A Unique Case of Basal-Bolus Therapy

R.R. is a 60-year-old white man whom we were asked to evaluate for perioperative glycemic control. We met on his postoperative day 2 after repair of an abdominal aortoiliac aneurysm.

His medical history was significant for peripheral vascular disease status post-left lower extremity revascularization. His hypertension was controlled with metoprolol and amlodopine, and he took atorvastatin for mixed hyperlipidemia. Preoperative evaluation included a left heart catherization,which demonstrated singlevessel disease and a depressed ejection fraction. His primary care physician had recently indicated that he may have“borderline diabetes.” The patient reported nocturia and polydipsia. He had an allergy to sulfa drugs, although he did not know the exact nature of the allergy.

His father passed away in his 70s during his second coronary artery bypass. There was no immediate family history of diabetes. R.R. is now retired, having previously worked as a plumber. He reported a remote though significant history of tobacco use.

On physical exam, he was comfortably sitting up in his hospital bed. Pulse was 95 bpm, blood pressure 120/80 mmHg, and temperature 100.1°F. His weight was 81 kg, and his height was 1.8 m, yielding a BMI of 25 kg/m². There were no xanthomas on the eyelids. His thyroid gland was not enlarged. Lungs were clear, and cardiovascular exam revealed the absence of jugular venous distension and a normal S1 and S2. There were no murmurs or gallops. His abdomen was appropriately tender along the incision site, which appeared to be healing well without any drainage and only minimal erythema. His vascular exam revealed the absence of carotid bruits. Dosalis pedis pulses were difficult to palpate on both right and left, although his feet were warm. He had a dime-sized, dry, nonerythematous ulcer on his right second toe. His neurological exam revealed intact ankle reflexes and decreased sensation to the 10-g monofilament exam on the soles of his feet bilaterally.

Hospital laboratory tests indicated fasting and postprandial blood glucose values ranging from 117 to 218 mg/dl. He had received ∼ 44 units of regular insulin in the past 24 hours. Liver and renal function was normal;serum albumin was 4.2 g/dl. His hematocrit of 30% represented a decrease from his baseline. R.R. was to be discharged the next morning with plans for revascularization of his right lower extremity in the near future.

The patient was given a diagnosis of hyperglycemia, the etiology of which was believed to be from a variety of factors. His sulfa allergy precluded the use of sulfonylureas. He had recently received contrast, and though now eating and drinking, he would unquestionably receive contrast multiple times in the next year. He had impaired cardiac function and was scheduled to undergo another surgery in a few weeks. Thus, he was a poor candidate for metformin or thiazolidinedione therapy. We therefore opted for a trial of monotherapy with nateglinide, 120 mg three times daily with meals.

R.R. returned to see us in the outpatient setting 5 days after discharge. His fasting morning blood glucose levels remained in the mid-200 mg/dl range and decreased minimally throughout the day. He did not experience any hypoglycemia. His hemoglobin A_1c (A1C) was 7.7%, and serum fructosamine was elevated at 286 umol/l. Thyroid function was normal. His spot albumin-to-creatinine ratio was mildly elevated at 32 μg/mg. The patient was started on ramipril, 2.5 mg daily, for renoprotection. Despite its being an “off label” use with nateglinide, glargine was started at a dose of 10 units nightly and titrated upward in the weeks that followed in an effort to control his fasting blood glucose levels.

One month later, R.R. was admitted for right lower extremity bypass in the setting of a gangrenous right foot. A computed tomography angiogram indicated the need for revascularization of his left lower extremity as well; this was undertaken 1 month later. He received intensive insulin therapy perioperately,during which time his dose of glargine was increased to 21 units nightly based on fasting blood glucose values of ∼ 120 mg/dl. His serum fructosamine was 231 umol/l.

Three months later, our patient underwent a left below-the-knee amputation for continued complications. Fasting blood glucose levels were between 99 and 140 mg/dl and ranged from 70 to 80 mg/dl during the remainder of the day. His serum fructosamine was 223 umol/l, and his A1C was 5.6%. Hematocrit was 27%. No changes were made to his regimen.

1. What factors affect the accuracy of the A1C measurement? What alternatives exist for the assessment of long-term glycemic control?

2. What are the indications for nateglinide?

3. What prompted the addition of basal insulin therapy? How does this complement the use of nateglinide?

Our patient presented with hyperglycemia postoperatively, which was likely secondary to the progressive loss of β-cells in the setting of early type 2 diabetes, as well as stress hyperglycemia from raised levels of counterregulatory hormones. These conditions were further exacerbated by the phenomenon of glucose toxicity, in which the hyperglycemia itself has a toxic effect on β-cell function.^1,2 When we met our patient, much of the stress surrounding surgery was resolving,and it was our hope that this treatment-naive patient may be a suitable candidate for oral therapy. He was initiated on therapy with nateglinide in an effort to primarily control his postprandial hyperglycemia, which had been prominent while hospitalized.

