Stewart G. Albert

Narrative Review: A Rational Approach to Starting Insulin Therapy

Tailoring insulin therapy to the blood glucose profiles of patients with diabetes is indisputably a rational strategy. Yet, with the advent of various insulin preparations, the pharmaceutical industry aggressively promotes products to fit the needs of most, if not all, patients with diabetes. Of note, the Diabetes Control and Complications Trial investigators used several different insulin regimens to achieve blood glucose control in patients with type 1 diabetes (1), a population generally more homogeneous in terms of underlying pathophysiologic characteristics than those with type 2 diabetes. Thus, the need for an individualized approach to insulin therapy in patients with diabetes cannot be overemphasized. Nevertheless, certain subgroups of patients with diabetes can be differentiated from each other according to the pattern of blood glucose changes during the day. Therefore, profiling these groups may help practitioners rationally choose a particular insulin regimen. The insulin regimen should subsequently be modified on the basis of the individuals response to therapy. We describe 3 common blood glucose profiles that represent typical patterns among patients with diabetes. On the basis of the blood glucose profile, we suggest an initial insulin regimen that would then be modified according to individual responsiveness. To prime the discussion, we briefly review the pharmacologic characteristics of currently available insulin products. This review is based on previously published manuscripts that were identified through a MEDLINE search (1996 to 25 February 2006) of English-language literature. The literature search was limited to core clinical journals that have accessible full texts, and the key phrase used was therapeutic use of insulin. A total of 420 manuscripts were reviewed, but only a select number are quoted to avoid repetitiveness and to adhere to space limitations. Individual references were chosen at the discretion of the authors. All authors independently reviewed the relevant available literature. This literature, along with our clinical experiences, was used to construct practical suggestions. Pharmacologic Characteristics of Currently Available Insulins There are several excellent reviews of the available insulin preparations (29). The pharmacokinetic variables of various insulins are summarized in Table 1. Regular human insulin peaks at 2 to 3 hours when given subcutaneously and has a variable duration of action that can range from 6 to 8 hours. Although regular insulin historically has been used to target postprandial hyperglycemia, its time-action profile is far from the physiologic pancreatic postprandial insulin burst. The advent of recombinant DNA technology has made it possible to improve the time-action profile of regular insulin. The structural modifications of these novel analogues are shown in Figure 1. Currently, there are 3 rapid-acting insulin analogues with similar pharmacokinetic profiles that are more suitable for targeting postprandial hyperglycemia: insulin lispro (Humalog, Eli Lilly, Indianapolis, Indiana), insulin aspart (Novolog, Novo Nordisk, Bagsvaerd, Denmark), and insulin glulisine (Apidra, Aventis Pharmaceuticals, Inc., Bridgewater, New Jersey). These insulin analogues are rapidly absorbed (< 30 minutes) after subcutaneous injection, peak at 1 hour, and have a shorter duration of action (3 to 4 hours) than regular insulin (1012). Furthermore, the intraindividual variability in time to maximum serum insulin concentration is clinically significantly less for rapid-acting insulin analogues than for regular human insulin preparations (1013). Table 1. The Pharmacokinetic Variables of Some of the Most Commonly Used Insulin Preparations* Figure 1. The structural modifications of insulin found in insulin analogues. = Insulin lispro differs from human insulin by the substitution of proline with lysine at position 28 and the substitution of lysine with proline at position 29 of the insulin chain. = Insulin aspart is designed with the single replacement of the amino acid proline by aspartic acid at position 28 of the human insulin chain. * = Insulin glulisine is designed with the substitution of the amino acid lysine with asparagine at position 3 of the human insulin chain and by substitution of the amino acid lysine at position 29 with glutamine. = Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and 2 arginines are added to the C-terminus of the chain. = Insulin detemir is designed to bind albumin in plasma after absorption. Threonine is omitted from position 30 of the insulin chain and replaced by myristic acid, a C14 fatty acid chain. Figure reprinted with permission from reference 2: Oiknine R, Bernbaum M, Mooradian AD. A critical appraisal of the role of insulin analogues in the management of diabetes mellitus. Drugs. 