basal-bolus-insulin-therapy

1 Practical Tools for Glycemic Control in Type 2 Diabetes: Introducing Basal/Bolus Insulin Therapy An Educational Resource for the Primary Care Provider

Luigi Meneghini, MD Associate Professor of Clinical Medicine Director, Eleanor and Joseph Kosow Diabetes Treatment Center Diabetes Research Institute of the University of Miami School of Medicine

Ariel Zisman, MD Assistant Professor of Medicine Adult Endocrinology and Diabetes Diabetes Research Institute of the University of Miami School of Medicine

Authored By:

Practical Tools for Glycemic Control in Type 2 Diabetes:

Introducing Introducing Basal / Bolus Basal / Bolus Insulin TherapyInsulin Therapy

A Certified Continuing Medical Education Activity

2 Practical Tools for Glycemic Control in Type 2 Diabetes: Introducing Basal/Bolus Insulin Therapy

These should be exciting times in the field of diabetes care. Over the last decade, the num-ber of therapeutic alternatives and devices for the treatment of patients suffering from diabe-tes has expanded greatly. Sadly, the outcomes for our patients have not improved in parallel with these therapeutic advances. The magni-tude of the epidemic continues to rise, leaving a great number of patients exposed to the dev-astating complications of this disease. Part of the challenge of achieving and main-taining adequate blood glucose levels is not delaying measures to intensify glycemic con-trol to reach targets. As two endocrinologists practicing in a large academic center who are concerned with this situation, we present prac-tical strategies to simplify the advancement of glycemic therapy, focusing in particular on the use of physiologic insulin replacement for pa-tients with type 2 diabetes in whom insulin is indicated. These tools are simple, effective and directly applicable to the primary care setting, where most of these patients are cared for. We hope that this review will be a valuable re-source in assisting you with the daily task of getting your patients to target.


Learning Objectives:

Upon completion of this activity, participants should be able to:

• Discuss the rationale for improving metabolic control in type 2 diabetes • Understand why and how to advance diabetes therapy • Initiate insulin therapy in type 2 diabetes • Recognize the physiology of glucose homeostasis and physiologic insulin secretion • Differentiate basal insulin replacement from bolus therapy • Translate basal/bolus concepts into an insulin prescription for intensive therapy • Identify and address patient and physician barriers to intensive insulin therapy

Audience:

Primary-care physicians (internist and family practitioners) and other providers (nurse practitioners and physician assistants) in the United States that care for patients with diabetes. These providers will be identified through respective professional organizations and available physician databases.

Format:

This Continuing Medical Education (CME) activity is designed as Self-Study. This monograph includes detailed information about the progression of type 2 diabetes, basal/bolus insulin therapy, its implementa-tion and practical applications.

Needs Assessment:

This activity was developed to help educate participants on the benefits of basal/bolus insulin therapy with regards to type 2 diabetes mellitus.

Accreditation Statement:

The University of Miami School of Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to sponsor continuing medical education for physicians. This activity was planned and produced in accordance with ACCME Essentials. Date of original release August 4, 2004.

Educational Support:

The Diabetes Research Institute, University of Miami School of Medicine, gratefully acknowledges an unrestricted educational support grant for this activity from Novo Nordisk Pharmaceuticals.

Credit Hours:

Physicians: The University of Miami School of Medicine designates this continuing medical education activity for a maximum of 2.5 credits in Category 1 towards the Physicians’ Recognition Award of the American Medical Association This credit is available for the period of August 4, 2004 thru July 31, 2006, upon successful completion of the post-test.

General Information


Faculty Disclosure: The University of Miami School of Medicine, in accordance with accreditation requirements, will disclose any significant fi-nancial interest or other relationship with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in an educational presentation and with any commercial supporters of the activity. This disclosure is not intended to suggest or condone bias in any presentation but is made to provide participants with information that might be of potential importance to their evaluation of a presentation.

I. The following speakers may discuss commercial products or services and have financial interest or relation-ships with any manufacturer, commercial products, and/or provider of commercial services.

Luigi Meneghini, MD Speaker’s Bureau -Company(s)-Novo Nordisk Pharmaceutical, Aventis Research Grant(s) -Company(s)- Novo Nordisk Pharmaceuticals, Aventis, Eli Lilly, Glaxo-SmithKline, Pfizer Consultant - Company(s)-Novo Nordisk

Ariel Zisman, MD Speaker’s Bureau -Company(s)- Novo Nordisk Pharmaceuticals, Aventis Pharmaceuticals Consultant -Company(s)- Aventis Pharmaceuticals

II. Significant relationships exist with the following speaker / companies or organizations whose products or ser-vices will be discussed.

Luigi Meneghini, MD Receives or has received clinical research grant support from Novo Nordisk Pharmaceuti-cals Is a member of Speaker’s Bureaus of: Novo Nordisk Pharmaceuticals Is a consultant for: Novo Nordisk Pharmaceuticals

Ariel Zisman, MD Is a member of Speaker’s Bureaus of: Novo Nordisk Pharmaceuticals III. The following activity will not include off-label or investigational use of a product.

Applying for Continuing Medical Education (CME) credit: Upon completion of this self-instructional activity, the participant has the option of taking the post-test to qualify for continu-ing medical education credits. To apply for CME Credits, circle the appropriate responses on the answer sheet, complete the activity evaluation form on page 25, and send to:

Diabetes Research Institute University of Miami School of Medicine

1450 NW 10th Avenue, Suite 1081 (R-77) Miami, Florida 33136

Or by fax : 305-243-1200 Participants must obtain a score of 70% or more in order to qualify for continuing medical education credit. The Division of Continuing Medical Education will issue a certificate of participation upon successful completion of the post-test.

For additional information contact: Division of Continuing Medical Education, University of Miami School of Medicine

Telephone: 305-243-6716 Fax: 305-243-5613

Toll Free: 1-800-U-of-M-CME Email: [email protected] Website: http://cme.med.miami.edu

General Information


Introduction

Diabetes Mellitus is among the most common meta-bolic diseases affecting mankind. It has reached epi-demic proportions worldwide with a predicted 87% increase in prevalence between 1995 and 2010 and some estimates predicting over 300 million people affected with this disease by 20251,2. In the United States, the prevalence of the disease has increased by one third in the last decade fueled by increas-ingly sedentary lifestyles, the epidemic of obesity and the expansion of ethnic populations at risk for the disease. The impact of diabetes on human health and suffer-ing is enormous and needs to be confronted aggres-sively in terms of prevention and control. Diabetes is the 6th leading cause of death in the United States and a major contributor to the number one cause of death, cardiovascular disease. Diabetes is associated with a 2-4 fold increase in the risk of heart disease and stroke, and it carries a 5 to 10-year reduction in life expectancy. Diabetes is the leading cause of kidney failure, non-traumatic limb amputations, and blindness in adults. Alarmingly, fifty percent of newly diagnosed patients in the UKPDS (United Kingdom Prospective Diabetes Study) already had documented chronic complications of the disease4.

