Diabetes Management in Primary Care

Authors: Unger, Jeff

Title: Diabetes Management in the Primary Care Setting, 1st Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > 4 - Managing Type 2 Diabetes in Adults

4

Managing Type 2 Diabetes in Adults

Take Home Points

• Screening for type 2 diabetes (T2DM) in low-risk individual should be performed at 3-year intervals beginning at age 45. High-risk patients who have a normal fasting blood glucose level should undergo a 75-g, 2-hour glucose challenge test to determine whether they have diabetes or a prediabetic state.

• Patients at high risk for diabetes developing can benefit from adopting lifestyle changes that may reduce their risk of progressing to T2DM by 58% over a 3-year period.

• Surgery for clinically severe obesity provides a potential for cure in patients with T2DM. Candidates for surgical correction of obesity should have the risks and benefits of any procedures evaluated by a specialty team of healthcare providers.

• T2DM is a progressive disease characterized by insulin resistance (IR) and reduced pancreatic beta-cell insulin production.

• Excessive plasma levels of free fatty acids contribute to IR, nonalcoholic steatohepatitis, and pancreatic beta-cell death.

• The treatment of patients with T2DM should be individualized. However, safely achieving a targeted A1C of 6.5% or less should be the goal for the majority of patients.

• Metformin should be considered the cornerstone therapeutic agent for nearly all patients with T2DM. The drug is inexpensive, well tolerated, efficacious and has positive metabolic effects beyond simply improving hyperglycemia.

• Thiazolidinedione (TZD) use should begin early in the course of diabetes treatment. TZDs improve insulin sensitivity, hyperglycemia, and pancreatic beta-cell function. Lipid profiles, vascular dynamics, inflammatory markers, fibrinolysis, blood pressure, ovulation, and endothelial cell function are all positively affected by TZD therapy.

• Newly diagnosed patients with T2DM in whom symptoms related to hyperglycemia have recently developed may respond positively to a high-dose challenge of sulfonylurea given over a period of 2 to 4 weeks.

• Therapies that combine the pharmacologic actions of two different drug classes are preferred to monotherapy, especially early in the course of the disease. Patients who are unable to maintain an A1C level 7% or less with oral hypoglycemic agents should be aggressively managed by adding an incretin mimetic or initiating insulin therapy.

• T2DM is not a mild form of diabetes. Physicians should screen high-risk patients for this disease, initiate aggressive treatment immediately after the diagnosis is confirmed, and advance the therapeutic interventions as needed to maintain as near normal A1C levels as possible to prevent long-term diabetes-related complications.

• Remember: A patient with an A1C of 7.1% has not been treated to target. A normal A1C is considered to be 6%. Always strive to treat a patient as close to the norm as possible while attempting to minimize weight gain and hypoglycemia.

Case 1

Mrs. Chung is 58 years old and appears for her annual physical examination. She has no specific complaints but is concerned about possibly having diabetes because of her family history. Both parents had type 2 diabetes, and one of her three sisters was diagnosed with type 1 diabetes just last year at age 45. Mrs. Chung's medical and surgical histories are unremarkable, except for having had three C-sections. (One of her babies weighed 10 pounds at birth.) Six years ago, Mrs. Chung entered menopause but has never used any hormone replacement therapy. She works as a bank executive, exercises 3 days a week at a ladies' fitness center, and denies use of both nicotine and alcohol. Over the past 6-month period, she has been using a Chinese herbal vitamin to combat the occasional fatigue she feels after eating lunch, her largest meal of the day.

Summarized below are the results of the patient's most recent physical examination and laboratory studies compared with those performed 1 year previously:

On reviewing the laboratory studies with Mrs. Chung, the physician notes that the fasting plasma glucose level is more than 100 mg per dL, suggesting that the patient has impaired fasting. This prediabetic condition places her in a high-risk category for future development of diabetes and cardiovascular disease.¹ Her lipid profile has shifted to an atherogenic profile with the elevation in triglycerides and reduction in high-density lipoprotein cholesterol (HDL-C). The triglyceride/HDL-C ratio has increased more than 3.5, which is a marker for insulin resistance (IR).²

Because Mrs. Chung is considered high-risk (Asian American, plus a family history of diabetes, and has an atherogenic lipid panel), a 2-hour postglucose challenge test is performed. At her follow-up appointment, she is informed that her 2-hour postglucose challenge level was 237 mg per dL, and her point-of-service A1C test is 7.6%. Her high sensitivity C-reactive protein (hs-CRP) level was 2.2 mg per dL (normal, <2 mg per dL). Other laboratory values, including her thyroid studies, urinalysis, liver panel, and complete blood count (CBC), were all normal.

