Diabetes Management in the Elderly Patient with Kidney Disease

Diabetes mellitus is the most common cause of chronic kidney disease (CKD) and kidney failure (1). More than one quarter of the United States population over age 65 has diabetes (2), and 37 percent of them have an eGFR <60 mL/min/1.73 m2 (3).

Whether the decreased GFR is due to age-related decline or to diabetic kidney disease (see other articles in this issue), it affects the clearance of insulin and many diabetes medications and raises the risk of hypoglycemia (4). Hypoglycemia is the major barrier to achieving near-normal glycemia, which has been shown to delay the progression of diabetic kidney disease (5, 6). If a low GFR is thought to not be due to diabetic kidney disease, then a more relaxed HbA1c goal may be appropriate to avoid hypoglycemia.

Older patients with diabetes are frail, unstable, prone to falls, and at increased risk of hip fracture (7, 8), augmenting the risk of an adverse outcome from hypoglycemia. They also have an increased risk of depression and cognitive impairment while at the same time being treated with myriad drugs; polypharmacy may put them at risk for medication errors and erratic medication adherence (7, 8). Thus, frail elderly individuals are at increased risk for medication-induced hypoglycemia for a variety of reasons in addition to their falling GFR. Severe hypoglycemia is associated with both short-term and long-term increased risk of major macrovascular events, death of cardiovascular causes, and all-cause mortality (4, 9, 10). Low HbA1c levels and insulin treatment are also associated with increased risks of falls and hip fracture (8).

It is important to assess the risks and benefits of adhering to glycemic goals in a given patient (11). According to the recent guidelines from the American Diabetes Association (12), unlike the goal of 7.0 percent for younger adults, 7.5 percent is a reasonable HbA1c goal for relatively healthy older patients who have few coexisting morbidities, have a reasonable life expectancy, and are at low risk for hypoglycemia. For those at intermediate risk with multiple comorbidities or some cognitive impairment, a goal of <8.0 percent is reasonable. For those with poor health with poor long-term outcomes and more severe cognitive impairment, a goal of <8.5 percent is recommended (12). HbA1c levels higher than 8.5 percent are associated with adverse effects of poor wound healing, catabolism with weight loss, and possible dehydration. The older patient with CKD stage 3 would likely fall at least in the intermediate category, so a goal of 8.0 percent or even higher would be appropriate for most such patients, especially if they are taking insulin. Trial data in such patients are sparse, but one study showed that HbA1c levels >9 percent or <6.5 percent were associated with increased mortality in the presence of CKD stage 3 or worse (13).

Diabetes treatment in older patients with CKD

Insulin

Reduced kidney function results in a prolongation of insulin half-life and a decrease in insulin requirements (14). All insulin preparations can be used in patients with CKD, and there are no specific reductions in dosing for patients. An inpatient study that randomized weight-based basal and bolus insulin in patients with a GFR <45 mL/min to 0.5 units/kg body weight versus 0.25 units/kg showed similar glycemic control but significantly less hypoglycemia in the group with the lower weight-based dose (15). A single dose of long-acting basal insulin can be added when oral agents do not obtain satisfactory control with a relatively low risk of hypoglycemia (16). However, the more complicated the regimen (i.e., adding prandial insulin to basal insulin), the more chances of dosing error and hypoglycemia, especially if there is cognitive impairment. Patients with CKD stage 4–5 often have delayed gastric emptying; giving rapid-acting insulin after the meal may be helpful for matching the insulin peak with the time of the postprandial blood glucose peak. Postprandial rapid-acting insulin with dose adjustment for how much was eaten may help in patients with varying food intakes.

Metformin

Metformin increases insulin sensitivity and decreases hepatic gluconeogenesis; it does not cause hypoglycemia. It reduces HbA1c by 1.0 to 2.0 percent and is the first drug generally used when lifestyle changes do not provide satisfactory control (17). The U.S. Food and Drug Administration recommends that metformin should not be used with serum creatinine ≥1.5 mg/dL in men and ≥1.4 mg/dL in women or with decreased creatinine clearance in people over age 80 to reduce the risk of lactic acidosis, which is actually very rare (17). Recently, it has been recommended that metformin be used without dose reduction with an eGFR >45 mL/min/1.73 m2, with a reduction to 1000 mg daily if the eGFR is ≥30 to 44 mL/min/1.73 m2 and stopped with an eGFR <30 mL/min/1.73 m2 or in situations associated with hypoxia or an acute decline in kidney function such as sepsis/shock, hypotension, and use of radiographic contrast medium or other nephrotoxic agents (17) (Table 1).