The direct and indirect costs of diabetes are stagger-ing. In the U.S., total costs attributable to diabetes were $132 billion in 2002 (Table 1) with some pro-jecting that these costs will reach ~$160 billion per year by 20106. Data is emerging that directly links metabolic control to real-time medical expenses. For example, in a large managed care organization

(MCO) the three year expense of caring for mem-bers with diabetes increased from $8,576 to $11,629 when comparing individuals with a base-line A1C of 6% vs. 10%, with over a 4-fold in-crease in these figures when concomitant hyperten-sion and heart disease were present5.

Intensive Glycemic Control: Examining the Evidence and

Rationale

The Diabetes Control and Complications Trial (DCCT) in type 1 diabetes, the UKPDS in type 2 diabetes, and other trials clearly demonstrated the benefits of improved glycemic control in reducing the microvascular complications of the disease7,8,9. In these studies, each 1% reduction in A1C trans-lated into a 20-30% relative risk reduction in neph-ropathy, retinopathy and neuropathy. A prospective observational analysis of the UKPDS cohort also demonstrated a statistically significant reduction in the risk for myocardial infarction (18%), stroke (15%), and diabetes-related deaths (21%) for each 1% reduction in A1C10. Data from these and other landmark studies have been used by professional groups to propose popu-lation-wide guidelines and treatment goals for the management of diabetes11,12. Whereas the American Diabetes Association (ADA) recommends a target A1C of less than 7%, with “action suggested” if this target is not met, both the American Association of Clinical Endocrinologists (AACE) and the Euro-pean Diabetes Policy Group have adopted even stricter guidelines, recommending an A1C goal of less than 6.5%, approximating the upper limit of normal (~6%) in individuals without diabetes (Table 2). In addition, a number of epidemiologic studies have demonstrated a significant increase in the prevalence of microvascular disease at glycemic levels barely above the upper limit of normal13. Thus, the trend is to intensify treatment to achieve and sustain the established goals which approxi-mate the non-diabetic level. To further prevent or reduce diabetes-specific vas-cular risk factors, aggressive management should be applied with particular attention given to blood

Condition Yearly Expense (billions)

Direct Medical Costs $91.8 Diabetes & Acute Glycemic Care $23.2

Chronic complications $24.5 General medical conditions $44.1

Indirect Medical Costs $39.8 Lost earnings due to premature death $21.6

Disability $18.2

Table 1: Annual Costs of Diabetes in the United States, 2002 (adapted from Diabetes Care 2003;26:917-932)


pressure and serum lipids. In the UKPDS each 10 mmHg reduction in systolic blood pressure was associated with reductions in the risk for mi-crovascular complications (13%), myocardial in-farction (11%), and death related to diabetes (15%)14. Blood pressure targets are currently de-fined as <130/80 mmHg for most patients, with lower levels indicated in selected high-risk pa-tients and those with nephropathy15. Serum lipids should follow the recommended goals defined by the Adult Treatment Panel III of the National Cho-lesterol Education Program, published in 200116. According to this report, diabetes is now classified as a coronary heart disease (CHD) risk equivalent and thus, the primary goal of therapy should be achieving LDL-C levels of less than 100 mg/dl. In the highest risk patient with documented cardio-vascular disease (CVD) evidence from recent trials supports an LDL-C reduction to less than 70 mg/dl17. In addition, secondary goals include triglyc-eride levels of less than 150 mg/dl, HDL-C greater than 40 mg/dl and 50 mg/dl (in men and women, respectively), and non-HDL-C of less than 130 mg/dl (or less than 100 mg/dl in patients with both

diabetes and CVD). These should be targeted once LDL-C goal is met (Table 3). Screening for microvascular disease should begin immediately after the diagnosis of type 2 diabetes, or 5 years after the diagnosis of type 1 diabetes, and performed annually. Patients should be re-ferred for dilated retinal exams, while screening of neuropathy and nephropathy have been simplified with point-of-care interventions, such as the use of a 10-gram monofilament and spot urine testing of albumin to creatinine ratio. These simple measures have a great impact on detection and prevention of complications that carry a great deal of morbidity, without requiring much time or effort during the routine medical contact with the patient. While most physicians are aware of and accept the current treatment goals for patients with diabetes made widely available by the American Medical Association (AMA) and the American College of Physicians (ACP), the majority of their patients fail to achieve and/or maintain these recommended targets. Data collected between 1988 and 1995 (before the advent of metformin or the insulin ana-logues) showed that less than half of all individu-als with diabetes achieved an A1C of 7% or less18. Despite a considerably larger therapeutic arma-mentarium, recently published data from a large MCO shows similar dismal outcomes. While the

frequency of annual testing for glycemic control (A1C), lipids (LDL) and blood pressure (BP) was

Measurement ADA AACE

A1C < 7% < 6.5%

Fasting/ pre-prandial

glucose (mg/dl) 90-130 < 110

Post-prandial glucose (mg/dl) <180 < 140

Bedtime glucose 100-140 100-140

Table 2 : Glycemic goals to reduce microvascular complica-tions

Lipid Measure Goal

LDL < 100 mg/dl <70 mg/dl with CVD

Triglycerides < 150 mg/dl

HDL > 40 (men) & > 50 (women) mg/dl

Non-HDL < 130 mg/dl <100 mg/dl with CVD

Table 3: Lipid goals for individuals with diabetes

Figure 1: Testing frequency and percentage achieving recommended targets for A1C, lipids and blood pressure (adapted from Beaton SJ. Diabetes Care 2004; 27: 694-698)


encouraging, the percentage of patients achieving A1C (37%), LDL-cholesterol (23%), and blood pressure (41%) targets were clearly suboptimal (Figure 1)19. Since the great majority of patients with diabetes receive their usual care from a primary care physi-cian (Figure 2), this monograph will focus on enabling these professionals to achieve best prac-tices and address the many frustrating barriers to care imposed by our current health care delivery system and culture.

Strategies for Advancing Glycemic Therapy

The results from UKPDS revealed the progressive nature of beta-cell loss in the natural course of type 2 diabetes. In this group of recently diag-nosed subjects who were followed for up to 20 years, the difference in median A1C between the conventional and intensive groups was only 0.9%. Moreover, excluding the initial 6 months follow-ing randomization, the yearly median A1C in both groups increased at a steady and parallel rate, re-flecting a progressive loss of blood glucose con-trol regardless of the type (sulfonylureas, met-formin, insulin) or intensity of the medical inter-vention (Figure 3). Although patient adherence to treatment recommendations could have played a part in the loss of glycemic control, intrinsic loss

of beta-cell function also emerges as a distinct possibility.

