Prolonged Hypoglycemia Associated with Use of Long Acting Basal Insulin Analogues in Geriatric Diabetic Patients

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Abstract

Hypoglycemia is among the most common complications of insulin therapy especially in the setting of attempting tight regulation of glucose. Data suggests that long-acting basal insulin analogues insulin glargine and detemir are safe and perhaps associated with significantly lower rates of hypoglycemia compared to NPH insulin. Reported are a series of 5 cases with persistent hypoglycemia associated with glargine insulin therapy in older diabetics with multiple co-morbidities. Four patients required hospitalization and had a range of clinical presentations of hypoglycemia, but all needed prolonged observation and intravenous dextrose infusions. The unique feature among these cases was that hypoglycemia occurred in the presence of a higher than normal level of HbA1c, which would suggest poorly controlled diabetes. We suggest that hypoglycemia can occur on glargine therapy in spite of elevated HbA1c levels and that older diabetics may present in a manner atypically, requiring vigilance for diagnosis.

Introduction

Hypoglycemia is among the most worrisome complications resulting from use of hypoglycemic agents in the management of diabetes, and contributes to significant morbidity and mortality in diabetics. Normally, the patient is protected from hypoglycemia through release of counter-regulatory hormones and suppression of endogenous insulin secretion. However, older adults in general have lesser physiological reserves and older diabetics are hence more vulnerable; there is inadequate neuro-endocrine response to hypoglycemia, secondary to deficient adrenal responses as well as poorer glucagon release response to hypoglycemia. The inadequate glucagon response to hypoglycemia in advanced type 2 diabetes may be the result of progressive pancreatic alpha-cell dysfunction. The glycemic thresholds for autonomic and symptomatic response to hypoglycemia are shifted to lower glucose levels in advanced diabetics. 1

Data from studies have led us to believe that hypoglycemia is less common with long-acting basal insulin analogues because these exhibit relatively constant glucose-lowering profile over 24 hours without a pronounced peak, to some extent resembling endogenous basal insulin secretary patterns. 2 3 4  And so long-acting basal insulin analogues were considered ideal insulins that not only achieve euglycemia but are associated with lower likelihood of hypoglycemia compared to shorter acting insulins.

Long Acting Insulin Analogues

Insulin glargine and insulin detemir are two long-acting basal insulin analogues currently in use for management of diabetes mellitus in adults. However, we believe their efficacy and safety is not well established and backed by data in the geriatric population. Insulin glargine is the first soluble basal long-acting insulin analog produced by recombinant DNA technology, approved by the FDA in April 2000. It is the most popular and commonly prescribed long-acting insulin in elderly, attributable to a lower risk of severe hypoglycemia in comparison to the traditional insulin Neutral Protamine Hagadorn (NPH). 5 6

Data from randomized clinical trials and meta-analysis have demonstrated that insulin glargine, compared to NPH insulin, reduces the risk of nocturnal and severe hypoglycemia by 40% to 60%, in addition to providing better or at least similar glycemic control.  Insulin glargine has long duration of action (24 hours) and a flat pharmacokinetics profile with absence of insulin peaks. 7  The onset of action is about 1.5 hours, with serum insulin concentrations over time profile relatively constant over 18 hours, followed by gradual decline in time period of 20-24 hours.  A pronounced peak insulin concentration is absent with insulin glargine in contrast to NPH and lente insulin. Insulin glargine is usually used once a day but can be administered twice a day for better glycemic control in difficult to control and labile diabetics.

Another new soluble basal long-acting insulin analogue, insulin detemir, was approved by FDA in 2005. This insulin, just as with glargine insulin, is stated to have a significantly lower risk of hypoglycemia compared to NPH insulin. The duration of action of insulin detemir is dose-dependent, and ranges from 6 (verify) (dose of 0.1u/kg) to 23 hours (dose of 1.6u/kg). There is moderate elevation in insulin levels in the first 5 hours following injection of detemir, with a slow decrement over the next 10 hours. Hence in reality, the insulin concentration is not really as flat as with glargine. Insulin detemir is typically used once a day for higher doses or twice a day in lower doses. Studies comparing twice daily treatment of detemir and NPH insulin in type 2 diabetics suggest that hypoglycemic episodes were fewer in the detemir group by 50-55%, while HbA1c levels, a parameter of diabetic control, were similar.8 Further, weight gain was less pronounce in the detemir group 9  A comparison of pharmacokinetics of selected long acting insulins is presented in Table 1.