2005;65:325-40. [PMID: 15669878] The rapid-acting insulin analogues should be injected 5 to 15 minutes before a meal. However, in infants or in older adults with dementia who both have unpredictable eating patterns, rapid-acting analogues can be administered after the meal without excessive deterioration of glycemic control (14, 15). Intermediate-acting insulins, such as neutral protamine Hagedorn (NPH) or lente insulin, have a delayed onset of action ranging between 2 to 4 hours, can take approximately 6 to 7 hours to reach peak concentration, and can last up to 20 hours. This leads to a distinct peak-and-trough effect, and therefore, when used as basal insulin, 2 or more injections are often required each day to minimize the daily excursions of insulin levels. Recently, production of lente and ultralente insulins was discontinued because of their decreasing market shares. Long-acting insulin glargine has an onset of action of approximately 2 hours, reaches a plateau of biological action at 4 to 6 hours, and lasts up to 24 hours (9, 16). The timing of insulin glargine administration should be individualized, although it is minimally important as long as the insulin is administered at the same time every day (17). Compared with bedtime NPH insulin, insulin glargine is associated with less nocturnal hypoglycemia in patients with type 2 diabetes (28.8% vs. 12.6%, respectively; P= 0.011) (18, 19). If nocturnal hypoglycemia occurs after evening or bedtime administration of insulin glargine, the timing of the injection should be changed to the morning. Insulin detemir is another long-acting basal insulin analogue that is soluble at neutral pH. It has a unique mechanism of action (2023). After subcutaneous injection, insulin detemir binds to albumin through its fatty acid chain. At steady state, the variability in the concentration of free, unbound insulin is then greatly reduced, resulting in stable plasma glucose levels (2023). The duration of action of insulin detemir is approximately 20 hours at a dose of 0.4 U/kg of body weight (22). Insulin detemir is therefore administered twice daily in most patients. As with insulin glargine, insulin detemir has a more stable, less variable pharmacokinetic profile than does NPH. There are 2 premixed conventional insulins: Humulin 50/50 (Eli Lilly, Indianapolis, Indiana), which consists of 50% NPH and 50% regular insulin, and Humulin 70/30 (Eli Lilly) or Novolin (70/30) (Novo Nordisk, Bagsvaerd, Denmark), which consists of 70% NPH and 30% regular insulin. In some countries, additional premixed insulins with different proportions of NPH and regular insulin are available. Rapid-acting insulin analogues are also available in premixed preparations with rapid and intermediate insulin activity (Table 1). Self-mixing of insulin combinations in 1 syringe may be difficult for some patients and may result in errors of dosing. Fixed-mixed combinations may simplify the insulin regimen and reduce the number of daily injections. Three types of fixed-ratio insulin analogue mixes are currently available: Humalog mix 75/25 (Eli Lilly), a 75% insulin lispro protamine suspension with 25% insulin lispro; Humalog mix 50/50 (Eli Lilly), a 50% insulin lispro protamine suspension with 50% insulin lispro; and Novolog mix 70/30 (Novo Nordisk), a 70% insulin aspart protamine suspension with 30% insulin aspart. Conventional premixed human insulins have an onset of action of approximately 0.5 to 2 hours, usually plateau at 3 to 6 hours, and last up to 24 hours. Insulin analogue mixes have an onset of action of approximately 15 minutes, reach a peak biological action at 1 to 4 hours, and last up to 24 hours (24). Of note, there is clinically significant interindividual variability in the pharmacokinetics of insulin, and the profile often depends on the dose that is administered. However, the pharmacokinetics of insulin analogues have less intraindividual variability than human insulin. The availability of insulin analogues enhances flexibility and convenience for insulin-treated patients, and this increased flexibility in insulin timing is associated with an improvement in quality-of-life measures (25). The increasing variety of insulin preparations allows more opportunities to achieve control. The downside is the increased challenge facing health care providers in making the right choices in insulin therapy. Choosing the Insulin Preparation Protocols for insulin use depend on patient location, comorbid conditions, and available resources. All patients with type 1 diabetes require insulin therapy, whereas the indications for insulin therapy in patients with type 2 diabetes include symptomatic hyperglycemia, failure of oral therapy, pregnancy, acute illness necessitating surgery, acute myocardial infarction or cardiovascular surgery, and admission to an intensive care unit. The proper timing of initiation of insulin therapy, when oral agents are not achieving glycemic goals, depends on such variables as severity of hyperglycemia, economic and psychosocial circumstances of the patie