Insulin resistance appears very early in the natural history of type 2 diabetes, up to 20 years before the diagnosis is made. During this phase, blood glucose remains within the normal range because pancreatic beta-cells are able to secrete enough insulin to overcome peripheral insulin resistance. This period of hyperinsulinemia is often charac-terized by other features of the metabolic syn-drome, such as hypertension, dyslipidemia, and excess atherosclerotic risk. At some point in the course of the disease, possibly due to pre-programmed beta-cell failure and/or glycotoxic and lipotoxic effects, the insulin-secreting cells become unable to maintain sufficient insulin pro-duction to match the continued insulin resistance. The result is Impaired Glucose Tolerance (IGT), also known as the “pre-diabetic” period. The con-tinued decline in insulin secretion results in an elevation in post-prandial glucose followed shortly by fasting hyperglycemia. Although the diagnosis of diabetes can be documented at this stage, many patients do not come to medical at-tention until the hyperglycemia becomes sympto-matic. The decline in beta-cell function once hy-perglycemia is established, is variable but pro-gressive (Figure 4)21. This progressive loss of insulin secretory capacity has several therapeutic implications. Oral agents can be effective early on in the disease when there is sufficient endogenous insulin secretion avail-

Figure 3: Median A1C levels during the UKPDS (Reproduced with permission from: The Lancet 1998; 352:837-853. Copyright© 1998 Elsevier )

Figure 2: Physician training and diabetes management20

(adapted from US Department of Health and Human Ser-vices, Public Health Service, Centers for Disease Control and Prevention, National Center for Health Statistics, 2001 data. Data unpublished)


able. Over time, combination oral agent therapy is invariably required to maintain blood glucose control as beta-cell function continues to decline. Eventually, with deficient endogenous insulin supply, exogenous insulin therapy becomes an expected sequence in the proper management of type 2 diabetes.

The pharmacologic options to treat type 2 diabetes have greatly expanded in the last decade. Current therapies are designed to address several of the pathophysiologic defects that characterize this dis-ease, namely, insulin resistance, pancreatic beta-cell dysfunction and exaggerated hepatic glucose output. Sulfonylureas and meglitinides (insulin secretagogues) are designed to enhance endoge-nous insulin release. Thiazolidinediones (rosiglitazone and pioglitazone) act as insulin sen-sitizers in classic target tissues such as fat and skeletal muscle. Recent evidence suggests that these agents may also have a role in the preserva-tion of beta-cell function. The biguanide met-formin primarily acts by controlling hepatic glu-cose production, but has also shown a mild insu-lin-sensitizing effect. Exogenous insulin therapy actually targets several of these pathways by re-placing the endogenous hormone when deficient, by suppressing hepatic glucose production and by improving insulin resistance through reduction of the gluco- and lipotoxic effects on its own signal-ing. The alpha-glucosidase inhibitors (acarbose, miglitol) provide modest reductions in postpran-dial hyperglycemia by delaying intestinal absorp-

tion of ingested carbohydrates. Newer agents cur-rently under development (incretins) will draw on our evolving understanding of the entero-insular axis to potentiate endogenous insulin release and to suppress glucagon secretion and appetite. All of the available agents have unique potencies to lower glycemia and specific side effect profiles. Among the orally administered compounds, sul-fonylureas, metformin and thiazolidinediones (TZDs) have the greatest blood glucose lowering effect, whereas glitinides and alpha-glucosidase inhibitors are considered less potent. Insulin, on the other hand, is the most potent and effective agent available since it can be adjusted until gly-cemic goals are achieved. Insulin, as well as other agents that act by increasing the supply of insulin, is potentially associated with weight gain and hy-poglycemia. Metformin is associated with gastro-intestinal side effects (common) and lactic acido-sis (rare). Thiazolidinediones are associated with weight gain, fluid retention (common) and un-masking or worsening of congestive heart failure (infrequent).

.

Evolving Treatment

Algorithm for Blood Glucose Control

Based on the multiple therapeutic alternatives available for glycemic control and data emerging from post-marketing trials with these agents, we have developed a simple, but effective decision tree to optimize glycemic control in patients with type 2 diabetes (Figure 5). Prescriptions for meal planning and therapeutic lifestyle changes should be emphasized through-out the course of type 2 diabetes, given the sub-stantial benefits that have been documented in im-proving glucose, lipids, and blood pressure22,23. The decision to add the first, or even the second oral agent (OA) when A1C goals are not being met is rather straightforward, and the type of agent prescribed often depends on the current status of the patient (trying to match therapeutics to the prevailing pathophysiology) and the physi-cian’s preferences. The first difficult choice arises in a patient whose A1C levels are not at goal on two oral agents.

Figure 4: Progressive beta-cell failure in type 2 diabetes. (Reproduced with permission from: Diabetes 1995;44: 1249-1258. Copyright© 1995 American Diabetes Associa-tion. Diabetes)


A number of studies addressing this particular issue have helped provide some guidance in choosing whether to add the third oral agent or to initiate insulin therapy. In two such studies, the addition of a TZD in patients not at target on combination sulfonylurea and metformin, achieved a reduction in A1C of 0.9 – 1.3% after 6 months24,25. The percentage of participants achieving an A1C goal of less than 7% depended on the baseline A1C, with only 14% of patients reaching goal when mean baseline A1C was 9.7% and 42% when mean baseline A1C was 8.1%. Thus, it must be appreciated that for those pa-tients who will not significantly change their die-tary and exercise habits, and whose A1C is > 1.5% above their target A1C level, the addition of a third oral agent to combination therapy will likely fail to achieve target A1C. These are the patients that will benefit the most from the addi-tion of insulin therapy to achieve the recom-mended A1C goal and minimize diabetes related complications. This by no means intends to dis-courage the use of additional oral agents when the rationale is focused on alternative benefits, such as weight control, reduction of circulating mark-ers of endothelial dysfunction or delaying specific complications.

Indications for and Barriers to the Use of Insulin

Therapy in Type 2 Diabetes Insulin therapy remains the most potent alterna-tive available to control hyperglycemia, with a relatively low risk-to-benefit ratio (Table 4). The availability of novel analogue insulin preparations (aspart, lispro, glargine insulin) allow for near physiologic replacement of insulin needs and more predictable absorption kinetics, thus reduc-ing the frequency and magnitude of hypoglyce-mia, hyperglycemia and weight gain. Addition-ally, with few exceptions the insulin dose can be safely titrated up to achieve target glycemia, whereas the maximal dose of an oral agent is fre-quently limited by side effects and higher risk-to-benefit ratio. Thus, insulin therapy is more likely to be effective when treating glycemia to target. Finally, insulin therapy has proven to be safe when used in combination to existing oral treat-ments, allowing for simplification of regimens, particularly in the transition from oral agents to combination therapy with insulin.

The advantages of insulin therapy are based on its potency and effectiveness, as it can lower glyce-mia to a greater extent than any other therapeutic

Figure 5: Treatment algorithm for type 2 diabetes - allow a maximum of 3-6 months of therapy prior to advancing to the next step

Indications for Insulin Therapy

Patients who are not achieving treatment goals despite aggressive combination oral therapy – This is particularly important in patients whose en-dogenous beta cell reserve is limited, but should also be considered to reduce glucotoxic and lipotoxic ef-fects in poorly controlled diabetes

Patients with intolerance or who have contraindi-cations to the use of oral agents– Such as those with severe liver disease, advanced renal or heart failure, or those who are pregnant

Patients with recent-onset disease but with a pre-dicted early beta cell failure and insulinopenia – Such as those with GAD (Glutamic Acid Decarboxy-lase) positive antibodies or latent autoimmune diabe-tes of the adult (LADA)

