with a low dose, and gradually titrating upward. Basal insulin, administered once daily, is the preferred option. In contrast, multiple-dose insulin therapy, which is more complex, should be avoided in older patients with advanced complications or reduced physical function. Among basal insulins, insulin glargine U300 and insulin degludec are associated with a lower incidence of hypoglycemia in older adults compared to insulin glargine U100 [46,47].

For older adults in long-term care facilities, who often have multiple comorbidities and varying life expectancies, it is essential to tailor treatment goals and approaches to the individual. Generally, overly strict glycemic control is not recommended. Instead, management should aim to maintain blood glucose levels that prevent symptoms of hyperglycemia, such as dehydration, infections, and urinary incontinence, while avoiding hypoglycemia. Additionally, self-monitoring of blood glucose should be minimized to preserve quality of life.