Table 1: Pharmacokinetics of select long acting insulins: a comparison
TYPE OF INSULINS ONSET OF ACTION INSULIN PEAK DURATION OF ACTION FREQUENCY OF DOSING CHARACTERISTICS
Insulin glargine 1.5 to 5 hours Does not peak 18 to 24 hours Once daily Long duration Fewer hypoglycemic episodes?
Insulin detemir 1 to 2 hours 1 to 5 hours Slow, blunted peak 6 to 23 hours, influenced by dose Once or twice daily Less hypoglycemic episodes? Less weight gain
NPH Insulin 1 to 2 hours 5 to 6 hours 8 to 12 hours Twice daily Less expensive Shorter action

A Mini Series of 5 Cases

The following is our experience with long-acting basal insulin analogues, specifically insulin glargine, in 5 older diabetics who presented with persistent, intractable hypoglycemia.

Case 1. 84 year old female with past medical history of diabetes, dementia, depression, hypertension, coronary artery disease and chronic kidney disease was hospitalized with delirium leading to stupor and unresponsiveness.  She was not well for 2 weeks and eating poorly according to the caregiver. Her glargine dose was 40 units, in addition to oral hypoglycemic drugs including, glyburide, glucophage and sitagliptin for diabetes management. Hypoglycemia was manifest in the emergency room, and persisted for 48 hours with all glucose values in the range 58 to 74 mg/dl, although she received intravenous 50% dextrose and dextrose continuous infusions in hospital. HbA1c values were high at 11.9 and 12.6 giving an erroneous feeling of uncontrolled diabetes.

Case 2. 62 year old male diabetic with hypertension, coronary artery disease and heart failure brought to the emergency room with unresponsiveness and a seizure. This patient was taking 45 units of glargine, dose recently increased by the primary physician, based on a HbA1c value of 8.9. He was also on glucophage and glyburide.  The ambulance personnel diagnosed hypoglycemia (glucose 29 and 31 mg/dl) and provided 2 boluses of 50% dextrose en route to the emergency room; the sugar remained low, with values at 51, 45, 68 and 74 mg/dl. The patient was also administered 50% dextrose bolus and infusions.

Case 3. 70 year old female with the past medical history of diabetes, hypertension and peripheral vascular disease and status/post amputee, experienced persistent hypoglycemia in the mornings. She was a nursing home resident on 18 U of glargine for diabetes. Her dextrose values were consistently low at 50, 62, 47 and 57 mg/dl in the morning, but postprandial glucose levels were normal. The dose of glargine insulin was reduced, in addition to increasing dietary calories, she received snacks at bed-time and juice or sweets in the morning.  HbA1c was 8 gm%.

Case 4.  76 year old male diabetic with co-morbidities including hypertension, chronic renal disease, chronic anemia, coronary artery disease and peripheral vascular disease was hospitalized for management of non-healing foot ulcer. His glargine dose was 20 units; he also received antibiotics for the foot ulcer. The renal function deteriorated during hospitalization and his hematocrit dropped following debridement of the ulcer. His lethargy and weakness may have been related to infection, anemia or more likely persistent hypoglycemia lasting beyond a day, with dextrose values at 40, 64, 72 and 74 mg/dl, in spite of 50% dextrose boluses and continuous infusion of 5% dextrose. HbA1c ranged from 7.8 to 8.4.

Case 5. 64-year old female with diabetes, hypertension, coronary artery disease, anxiety and depression, was hospitalized with chest pain and fatigue. She was on 100 units of glargine insulin for diabetes. Hypoglycemia was detected in the emergency room, and persisted for 24 hours (dextrose values were 58, 70, 65 and 74 mg/dl) in spite of 3 boluses of 50% dextrose and administration of 5% dextrose continuous infusion. HbA1c values were quite high at 10.2 and 11. She experienced multiple admissions with vague complaints and manifestations of anxiety and depression.