Table 4: Indications for insulin therapy


option. In addition, it improves insulin sensitivity and probably reduces cardiovascular risks in this setting. All of these effects are often achieved with only modest increases in weight and with a low risk of severe hypoglycemia. Barriers to the use of insulin in type 2 diabetes can be classified as those that are patient-related and those related to the physician/provider or the healthcare system. Interestingly, most of the pa-tient-related concerns are raised by existing mis-conceptions, myths or lack of proper patient dia-betes education. The need to inject the drug and the associated perception of complexity, discom-fort, and lifestyle intrusion is among the major limitations. Patients also fear hypoglycemia, are concerned about weight gain, and often associate the use of insulin therapy with the onset of end-stage complications of the disease. In addition, patients often feel “guilty” for not being able to “avoid” the use of insulin, when after many years of threats by the provider they face the unavoid-able reality of insulin, now being used as a “last resort”. Many of these important issues, includ-ing lack of proper understanding of the treatment goals and the associated failure to intensify diabe-tes treatment when indicated, are amenable to proper patient education, optimized by the use of certified diabetes educators available in the com-munity and through diabetes centers of excel-lence. Patients that recognize the natural history of the disease will more readily accept the fact that, given time, exogenous insulin replacement is an expected modality in the long-term manage-ment of diabetes. The barriers related to the providers and the healthcare system may include similar fears of hypoglycemia, weight gain, as well as misconcep-tions about the possible promotion of vascular complications. Another challenge is the per-ceived complexity in the transition from oral ther-apy to insulin, combined with limited time to edu-cate the patient during a physician encounter (treatment goals, injection techniques, glucose self-monitoring, carbohydrate counting, trouble-shooting, etc.). Regrettably, primary care physi-cians who shoulder the majority of the burden for diabetes management in this country are the ones with the least “access” to essential resources such

as established networks of certified diabetes edu-cators and/or registered dietitians that are trained, and sometimes better suited, to provide specific diabetes education, and obtain reimbursement for these services. In addition insurers often enforce, through financial disincentives, limitations in therapeutic approaches creating substantial barri-ers and frustration for the physician attempting to practice best medicine. Unless these challenges are addressed in a collaborative and comprehen-sive manner by all stakeholders, the state of dia-betes management in this country will continue to be substandard. In the end, we should recognize the merits of insulin therapy in type 2 diabetes, and understand that delaying its use when indi-cated goes against providing the best medical care to our patients.

Initiating Insulin Therapy Once the decision to begin insulin therapy is made, the patient and physician need to determine which strategy is best suited to achieve treatment goals, while minimizing treatment-related side effects. In addition, thought should be given to making the transition acceptable to the patient, including consideration of how insulin therapy might impact lifestyle. In contrast to patients with type 1 diabetes who must accept full insulin replacement from the start, most patients on oral agents resist the idea of injecting insulin until convinced of the actual need for and the benefits of this therapy. Thus, there are major advantages in devising simple approaches that are both ac-ceptable and effective. A1C levels are determined by the combination of fasting and post-prandial blood glucose values. In diabetes, fasting hyperglycemia, in part, reflects unrestrained hepatic glucose output, while post-prandial hyperglycemia is a sign of insufficient beta-cell response to ingested carbohydrates. These two major determinants of blood glucose are somewhat interdependent. For example, fast-ing and pre-prandial hyperglycemia aggravate beta-cell dysfunction through “glucose toxicity” resulting in further sluggishness in the response of beta-cells to meal-related rises in glycemia. Simi-larly, inappropriately corrected glucose excur-sions following carbohydrate ingestion add to ex-


cessive hepatic glucose output and contribute to the non-prandial (including fasting) hyperglyce-mia. While numerous studies are emerging looking at various methods for adding insulin therapy to on-going treatment with oral agents, the debate at this point focuses on whether one should start by replacing only basal insulin needs or use pre-mixed insulin preparations to cover both basal and meal-related insulin requirements. Given that in type 2 diabetes fasting hyperglycemia is a ma-jor contributor to overall glycemic exposure26, and given the relative simplicity of initiating basal insulin replacement, our preference has been to begin with basal insulin replacement, and when needed, advance therapy by adding a rapid-acting component to cover post-prandial blood glucose excursions (Figure 5). On the other hand, a study presented at the 2004 meetings of the American Diabetes Association comparing a pre-mixed insulin analogue to insulin glargine as add-on therapy in patients not con-trolled with oral agents yielded some interesting results27. In this study, Raskin and colleagues showed more effective lowering of A1C over a 24-week period when biphasic (pre-mixed) insu-lin aspart (Novolog Mix® 70/30) given before breakfast and dinner was compared to insulin glargine administered once daily at bedtime (Figure 6). Specifically, 66% of the patients ran-domized to biphasic insulin aspart achieved the goal A1C of < 7%, while only 42% of those on insulin glargine achieved the same target. Unfor-tunately, the study design mandated that all pa-tients stop taking secretagogue agents (most likely sulphonylureas) and alpha-glucosidase inhibitors prior to assignment to either Novolog Mix® 70/30 or glargine therapy, leaving postprandial insulin needs unmet in the basal insulin (glargine) group, and thus creating a therapeutic disadvantage. Of note is that the group using the pre-mixed insulin analogue, used higher insulin doses than the pa-tients receiving insulin glargine (0.82 u/kg/day vs 0.55 u/kg/day, respectively), and had greater weight gain (5.4 kg vs 3.5 kg, respectively). The results of the Treat-To-Target Trial reported by Riddle and Rosenstock28 have provided a sim-

ple framework for initiating and adjusting basal insulin therapy in patients unable to achieve target A1C on oral agents. In this study, patients were continued on their oral agents and started on ei-ther NPH insulin or insulin glargine 10 units at bedtime, with weekly adjustments of the doses based on a titration algorithm (Figure 7).

The goal of the algorithm was to achieve fasting blood glucose levels under 100 mg/dl, while avoiding hypoglycemia. Over a 24-week titration period, A1C levels decreased from 8.6% at base-line to less than 7% in both the NPH and the glargine group, with a third of subjects achieving a fasting blood glucose under 100 mg/dl and 58%

Figure 6: Comparison of Pre-Mixed Insulin Analogue and Insulin Glargine in Patients Not Controlled on Oral Agents (adapted from Raskin P, et al. Diabetes 2004; 53 (suppl 2): A143)

Figure 7: Titration algorithm in the Treat-to-Target Trial (Reproduced with permission from: Diabetes Care 2003; 26:3080-3086 Copyright © 2003 American Diabetes Asso-ciation)


of all subjects achieving target A1C of under 7% (Figure 8). On average, patients were injecting between 42-47 units of insulin at bedtime and had gained 2.8-3.0 kg over the six months of the study.

Starting insulin replacement with one daily injec-tion of basal insulin and providing patients with simple instructions to adjust insulin doses to meet pre-defined fasting blood glucose goals is a sim-ple, effective, safe and patient-friendly strategy to initiating insulin therapy when combining it with existing oral therapy. Once patients are shown how to inject insulin, recognize and treat hypogly-cemia, and adjust insulin levels to meet target goals, they generally are much more receptive and willing to start or advance insulin therapy.