Thyroid dysfunction during chronic amiodarone therapy.

Clinical and laboratory features of 99 patients receiving long-term amiodarone therapy were analyzed to determine which individuals may be at a high risk for developing amiodarone-induced thyroid dysfunction. The group of 68 men and 31 women was followed up for an average of 27 months (range 3 to 60). There were no differences in age, sex, dose of amiodarone, type or severity of underlying heart disease or baseline serum thyroxine levels in patients who developed hypothyroidism (n = 32) or hyperthyroidism (n = 5) or remained euthyroid (n = 62). Baseline serum thyrotropin levels were statistically higher in patients who became hypothyroid, but there was considerable overlap with the other patient groups. Serum reverse triiodothyronine (reverse T3), which has been suggested to be a marker of amiodarone efficacy, correlated directly with serum thyroxine levels, and was not an independent variable. There was no pattern to the time course for development of thyroid dysfunction, which occurred in 49% of those followed up and developed as early as 1 month or, in one individual, as late as after 3 years of amiodarone therapy. There are few guidelines for replacement therapy in patients with amiodarone-induced hypothyroidism. L-thyroxine dosage was adjusted cautiously in these high risk individuals to achieve serum thyroxine levels within the reference range of euthyroid individuals taking amiodarone: the mean dosage required was 136 micrograms/day. Normalization of serum thyrotropin (TSH) would have required doses of L-thyroxine that were judged to be excessively high.(ABSTRACT TRUNCATED AT 250 WORDS)

Promoting diabetes self-management and independence in the visually impaired: a model clinical program.

Program Structure and Content A program has been developed at the St Louis University School of Medicine aimed at encouraging independence and improved self-esteem for the visually impaired individual with diabetes. This clinical program employs an integrated multidisciplinary approach to include ( 1 ) diabetes education focusing on the teaching of skills and devices needed by the visually impaired for diabetes selfmanagement ; (2) a monitored exercise program, individually tailored to accommodate visual, cardiovascular, and neurologic limitations; (3) group support with individual counseling as indicated; and (4) a prospective evaluation of measures of glucose control, exercise tolerance, and psychological adjustment. The program was initiated by several St Louis University diabetologists, and was designed through collaboration with consultants in the areas

Possible association between high-dose fluconazole and adrenal insufficiency in critically ill patients.

ObjectiveWhereas the antifungal azole ketoconazole interferes with steroidogenesis and can cause adrenal insufficiency, fluconazole in standard doses is thought to not interfere with cortisol production. The objective was to evaluate the effect of high-dose fluconazole therapy on adrenal function in critically ill patients in an intensive care setting. DesignDescriptive case reports. SettingMedical intensive care unit in a university hospital. PatientsTwo patients, a 77-yr-old man (case 1) with esophageal cancer and a 66-yr-old woman (case 2) with multiple organ failure developed reversible adrenal insufficiency temporally related to the institution and withdrawal of high-dose fluconazole. InterventionsShort cosyntropin (adrenocorticotropic hormone; ACTH) stimulation tests. Measurements and Main Results Two days after high-dose fluconazole in case 1, the serum ACTH level was 121 pg/mL (normal range is 9–52 pg/mL), and the peak cortisol after ACTH stimulation was 15.5 &mgr;g/dL (normal response is ≥18 &mgr;g/dL). Eleven days after discontinuation of fluconazole, the peak cortisol level after ACTH stimulation was 43.4 &mgr;g/dL. Twenty-four hours after high-dose fluconazole in case 2, an ACTH stimulation test had a low peak serum cortisol of 16.8 &mgr;g/dL. Fluconazole was withdrawn, and 5 days later, the peak stimulated cortisol was 20.6 &mgr;g/dL. ConclusionsAlthough fluconazole is the therapy of choice for patients in the intensive care setting with Candida infections, two patients with multiple organ failure who received high-dose fluconazole appeared to develop adrenal insufficiency. Although preliminary and anecdotal, these data suggest a need to further investigate the possibility that high-dose fluconazole might cause adrenal insufficiency in already compromised critically ill patients.