Postprandial hyperglycemia is caused primarily by an impairment in the early phase of insulin secretion after intake of a meal. This rise in blood glucose after a meal has been demonstrated physiologically to impair fibrinolysis, trigger the atherogenic process, and thus lead to increased cardiovascular risk in patients with type 2 diabetes. Indeed, studies have demonstrated that a 2-hour postprandial blood glucose is a better predictor of premature death than a fasting blood glucose.^3,4 

Early in the disease process, patients with type 2 diabetes exhibit impairment in their insulin secretory capacity, which is particularly challenged in the postprandial setting. Although oral agents such as metformin and thiazolidinediones effectively correct fasting blood glucose levels, they have less effect on blood glucose excursions that occur after a meal. Nateglinide is a rapid-acting secretagogue that augments this early phase of insulin secretion after food intake. The agent competitively binds to sulfonylurea receptors within the pancreatic β-cells to stimulate insulin release in a manner that is dependent on existing glucose levels. This mechanism of action thereby precludes the use of these agents either with or after sulfonylureas.⁴ 

Nateglinide is indicated as monotherapy in patients with type 2 diabetes who are treatment naive or in the early stage of diabetes, as well as those with only moderately elevated plasma glucose levels. It additionally is used with success in the elderly, given its low incidence of hypoglycemia, as well as after a period of glucose toxicity in which insulin was administered. The administration of nateglinide before a meal in patients with type 2 diabetes induces insulin secretion comparable to that seen with a bolus dose of insulin therapy. Often, however, insulin secretory reserves become diminished to the extent that basal insulin secretion is inadequate.⁴ 

Adequate basal insulin is essential to regulate glucose production via suppression of hepatic gluconeogenesis and by the stimulation of glucose uptake within the muscle and adipose tissue. Thus, the normal physiological pattern of insulin secretion consists of a sustained phase in which short bursts of insulin are superimposed during the course of the day to maintain adequate glycemic control after periods of food intake.²  Although metformin or thiazolidinediones may complement the use of nateglinide quite successfully by serving as a basal insulin component and thus controlling fasting blood glucose levels, the use of this medication was not possible in our patient. Although not officially indicated for use with nateglinide, the addition of the long-acting insulin glargine accomplished this goal quite effectively.

The treatment goal in all of our patients with diabetes is the prevention of short- and long-term complications. The U.K. Prospective Diabetes Study demonstrated a 25% reduction in the development of microvascular complications with tight blood glucose control, defined as the maintenance of an A1C value< 7%. Our aims for this patient were thus twofold: to control his postprandial glucose in an effort to decrease his cardiovascular risk profile and to lower his A1C in an effort to prevent microvascular complications.

The American Diabetes Association recommends the assessment of A1C values at least twice a year in patients who meet the A1C goal of < 7%, and at least four times a year in patients with fluctuating therapy or in those who have not yet met this goal. Although A1C is accepted as the gold standard assessment of glycemic control, it must be noted that its accuracy is questioned in patients with disorders that either shorten the life span of erythrocytes or those with increased blood cell survival. In these situations,relying on the average serum blood glucose levels and obtaining a serum fructosamine level may yield a more accurate assessment of glycemic control.⁵  Serum fructosamine, which represents primarily glycated albumin, yields an assessment of glycemic control over a period of 2-3 weeks. The assay is not standardized, and the measurement is inaccurate in patients with alterations in albumin secondary to nutritional status or liver or kidney disease.⁶  Our patient demonstrated multiple episodes of acute blood loss requiring transfusions. The additional measurement of fructosamine thus served as a useful adjunct to the assessment of his glycemic control.

• Nateglininde is effective in controlling postprandial hyperglycemia. It may be used as monotherapy or in conjunction with metformin or a thiazolidinedione. Postprandial hyperglycemia has recently been demonstrated to contribute to increased cardiovascular risk in patients with type 2 diabetes.

• Progression of type 2 diabetes and subsequent loss of insulin secretory reserves necessitates intensified therapy. In this case, nateglinide provided adequate bolus coverage, whereas glargine was later added to provide basal coverage. Though effective in this case, this use of nateglinide is not currently approved by the U.S. Food and Drug Administration.

• Our current gold standard of glycemic control, the A1C test, has recognized limitations in its diagnostic accuracy that must be taken into consideration in certain subgroups of patients. The assessment of average serum blood glucose and serum fructosamine may serve as a useful adjunct to the measurement of A1C.