Patients that are able to achieve and maintain ap-propriate A1C levels can be continued on basal insulin therapy (plus oral agents). On the other hand, a number of patients will need to consider adding prandial or bolus therapy to achieve de-sired therapeutic goals. Based on Treat-To-Target Trial, over 40% of patients started on basal insulin replacement were unable to achieve an A1C < 7%. This group of patients could possibly benefit from the addition of fast-acting insulin to one or more meals. Patients attaining fasting blood glucose levels < 100 mg/dl, but with A1C levels persistently greater than 7% usually lack sufficient beta-cell responsiveness to control post-prandial hyperglycemia (target level < 160 mg/

dl). These individuals would also benefit from the addition of rapid-acting insulin. Other pa-tients on basal insulin replacement that should be considered for bolus therapy include those experi-encing nighttime hypoglycemia, daytime hypo-glycemia when meals are skipped or delayed, and those not achieving A1C goal despite attaining adequate fasting glucose. These situations often reflect over-reliance on basal insulin to cover de-ficient endogenous insulin response to meals (Table 5).

Adding Rapid-Acting Insulin to Basal Insulin Replacement As beta-cell function continues to deteriorate in type 2 diabetes, basal insulin replacement alone may not be sufficient to maintain adequate blood glucose control. At this point, the physician and patient need to consider adding a rapid-acting component to the therapeutic regimen. Two ac-ceptable options at this point are the use of pre-mixed insulin preparations or the addition of one or more pre-meal injections of rapid-acting insu-lin (Table 6).

The most common approach in primary care prac-tice has been the discontinuation of oral agents with the start of pre-mixed insulin formulations injected twice-daily . The rapid-acting compo-nent in the pre-mixed insulin attempts to cover the glycemic excursions related to breakfast and din-ner, whereas the protaminated component is aimed at providing coverage of the basal needs (between meals and overnight) and the glycemic load of lunch. While simple in application, this

Figure 8: A1C levels in the Treat-to-Target study (Reproduced with permission from: Diabetes Care 2003; 26:3080-3086 Copyright © 2003 American Diabetes Asso-ciation)

Indications for adding bolus insulin therapy

Patients attaining fasting blood glucose target (<100 mg/dl), but with A1C ≥ 7%

A1C ≥ 7% with evidence for frequent 2-hour post-prandial glucose values > 160 mg/dl

Patients experiencing nighttime hypoglycemia, or daytime hypoglycemia when meals are skipped or delayed

Table 5: Considerations for adding rapid-acting insulin to basal insulin replacement


approach has the disadvantage of providing lim-ited flexibility to the patient, with periods of ex-cessive insulin (leading to hypoglycemia) and pe-riods of insufficient insulin (and hyperglycemia) reflecting the profiles of the protaminated compo-nent. In addition, the timing and the content of meals need to be tailored to the dose and action profile of the pre-mixed insulin components, and this regimen often requires snacks to be eaten mid-morning and at bedtime to prevent hypogly-cemia induced by the peak in action of the pro-taminated insulin component, promoting weight gain.

The other option for adding bolus to basal insulin coverage is the administration of a rapid-acting insulin analogue before one or more meals, as needed to maintain 2-hour post-prandial blood glucose levels within the target range. This ap-proach allows the patient greater flexibility in terms of meal timing since the bolus is adminis-tered right before the meal is eaten. Even greater flexibility in terms of meal content can be pro-vided if the patient is willing and able to learn how to estimate the carbohydrate content of a meal and match it to a pre-determined insulin-to-carbohydrate ratio. Rapid-acting boluses can be started once a day to cover the meal with the highest post-prandial blood glucose values, and advanced to cover other meals if the need arises.

With regard to the concomitant use of oral agents, the decision to continue or stop specific medica-tions needs to be tailored to the individual situa-tion. As a rule, when at least two meals are cov-ered by rapid-acting insulin added to basal insulin replacement, insulin secretagogues (sulfonylureas and meglitinides) are no longer necessary for post-prandial glucose control. Metformin may be continued for its weight limiting effects. TZDs could be used for their potential non-glycemic benefits, as well as their insulin sensitizing prop-erties, as long as weight gain and fluid retention are carefully monitored. One significant progress in the application of meal-related insulin has been the development of insulin analogues. The newer rapid-acting ana-logues, aspart and lispro insulin, have a much shorter onset of action, achieve higher peak con-centrations in the bloodstream and display a shorter duration of action than human crystalline zinc (Regular) insulin. These rapid-acting ana-logues more closely match the prandial insulin secretion of the non-diabetic individual (Figure 9). The result is better control of post-prandial blood glucose peaks and reduced risk of hypogly-cemia occurring 3-6 hours following a meal bo-lus. Unless there are specific indications for the use of Regular insulin, such as cost constraints or delayed gastric emptying, rapid-acting insulin analogues should be the preferred insulin type for coverage of meal-related carbohydrates or rapid correction of hyperglycemia.

Insulin Brand name

Fast-acting Insulin

Component

Slow-acting Insulin

Component Novolin or Humulin Regular

Human Crystalline Zinc None

Humalog Lispro None

Novolog Aspart None

Novolin or Humulin 70/30 30% Regular

70% Protaminated

Regular (NPH)

Humalog 75/25 25% Lispro

75% Protaminated

Lispro

Novolog Mix 70/30 30% Aspart

70% Protaminated

Aspart

Table 6: Insulin preparations & components

Figure 9: Comparison of action profiles of rapid-acting ana-logues to regular insulin, superimposed on a normal insulin secretion curve.


Calculating Insulin Replacement Algorithms

There are various formulas that can be used to determine the initial dose of insulin. An easy rule of thumb is to start with 0.5 units/kg/day for the initial total daily dose (TDD) of insulin. Once this TDD is calculated it can then be easily dis-tributed among its various basal/bolus compo-nents.

When using pre-mixed insulin, rules for dosing have suggested that 2/3 of the TDD be adminis-tered before breakfast, and the remainder 1/3 of the dose be given before dinner. For example, a 120 kg male would start with a TDD of 60 units, of which 40 units are given before breakfast and 20 units are injected before dinner. Once a pre-mixed insulin schedule has been started, adjustments to the pre-mixed insulin dose should be based on the patient’s self-monitoring of blood glucose (SMBG) results, which are often available from the meter’s memory by manual review or download to a computer program. Pa-tients should be encouraged to both record their SMBGs in a log or diary and review them on a periodic basis, in order to better understand the variables affecting blood glucose control. This should enable them to implement, in consultation with their physician, appropriate changes in thera-pies. Patients who are testing their blood glucose levels before meals can also be provided with a supplemental scale of rapid-acting insulin to cor-rect for blood glucose readings above the estab-lished target range. This supplemental dose of insulin is intended to correct the prevailing blood sugars when they deviate from the established pre-meal targets and is given at the same time and in addition to the insulin estimated to cover the carbohydrate load of the meal. The correction ratio, or supplemental scale, can

be estimated using the same TDD of insulin. The calculation involves dividing either 1800 (if using a rapid-acting analogue preparation) or 1500 (if using regular insulin) by the TDD to estimate the predicted fall in blood glucose for each unit of rapid-acting insulin. In our example, one unit of Novolog or Humalog should lower the blood glu-cose level by 30 mg/dl. Therefore, for every 30 mg/dl that the patient’s pre-meal blood glucose is above the target range, another unit of Novolog or Humalog is added to the insulin amount the pa-tient is to inject before his/her meal.