The physician explains that Mrs. Chung has newly diagnosed T2DM. After being counseled on diabetes, she is asked to join the American Diabetes Association (ADA). Although she is already doing some light exercise, Mrs. Chung will eventually need to increase the frequency of her exercise to 5 days per week. The patient's 10-year Framingham Risk Score is only 4% (http://hp2010.nhlbihin.net/atpiii/evalData.asp). However, CRP may be a stronger predictor of cardiovascular events than the low-density lipoprotein cholesterol (LDL-C) conveyed by the Framingham risk score.³ Therefore, the patient will be scheduled for a graded exercise stress test before being allowed to increase the frequency, intensity, and duration of her exercise.

A dietary prescription is provided, which suggests limiting the patient's fat intake to 30% of total calories. Less than 5% of the caloric intake should come from saturated fat, with the remaining 25% coming from monounsaturated and omega 3 polyunsaturated fat sources. Although her body mass index (BMI) is only slightly above the recommended level of 25 kg per m², caloric restriction and weight reduction are not necessary. Focus should be placed, instead, on weight maintenance.

Mrs. Chung wants to know if she has type 1 diabetes (T1DM) or T2DM. Because the patient has a primary relative with T1DM, a glutamic acid decarboxylase (GAD) antibody screening study was performed, which was negative, indicating that she does not have autoimmune T1DM (see Chapter 5).

The nurse provides her with a blood glucose meter and then explains how to obtain the blood sample and perform the test properly. Mrs. Chung is asked to begin testing fasting and at bedtime on the first 7 days of each month and to bring her meter in with her at each visit for data downloading. The physician recommends that she begin taking low-dose aspirin daily as well as metformin. Because she is older than 40, a statin also is prescribed. Finally, Mrs. Chung was invited to attend the monthly diabetes classes, which are provided free of charge through the medical group's medical education department.

Introduction

Type 2 diabetes is a metabolic disorder characterized by abnormalities at multiple organ target sites, including the pancreatic beta cells, skeletal muscles, adipose tissue, and liver. The hyperglycemia characteristic of T2DM develops slowly over time as the pancreatic beta cells fail to produce insulin in response to a glucose stimulus. The resulting elevated plasma glucose levels become cytotoxic, leading to the loss of beta cell function and mass.

In the United States, 6.3% of the population (18 million individuals) have diabetes, with estimates between 90% to 95% having T2DM.⁴ Approximately 90% of patients with diabetes are managed by primary care physicians (PCPs), many of whom have had little education in screening for, diagnosing, and managing this complicated metabolic disorder.⁵ Successful management of T2DM requires an understanding of the pathophysiology of IR, a strategy to promote lifestyle modifications, surveillance for identifying and preventing long-term diabetes-related complications, knowledge of intensive pharmacologic interventions, and professional skills for providing patient education. Pursuing an aggressive approach to diabetes management can lead to positive treatment outcomes as well as to improvement in the quality of life for these patients.

Screening for and Diagnosing Type 2 Diabetes

Screening for diabetes should be performed by a health care provider at 3-year intervals beginning at the age of 45 years, particularly in patients with a BMI of 25 kg per m² or greater.^6,7 The ADA discourages screening for diabetes in a nonmedical environment because patients with positive findings may not be provided with appropriate follow-up instructions, repeated testing, or care. Screening should be performed at a younger age and more frequently if other risk factors for diabetes are present, as listed in Table 4-1.

The easiest way to screen for diabetes is by obtaining a fasting plasma glucose (FPG) level. A FPG of 126 mg per dL or more is an indication for retesting on a different day to confirm the diagnosis of diabetes. When the FPG is less than 126 mg per dL and a high index of suspicion exists for diabetes based on the patient's risk factors, a 2-hour postchallenge glucose test should be administered on an alternate day. Two hours after consuming a 75-g glucose drink, a blood glucose level is obtained. A level above 140 mg per dL indicates that the patient has abnormal glucose homeostasis (Fig. 4-1).