Sulfonylureas and meglitinides

Sulfonylureas and meglitinides increase insulin secretion and can cause hypoglycemia. Sulfonylureas and their metabolites are renally cleared, leading to an increased risk of hypoglycemia as GFR declines. Glyburide should be avoided with eGFR <60 mL/min/1.73 m2 (18) and also in the elderly. Glimepiride should be used with caution if the eGFR is <60 mL/min/1.73 m2 and should not be used with eGFR <30 mL/min/1.73 m2 (19). Less than 10 percent of glipizide is cleared renally, but it should still be used with caution with an eGFR <30 mL/min/1.73 m2 (20, 21).

Nateglinide and repaglinide result in a rapid and short duration of insulin release and should be taken before meals. The active metabolite of nateglinide accumulates in CKD; nateglinide should not be used with an eGFR <60 mL/min/1.73 m2 (22). Repaglinide appears safe to use in CKD (23).

Thiazolidinediones

Pioglitazone and rosiglitazone increase insulin sensitivity and do not cause hypoglycemia. They are hepatically metabolized and can be used in CKD without dose adjustment. However, fluid retention is a major adverse effect, which may worsen heart failure and makes the use of these agents in CKD limiting. They are associated with increased fracture rates and bone loss in women (24); thus, their use in patients with underlying bone disease (such as renal osteodystrophy or osteoporosis) potentially could be problematic.

Alpha-glucosidase inhibitors

Acarbose and miglitol decrease the breakdown of oligosaccharides in the small intestine, delaying the absorption of glucose after a meal, and do not cause hypoglycemia. Neither drug has been studied over the long term in patients with creatinine >2 mg/dL, so their use should be avoided in these patients.

Dipeptidyl peptidase-4 inhibitors

Dipeptidyl peptidase-4 inhibitors (sitagliptin, saxagliptin, linagliptin, alogliptin) decrease the breakdown of incretin hormones such as GLP-1 and do not cause hypoglycemia. All but linagliptin have some renal clearance and need dose adjustment in patients with reduced eGFR (25, 26) (Table 1). In general, they are very well tolerated, and there are no special concerns for the elderly.

Sodium-glucose cotransporter 2 inhibitors

Sodium-glucose cotransporter-2 inhibitors reduce glucose reabsorption in the proximal tubule, leading to an increase in glucose excretion, a reduction in A1c of ∼0.8 percent, and weight loss; they do not cause hypoglycemia. Because of a small increase in adverse events related to intravascular volume contraction, no more than 100 mg once daily of canagliflozin should be used in patients with an eGFR of 45 to <60 mL/min/1.73 m2 (27). Canagliflozin and empagliflozin should be stopped if the eGFR is <45 mL/min/1.73 m2 and dapagliflozin stopped at 60 mL/min/1.73 m2, primarily because of a decrease in efficacy.

Glucagon-like peptide-1 receptor agonists

Exenatide, liraglutide, dulaglutide, and albiglutide are injectable glucagon-like peptide 1 receptor agonists, leading to increased insulin release, delayed glucagon secretion, delayed gastric emptying, and appetite suppression with weight loss; they do not cause hypoglycemia. Clearance of exenatide decreases with declines in GFR (28). Cases of acute renal failure associated with exenatide use have been reported, and it should not be used if the GFR is <30 mL/min/1.73 m2 (29). Liraglutide is not metabolized by the kidney, and no dose adjustment is indicated in those with renal impairment, including ESRD, although data in this population are limited (30). No dose changes are needed for dulaglutide or albigutide with worsening renal function. Nausea is a common side effect and potentially could be problematic in older patients with compromised intake.

Strategy for glycemic control

Glycemic control should be optimized individually for the patient, attaining the necessary control to reduce complications but done in a safe, monitored manner. Usually one or two oral agents or a glucagon-like peptide-1 receptor agonist are added to metformin in a stepwise fashion; if control is still not achieved, basal insulin can be added. If prandial insulin is ultimately needed, special care is needed to avoid hypoglycemia.

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