For patients on pre-mixed insulin regimens who find it difficult to add a correction dose of rapid-acting insulin, either because of difficulty in mix-ing two types of insulin in a syringe or because they use an insulin pen, we often give them a sup-plemental scale using the same pre-mixed insulin. We calculate that for every unit of additional rapid-acting insulin that would normally be pre-scribed to correct hyperglycemia, they should use 2-3 units of the pre-mixed formulation (Table 7). Although there is no data supporting the use of a pre-mixed supplemental scale, we have had good results applying this concept in our practice.

TDD = Weight in kilograms x 0.5 units/kg/day

A 120 kg (264 lbs) person would require an esti-mated total of 60 units of insulin per day (120kg

x 0.5 u/kg/day)

Correction ratio (supplemental scale) = 1800 ÷ TDD

1800 ÷ 60 = 30 mg/dl fall in BG per unit of

Novolog or Humalog

Blood Glucose (mg/dl)

Rapid-Acting Analogue

Supplement

Pre-mixed Analogue

Supplement < 120 0 0

121-150 1 2-3 151-180 2 4-6 181-210 3 6-9 211-240 4 8-12 241-270 5 10-15 271-300 6 12-18

> 300 7 14-21 Table 7: Correction (supplemental) scales for a pre-meal blood glucose target of < 120 mg/dl using either rapid-acting analogue (Novolog or Humalog) or a pre-mixed ana-logue insulin (Novolog Mix 70/30 or Humalog 75/25). The above scales are based on the example in the text assum-ing a 30 mg/dl fall per unit of rapid acting analogue.


Basal/Bolus Insulin Replacement

With the advent of more physiologic insulin therapies, improved monitoring technologies and more effective delivery tools, physiological re-placement of insulin in the insulin deficient indi-vidual with diabetes is rapidly becoming the gold standard for blood glucose management. This approach should be the standard of care in all in-dividuals with type 1 diabetes and should strongly be considered in the approach to the patients with type 2 diabetes not achieving recommended gly-cemic goals on their current therapies. The first step in using a basal/bolus approach to insulin therapy involves understanding the physi-ology of glucose homeostasis and insulin secre-tion. Very simply, the two main sources for plasma glucose are endogenous (hepatic glucose output or HGO) and exogenous (carbohydrate in-take through the gut). The beta-cells of the pan-creas respond to glucose entry from these two sources by both secreting a nearly-constant supply of insulin (basal insulin) over a 24-hour period and by releasing bursts of insulin (bolus insulin) when glucose enters the circulation from food in-take. Hepatic glucose output results from glycogenoly-sis (breakdown of stored glycogen into glucose) and gluconeogenesis (production of glucose from non-glucose precursors such as lactate, alanine and glycerol), and is under the control of both in-sulin (suppresses HGO) and counter regulatory hormones (increase HGO) such as glucagon, epi-nephrine, cortisol and growth hormone. HGO ensures a steady glucose supply to the brain and other tissues in the absence of food intake. Al-though the production of glucose from the liver is relatively constant, there are circumstances that can affect the amount of glucose released in the circulation. Stress, illness, trauma, and infections, by increasing counter regulatory hormone levels, can result in increased HGO and therefore in-creased insulin requirements. About one third of individuals with diabetes experience an increase in HGO in the early morning hours (Dawn phe-nomenon) largely due to the higher levels of

growth hormone and cortisol at that time. Exogenous glucose on the other hand is mostly a result of the conversion of ingested carbohydrates to glucose in the gut with subsequent absorption into the circulation. Although different types of carbohydrates may have different rates of absorp-tion (glycemic index), it appears that the total amount of carbohydrate ingested (versus the type) ultimately determines the post-prandial glycemic excursion and subsequent insulin response.

The basal/bolus need for insulin is analogous to physiologic insulin secretion. Insulin is con-stantly secreted by beta-cells to match corre-sponding HGO, whether an individual is eating or not. During meals an appropriate amount of insu-lin is bolused into circulation by beta-cells de-pending on the ingested carbohydrate (glucose) load. Physiologic insulin replacement involves the ad-ministration of insulin therapy using an approach that takes into consideration both basal insulin requirements (to match HGO) and bolus insulin replacement (to match carbohydrate ingestion and if needed to correct an elevated blood glucose). While in someone with type 1 diabetes (absolute insulin deficiency) both basal and bolus insulin replacement are mandatory, patients with type 2 diabetes not controlled on oral agents may at first require only basal insulin replacement for control of their fasting blood glucose. With time, as their beta-cell deficiency progresses they will require the addition of rapid-acting bolus insulin replace-ment to control post-prandial hyperglycemia. In any case, once the algorithms for basal/bolus in-sulin replacement have been calculated, basal or both basal and bolus insulin therapy can be imple-mented according to the specific needs of the pa-tient.

Example:

The beta-cells of a 70 kg individual will produce approximately 24 units of insulin per day and secrete about 1 unit of insulin for every 10 grams of ingested carbohydrates


Practical Tools for Implementing a

Basal/Bolus Regimen

Similar to our previous discussion, the first step in formulating the appropriate algorithms for basal/bolus insulin replacement involves determining the estimated total daily dose of insulin (TDD). The TDD is the full insulin requirement (consisting of both basal and bolus insulin amounts) that an individual needs in order to maintain normoglycemia. The TDD amount will be used to determine the rest of the basal/bolus insulin prescription. We use the TDD to estimate the basal insulin dose, as well as the pre-meal in-sulin dose for carbohydrate coverage and the cor-rection (supplemental) insulin dose in case of pre-prandial hyperglycemia. Finally, we need to set a pre-prandial blood glucose target that the patient will use in order to calculate the corrective insulin component of the bolus. Basal insulin replace-ment is best done with long-acting (>20 hours), usually peakless insulin types, while bolus insulin needs are best met by rapid-acting insulin ana-logues. The TDD can be estimated using a person’s cur-rent weight in kilograms and multiplying that weight by an insulin sensitivity index. For exam-ple, a very insulin sensitive individual (child or thin elderly) may require 0.2-0.3 units/kg/day, a very insulin resistant person (pubertal child, insu-lin resistant type 2) may need 1.0-1.5 units/kg/day and a normal weight adult usually requires 0.4-0.7 units/kg/day. For simplicity we recommend using 0.5 units/kg/day as a default since this amount approximates the need of adults with type 1 dia-betes and individuals with type 2 diabetes who are also on other oral anti-glycemic agents. We will base the calculations for the ensuing discussion on a patient that weighs 60 kgs (132 lbs).

Next we calculate the basal insulin replacement dose. This usually represents half of the TDD.

The dose will then need to be distributed appro-priately to match HGO. In over 2/3 of cases this will mean a constant, predictable amount of insu-lin with minimal peaks of activity. Either insulin glargine or rapid-acting insulin delivered at a con-stant rate by an insulin pump are good choices. The best measure to determine whether the basal insulin dose and distribution are appropriate is to have the patient skip a meal (or preferably two meals) or fast for a period of time. The blood glu-cose level should remain within a 30 mg/dl range while the patient is not ingesting any calories, but is replacing basal insulin as prescribed.