Discussion

Hypoglycemia is a common complication of traditional insulin therapy in diabetics with good glycemic control. The pharmacokinetics and dynamics of long-acting insulin analogues are said to characterize lesser pharmacologic variability, lower hypoglycemia risk, greater impact on quality of life, and higher treatment satisfaction compared with traditional insulin formulations. 4 10  However, our case series comprised of patients in the last year and a half, brings out variable presentations all from hypoglycemia in association with the use of long-acting insulin analogues, in this case glargine. In all cases the hypoglycemia was persistent and intractable, requiring infusions of oral or intravenous glucose. Hypoglycemia would traditionally be linked to low or normal HbA1c; in contrast the HbA1c values were all high (in the range of 8 – 12) in fact suggesting poor glucose control, which would prompt health providers to raise the dose of insulin.

While no explicit guidelines are available for target HbA1c levels in long term care residents, the American Geriatric Society Panel on Improving Care for Elders with Diabetes recommended in 2003 that HbA1c target for older adults be individualized: a reasonable target for HbA1c in healthy older adults with relatively good functional status is <7% and for frail elderly with less than 5 years life expectancy in whom risks of intensive glycemic control appear to outweigh the benefits, a less stringent HbA1c target of 8% is appropriate. HbA1c values are useful markers to monitor adequacy of diabetes control and compliance and an indirect measure of overall glycemic exposure over the preceding 2 to 3 months. Fasting plasma glucose is a major contributor to HbA1c in poorly controlled diabetes. 11  The clinical manifestations of glargine-induced hypoglycemia in our series included lethargy, weakness, delirium, altered mental status, unresponsiveness and seizure. Of note, one of the nursing home patient (case 3) was asymptomatic even during hypoglycemia. These presentations are important in that, older adults, especially in long term care have a high comorbidity profile; these include cognitive impairment and behavioral problems. In such situations, behavioral abnormalities and hypoglycemia may not be necessarily linked, providing difficulty in diagnosis. The cognitively impaired may not react to symptoms of hypoglycemia and be unable to complain; alternatively the manifestations may be misinterpreted as dementia, delirium or depression; 12  additional manifestations may include organ damage, falls or seizure. 13

Our series of elderly patients were unique and may not resemble the older community adult or the younger adults. They did have multiple associated co-morbidities, including cardiac, renal, hepatic and endocrine dysfunction, in addition to dementia and emotional disturbances (anxiety and depression). Such patients make management more difficult and there could be a delay in diagnosis and instituting corrective measures. Insulin requirements are altered with illness; further the kinetics of insulin are altered by sarcopenia, fat stores, hepatic and renal function. Long acting insulins such as glargine may actually provide a risk in the presence of illness and defective neuro-endocrine function; this may be the explanation for prolonged hypoglycemia in our older diabetics.

Our patients had hypoglycemia that persisted 24 to 48 hours, despite efforts at normalization with boluses or continuous glucose infusion. Such patients require close monitoring in hospital and followed intensely. The cost of care in such situations is high.

Discussion

Our mini-series highlights the fact that one should be cautious with use of new medications. New drugs may be more efficient, but may also have adverse effects. Trials are seldom conducted in the frail elderly. In the world of practice, particularly in long term care, patients are frail and have illness. In such situations the use of long acting insulins must be linked to closer monitoring of glucose control and a watch for adverse events. The most interesting aspect was the fact that our patients had prolonged and severe hypoglycemia, with manifestations, but at the same time had elevated HbA1c levels, suggesting suboptimal glucose control. Four of our five patients required hospitalizations, and therefore entailed health care costs. Our cases illustrate the fact that long acting insulins should be used with caution in older adults and care individualized, with close monitoring. As we know, it is important that first we do no harm! New onset behavioral alterations in older diabetics calls for prompt blood sugar measurements prior to considering another diagnosis.  And finally, the elderly are most vulnerable; the physiological decline in reserves with aging 14 coupled with illness render the frail elderly to adverse effects of medications, especially long acting drugs, warranting close monitoring.

References

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