Vasopressin Response to Dehydration in Alzheimer's Disease

Alzheimers disease is a progressive deterioration of neuropsychological functioning. One of the main neuropathological correlates of the disease is a drop‐out of cholinergic neurons within the central nervous system. The neuropeptide that is responsible for water homeostasis and defense against dehydration, vasopressin, is also under direct cholinergic control. Several studies have suggested that in Alzheimers disease there has been a trend toward lower vasopressin levels than in age‐matched controls. In order to improve discrimination of normal from diminished vasopressin levels, nine subjects with Alzheimers disease (mean age 65 ± 2 years) and nine age‐ and sex‐matched controls (68 ± 3 years) underwent a mild provocative challenge of overnight fluid restriction. Individuals with Alzheimers disease had a greater degree of dehydration, with overnight serum osmolality of 313 ± 4 vs 300 ± 3 Mosmol/kg, P = .01, and diminished “thirst” as measured by water ingested in one hour of ad libitum water intake. Eight of the nine with Alzheimers disease had levels of vasopressin which, by extrapolation, appear to be subnormal for their serum osmolalities, whereas seven of the nine control subjects has vasopressin levels within or above the reference range (P < .05). Elderly individuals with Alzheimers disease may be at increased risk of dehydration during periods of fluid restriction due to the loss of normal physiological responses of “thirst” and vasopressin secretion.

Psychosocial Profiles in Patients With Visual Impairment Due to Diabetic Retinopathy

The psychological impact of vision loss due to diabetic retinopathy is compounded by the loss of diabetes self-management skills. The appropriate role and timing for rehabilitative intervention has not been determined. Twenty-nine individuals with diabetes mellitus, 16 with stable visual impairment and 13 with fluctuating and transitional visual impairment, underwent psychological assessment before and after entering into a specially designed rehabilitation program. Low levels of performance were demonstrated by the Rosenberg Self- Esteem Scale and the Diabetes Self-Reliance Test in both groups. The Minnesota Multiphasic Personality Inventory, the Zung Self-Rating Depression Scale, and the Rand Mental Health Index suggested that subjects with stable vision impairment were moderately compensated relative to the transitional group, although the former group may have been totally blind. Both groups demonstrated significant improvements in psychological profiles after the program. It is suggested that a rehabilitation program may be of clinical benefit early in the course of vision loss associated with diabetic retinopathy.

Testosterone therapy, association with age, initiation and mode of therapy with cardiovascular events: a systematic review.

Although male hypogonadism is associated with increased cardiovascular events (CVE), recent concerns are that testosterone supplementation may increase CVE. The purpose was to determine associations with age, initiation or mode of therapy to explain these discrepancies.