The other half of the TDD will be used to cover carbohydrate intake during meals. The pre-meal bolus of insulin usually incorporates both cover-age for ingested carbohydrates and a supplemen-tal amount of insulin if the pre-meal blood glu-cose is above target. The meal-related component of the bolus can be calculated as a fixed insulin amount via a simple (but less flexible and precise) method or can be given as a variable dose via an insulin-to-carbohydrate ratio (more flexible, but more complex). The insulin-to-carbohydrate ratio (CHO ratio) requires patients to estimate the quantity of carbohydrates they plan on ingesting with the meal. To use this system patients need to be able to recognize which foods contain carbo-hydrates and how many carbohydrates are in spe-cific volumes or weights of foods. Although more complex, using a CHO ratio allows patients more flexibility in their food choices. To calculate the estimated fixed amount of pre-meal insulin, take the other half of the TDD and divide it into three meals per day. This approach assumes that if a patient is planning on eating a meal, the carbohydrate content of that meal is more or less constant (fixed). The pre-meal dose should be administered if the patient plans on eat-ing the meal, or should be withheld if the patient decides to skip the meal. This approach is also well suited for managing diabetes in the in-patient setting.

Example:

A 60 kg person would require 30 units of insulin per day

Basal insulin dose = TDD ÷ 2

30 units ÷ 2 = 15 units per day


To calculate a CHO ratio the TDD is used in a formula that was originally derived from the ex-perience gained from insulin pump management. The formula estimates the amount of carbohy-drates (in grams) covered by one (1) unit of insu-lin, by dividing a constant value by the TDD. This constant is 500 if a rapid-acting insulin ana-logue is used (Novolog or Humalog) or 450 if Regular insulin is used.

To calculate the correction ratio (supplemental scale) the TDD is also used (as was described above). The formula estimates the expected fall in blood glucose (in mg/dl) for one (1) unit of in-sulin, by dividing a constant value by the TDD. This constant is 1800 if a rapid-acting insulin ana-logue is used (Novolog or Humalog) or 1500 if Regular insulin is used as the bolus insulin.

The final step in deriving the pre-meal bolus amount is giving the patient a pre-meal target blood glucose level (Table 8). This practice can-not be overemphasized. Patients consistently do

better if the goals of therapy are clearly explained and specific targets are discussed.

If the pre-meal blood glucose is below the estab-lished target level, the patient will only cover meal-related needs. If on the other hand the blood glucose is elevated, then the bolus will consist of both the meal-related insulin dose plus a supple-mental dose of insulin to lower the blood sugar to target levels. The bolus dose may need to be adjusted if the pa-tient is planning to engage in physical activity within 3 hours from the bolus. We usually rec-ommend that the calculated bolus be halved if the exercise is of moderate or greater intensity and if it will last 30 minutes or more. Checking blood sugars before and after exercising will be very useful in determining the actual needs of an indi-vidual patient.

Concluding Remarks

We have attempted to present a simple and thoughtful rationale for the implementation of in-sulin therapy in patients with type 2 diabetes. The algorithms presented in this monograph are meant to provide guidelines to the treating physician for initiating and advancing insulin therapy in the ap-propriate candidates. Once insulin therapy is be-gun, additional adjustments in doses and algo-rithms may be required and should be based on each individual’s response to therapy, as reflected by their self-monitoring results. We are confident that the application of these practical strategies in the primary care setting will facilitate the achievement of recommended glyce-mic targets and translate into considerable im-provement in the health and well being of patients with diabetes.

Fixed pre-meal dose = 1/2 TDD ÷ 3

15 units ÷ 3 = 5 units before each meal

For Novolog or Humalog

CHO ratio = 500 ÷ TDD

500 ÷ 30 ≅ 17 grams of carbs covered by 1 unit of insulin

Basal/Bolus Insulin Prescription using example in text (TDD of 30 u/day)

♦ Lantus insulin 15 units a day

♦ Novolog or Humalog insulin 5 units before each meal

♦ Novolog or Humalog insulin 1 unit for every 60 mg/dl above target

♦ Pre-meal blood glucose target < 120 mg/dl

Table 8: Basal/Bolus Insulin Prescription for case presentation

For Novolog or Humalog

Correction ratio = 1800 ÷ TDD

1800 ÷ 30 ≅ 60 mg/dl fall in blood glucose per 1 unit of insulin

Example using fixed pre-meal insulin bolus:

The patient has a pre-meal target glucose of 120 mg/dl. He is planning on eating his usual meal and correcting a blood glucose of 240 mg/dl. He is using Novolog insulin as his bolus insulin. He would therefore take 5 units as the set meal coverage plus 2 additional units to drop his blood glucose from 240 mg/dl to 120 mg/dl.


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References


Post Test

Credit will be awarded to those providers who read the monograph, complete the post-test and evaluation. Each ques-tion has only one answer. Any question you leave blank or record more than one answer will be marked as incorrect. You must score 70% or above (9 or more correct answers) , and complete the evaluation to receive credit. Your test and evaluation will be documented at the CME Department at the University of Miami School of Medicine. Your score will be mailed to you along with the correct answers, and a certificate. There is no fee for participation.

1) What percentage of patients with type 1 diabetes receive their usual care from a primary care physician? a. 5-10% b. 25-30% c. 50-55% d. 75-80%

2) In the UKPDS, what percentage of patients with recent-onset type 2 diabetes already had a documented complication of diabetes? a. 10% b. 25% c. 50% d. 75%

3) To reduce the risk of vascular complications, the American Diabetes Association recommends achieving and maintaining an A1C under 7%. Historically, the majority of patients in the USA failed to achieve this goal. However, with the advent of new oral therapies and new insulin analogues our ability to improve glycemic control has been enhanced. In a recent survey of individuals with diabetes enrolled in large MCO, what percentage of patients achieved an A1C <7%? a. 22% b. 37% c. 55% d. 72%

4) Diabetes is now considered a cardiac risk equivalent. Based on this new classification of vascular risk it is recommended that in patient with diabetes without documented vascular disease LDL cholesterol be low-ered to under 100 mg/dl. a. True b. False

5) In the UKPDS the intensively treated group achieved a lower median A1C than the conventionally treated cohort, with a concomitant reduction in microvascular disease risk. Which statement is true regarding gly-cemic control in the two treatment groups? a. The conventionally treated group required more insulin b. The rate of loss of glycemic control was similar in the two groups c. Patients treated with metformin had greater preservation of beta cell function d. Patients treated with insulin had more cardiovascular events than those treated with sulfonylureas

6) A 56 year-old patient with type 2 diabetes and minimal microvascular complications on glyburide 10 mg QD and metformin 1000 mg BID for over 6 months presents with an A1C of 9.2%. Which change would most likely achieve the target A1C? a. Increase glyburide to 10 mg BID and increase metformin to 2500 mg a day b. Maximize both oral agents (as described in “a”) and add pioglitazone 30 mg a day c. Maximize both oral agents (as described in “a”) and add rosiglitazone 4 mg BID d. Start basal insulin replacement (NPH or insulin glargine) 10-15 units at bedtime


The rest of the questions that follow will be based on the following clinical vignette. A 62 year-old male with a history of type 2 diabetes for 18 years is admitted to the hospital for an elective cardiac cath-erization scheduled for the next morning. He is currently using human insulin 70/30 for blood glucose management. He injects 30 units in the morning and 20 units before dinner. His most recent A1C is 7.8%. He experiences occa-sional hypoglycemia (no severe episodes) when lunch is delayed or during the night. The patient weighs 220 pounds (100 kg) with a BMI of 32. His other medications include simvastatin, enalapril and a baby aspirin.