Glucagon-like peptide-1 response to acarbose in elderly type 2 diabetic subjects

The anti-hyperglycemic effect of alpha-glucosidase inhibitors (AGI) is partly attributed to their ability to stimulate the secretion of glucagon-like peptide-1 (GLP-1), a gut hormone with insulin stimulating capability. To determine if this mechanism of action contributes significantly to the therapeutic efficacy of AGI in the elderly, 10 type 2 diabetic subjects over the age of 65 years were given a standardized test meal with or without 25, 50, or 100 mg acarbose. The serum glucose, insulin, triglycerides and GLP-1 levels were measured at baseline and at 1 and 2 h postprandially. The anti-hyperglycemic effect of acarbose was maximal at 25-mg dose under these experimental conditions. Serum postprandial insulin and triglycerides levels were not significantly altered with acarbose treatment. The postprandial serum GLP-1 levels rose significantly only in two subjects and only during treatment with 100-mg acarbose. There were no significant correlations between serum GLP-1 and serum glucose or insulin levels. It is concluded that in most elderly type 2 diabetic subjects, maximal anti-hyperglycemic effects can be achieved with relatively small doses of acarbose and that GLP-1 is unlikely to contribute to the clinical efficacy of this agent in this subgroup of subjects.

Analysis of radiocontrast-induced nephropathy by dual-labeled radionuclide clearance

RATIONALE AND OBJECTIVES.This study was devised to develop a method of measuring the acute effects of radiocontrast media on renal function and assessing the relationship of the dose of radiocontrast media infused with the incidence of radiocontrast- induced renal failure. In addition, the drug adenosine phosphate-magnesium chloride (ATP-MgCl2) was evaluated as a renoprotective agent. METHODS.Eighteen patients with pre-existing renal impairment, (serum creatinine greater than 133 µmol/L) were randomized to receive a continuous infusion of ATP-MgCI2 or placebo before and during a radiocontrast procedure. Subjects were monitored with daily serum creatinine and with radionuclide renal clearance studies at baseline, during, and 24 hours after the radiocontrast procedure. RESULTS.There was an initial deterioration in renal clearance in the entire study group (from 44.2 ± 4.6 to 32.6 ± 3.9 mL/min, P = .001) which was independent of the dose of radiocontrast infused. There was a persistent deterioration in renal clearance only in those who received greater than 135 mL of contrast media (from 48.6 ± 7.8 to 37.1 ± 3.9 mL/min, P = .05). There also was an increase in serum creatinine that persisted only in those subjects who received greater than 135 mL of contrast media (230 ± 27 to 283 ± 44 ( µmol/L, P = .01). CONCLUSION.Persistent deterioration in renal function after radiocontrast administration appears to be dose-dependent and is not prevented by the use of ATP-MgCl2. Radionuclide techniques are useful in monitoring acute changes in renal function during radiocontrast procedures and may be of value in assessing renal impairment in future intervention studies.

Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Cohort.

OBJECTIVE The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial demonstrated similar long-term clinical effectiveness of insulin-sensitizing (IS) versus insulin-providing (IP) treatments for type 2 diabetes on cardiovascular outcomes in a cohort with documented coronary artery disease. We evaluated the effects of randomized glycemic control strategy (IS vs. IP) on the prevalence and incidence of diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS DPN (defined as Michigan Neuropathy Screening Instrument [MNSI] clinical examination score >2) was assessed at baseline and yearly for 4 years. DPN prevalence and incidence were compared by intention-to-treat modeling by logistic generalized estimating equation models for prevalence and Kaplan-Meier estimates and Cox regression models for incidence rates. RESULTS Results are reported for 2,159 BARI 2D participants (70% males) with valid baseline and at least one follow-up MNSI score (mean age 62 ± 9 years, mean HbA1c 7.7 ± 1.6%, diabetes duration 10 ± 9 years). There were no differences in the prevalence of DPN between the IS and the IP groups throughout the 4 years of follow-up. In 1,075 BARI 2D participants with no DPN at baseline, the 4-year cumulative incidence rate of DPN was significantly lower in the IS (66%) than in the IP (72%) strategy group (P = 0.02), which remained significant after adjusting for the in-trial HbA1c (P = 0.04). In subgroup analyses, IS strategy had a greater benefit in men (hazard ratio 0.75 [99% CI 0.58–0.99], P < 0.01). CONCLUSIONS Among patients with type 2 diabetes followed for up to 4 years during BARI 2D, a glycemic control therapy with IS significantly reduced the incidence of DPN compared with IP therapy and may add further benefit for men.