7) Upon admission to the hospital you decide to switch him to basal/bolus insulin replacement to facilitate insulin management. Calculate his total daily dose (TDD) of insulin based on either his weight or current insulin prescription. a. 100 units a day b. 75 units a day c. 50 units a day d. 25 units a day

8) Based on his calculated TDD, what is the correct dose of basal insulin? Assume you will be using insulin glargine for basal insulin replacement. a. 50 units a day b. 35 units a day c. 25 units a day d. 15 units a day

9) Assume you will start him on a fixed dose of a rapid-acting insulin analogue to cover meal related needs. What is the approximate dose of Novolog or Humalog you would prescribe before each meal? a. 4 units b. 8 units c. 10 units d. 12 units

10) The patient would like to be given an insulin-to-carbohydrate ratio in order to have greater flexibility with regard to meal content once he is discharged. Assuming you will be using either Novolog or Humalog insulin as the bolus insulin, calculate the correct insulin-to-carbohydrate ratio. a. 1 unit of insulin will cover 8 grams of carbohydrates b. 1 unit of insulin will cover 10 grams of carbohydrates c. 1 unit of insulin will cover 12 grams of carbohydrates d. 1 unit of insulin will cover 15 grams of carbohydrates

11) Next you need to calculate the patient’s correction ratio (supplemental scale). Again assuming you will be using Novolog or Humalog insulin as the bolus insulin, what is the approximate correction ratio (fall in blood glucose per 1 unit of rapid-acting insulin)? a. 40 mg/dl b. 60 mg/dl c. 80 mg/dl d. 100 mg/dl

The patient is now on a basal/bolus regimen as prescribed following the preceding calculations. While in the hospital he will be injecting Novolog insulin before each meal based on the fixed dose you previously calculated and the blood glucose level prior to the meal. You have determined that his blood glucose targets should be < 120 mg/dl before meals or < 180 mg/dl if the patient is fasting for a procedure.

12) You have placed orders on the chart to keep the patient NPO after dinner. At bedtime the nurse checks the patient’s blood glucose and reports to you a value of 260 mg/dl. Which of the following is the correct action at this time? a. Hold the bedtime Lantus insulin since the patient is NPO b. Give 2 units of Novolog insulin to correct the hyperglycemia c. Give 4 units of Novolog insulin to correct the hyperglycemia d. Give the Lantus, but do not give any supplemental Novolog insulin


13) The next day the cardiac catherization is performed and the patient is scheduled to eat his dinner that eve-ning. His blood glucose before dinner is 200 mg/dl. What is the correct bolus dose at this time? a. No bolus should be given b. Administer 2 units of Novolog before dinner c. Administer 8 units of Novolog before dinner d. Administer 10 units of Novolog before dinner


Basal-Bolus Calculator Card:

The practical strategies to achieve and maintain glycemic control using the basal/bolus insulin replace-ment approach have been compiled into a small, pocket-size card presented below. It describes step-by-step how to estimate the total daily dose of insulin, as well as the basal and meal-related components applied to an individual patient. Please cut out, take it with you and try it out in your daily practice.

Algorithm Worksheet for Basal/Bolus Insulin

Therapy

1) Revised total daily dose of insulin (TDD) (a) Total amount of insulin the patient is currently injecting =______

(b) Current weight in kilograms x 0.5 units/kg/day:= ______ (or weight in pounds x 0.23 units/lbs/day)

Revised TDD is a + b ÷2= ______

2) Basal insulin dose (use glargine or NPH) TDD ÷ 2 = ______

3) Insulin coverage for each meal (use Novolog, Humalog, or Regular) TDD ÷ 6 = ______ 4) Corrective insulin ratio or supplemental scale (use Novolog or Humalog)

1800 ÷ TDD = ______ 5) Pre-meal blood glucose target = ______

1450 NW 10th Avenue Miami, Florida 33136 305-243-1062


Algorithm Calculations for Basal/Bolus Insulin Therapy

1) First, estimate the patient’s total daily dose of insulin (TDD) a. Add up the total amount of insulin the patient is currently inject-

ing on a day to day basis b. Multiply the patient’s weight in kilograms (or pounds ) by 0.5

units/kg/day (or 0.23 units/lbs/day ) c. If the patient is using insulin take the average of a and b: the

result is the patient’s revised TDD, which you will use for the rest of your calculations

2) Second, calculate the basal insulin dose. You will have to distribute this dose over a 24-hour period (basal insulin includes glargine or NPH) a. TDD ÷ 2 = basal insulin dose

3) Third, calculate the fixed insulin dose for each meal (bolus insulin includes Novolog, Humalog or Regular) a. TDD ÷ 6 = pre-meal insulin dose

4) Fourth, calculate the corrective insulin ratio (supplemental scale) a. 1800 ÷ the TDD = fall in blood glucose per 1 unit Novolog or

Humalog b. 1500 ÷ the TDD = fall in blood glucose per 1 unit Regular insulin

5) Finally, give the patient a pre-meal blood glucose target (usually less than 120 mg/dl for tight blood glucose control)

1450 NW 10th Avenue Miami, Florida 33136 305-243-1062


Please submit your completed post-test and evaluation form via mail or fax. To mail, please send to the Diabetes Research Institute, 1450 NW 10th Avenue, Suite 1081 (R-77), Miami, FL 33136; or fax to 305-243-1200. You must score 70% or above (9 or more correct answers) , and complete the evaluation to receive credit. Your test and evaluation will be docu-mented at the CME Department at the University of Miami School of Medicine. Your score will be mailed to you along with the correct answers and a certificate. There is no fee for participation. Questions or additional information: Contact the Division of Continuing Medical Education at 305-243-6716; toll-free: 1-800-U-OF-M-CME; email: http://cme.med.miami.edu.

After reading this monograph I am able to: Strongly Agree Agree Disagree Strongly

Disagree Recognize the metabolic goals for patients with type 2 diabetes 1 2 3 4

Identify appropriate candidates for insulin therapy 1 2 3 4

Understand how to initiate insulin therapy, starting with basal insulin re-placement 1 2 3 4

Translate basal/bolus concepts into an insulin prescription for intensive therapy 1 2 3 4

Identify and address patient and physician barriers to intensive insulin ther-apy 1 2 3 4

Overall Effectiveness Information was applicable to my practice 1 2 3 4

I gained a clearer understanding of diabetes management 1 2 3 4

Overall quality of material was good 1 2 3 4 Discussion of prevailing information was balanced and avoided commer-cial bias 1 2 3 4

Topics I would like to see included in future CME activities: __________________________________________________________________________________________________________________________________________________________________________________________________________

Additional comments, suggestions: __________________________________________________________________________________________________________________________________________________________________________________________________________

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This activity is supported by an unrestricted educational grant from Novo Nordisk Pharmaceuticals , Inc.

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