Plasma glucose levels also may be obtained from patients who have eaten before testing. Patients who have a casual plasma glucose level of 200 mg per dL or more and who have symptoms of diabetes should be considered

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Prevention of Type 2 Diabetes by Using Diet, Exercise, and Pharmacologic Interventions

Both genetic and environmental factors contribute to the development of T2DM. Specific at-risk population groups have a high prevalence of T2DM, as do individuals with an afflicted first-degree relative. The most dominant determinant in the development of diabetes appears to be one's BMI.⁸ An estimated 65% of Americans have a BMI of 25 kg per m² or more and are thus labeled overweight by U.S. standards.⁹ The direct relation between obesity and the increasing prevalence to T2DM suggests that lifestyle interventions for weight reduction and improvement in physical activity participation could slow or prevent the progression from normoglycemia to prediabetes and beyond. Weight reduction and physical activity can improve insulin-mediated glucose disposal, reduce postprandial hyperglycemia, delay beta-cell death (apoptosis), and slow the progression of glucose intolerance to T2DM.^10,11 Table 4-3

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The most comprehensive clinical trial that evaluated the importance of lifestyle modification as a deterrent to diabetes was the Diabetes Prevention Program (DPP).¹² This $174 million National Institutes of Health (NIH) study

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DPP subjects were randomized into one of three treatment arms: (a) intensive individualized lifestyle intervention with the aim of reducing weight by 7% through low-fat diet and exercising 150 minutes per week, (b) treatment with metformin (850 mg twice daily), or (c) a standard group taking placebo pills in place of metformin. The metformin and placebo groups also received information about the importance of diet and exercise. A fourth arm of the study, using troglitazone combined with standard diet and exercise recommendations, was discontinued in June 1998 because of the potential for liver toxicity. DPP participants ranged in age from 25 to 85 years, with an average of 51 years. On entry into the trial, all had IGT, as measured by an oral glucose tolerance test, and all were overweight, with an average BMI of 34 kg per m².

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Lifestyle intervention worked as well in men and women as well as in all ethnic groups irregardless of their baseline BMIs.¹¹ In subjects older than 60 years, lifestyle intervention reduced the progression to diabetes by 71%. Metformin was not as effective as lifestyle intervention in reducing diabetes risk in the population older than 60 years or in those who were less obese.

Diets that include mono- or polyunsaturated fatty acids may alter the composition of membrane phospholipids and improve insulin sensitivity. Specific dietary patterns that are high in fruits, vegetables, and whole grains and low in red or processed meat, sugars, and high-fat dairy products also appear to reduce the risk of T2DM.¹¹

Physical activity improves insulin sensitivity independent of its effect on weight loss or improvement of fat distribution.¹³ A study of Pima Indians showed that the incidence of T2DM, as determined by oral glucose tolerance testing, was lower in more active individuals regardless of their BMI.¹⁴

Although lifestyle intervention might be useful in preventing or reducing diabetes risk, the adaptation of interventional strategies may be expensive or unacceptable to certain ethnically, socially, and culturally diverse populations. To that end, pharmacologic interventions have also been found to delay or prevent diabetes in the short term. The DPP demonstrated that metformin reduced the incidence of diabetes by 31% in comparison with placebo. However, metformin was less effective in patients with lower fasting glucose levels who were not obese. Metformin has been shown to improve insulin sensitivity in obese adolescents.¹⁵

High-risk Hispanic women with a history of gestational diabetes who took troglitazone were able to preserve the pancreatic beta-cell function and prevent T2DM, as demonstrated in the TRIPOD study.¹⁶ While being monitored for an average of 30 months, these subjects also received dietary and exercise counseling. Troglitazone reduced the annual incidence of T2DM to 5.4% versus 12.1% of women treated with placebo. The 50% reduction in the annual incidence of T2DM was dependent on an initial improvement in insulin sensitivity and reduction in glucose-stimulated insulin production from the beta cells. Although the protective effects of troglitazone on beta-cell function were effective for 8 months after the discontinuation of the drug, persistence of the improved beta-cell status has not been consistently demonstrated.¹⁷ The TRIPOD study does suggest that using an insulin-sensitizer drug such as a TZD early in the course of diabetes successfully rests beta cells, thereby preserving and prolonging beta-cell responsiveness to future hyperglycemic challenges.

The use of acarbose has been shown to reduce the incidence of T2DM by 25% over a 3.3-year period compared with placebo, regardless of age, sex, or BMI.¹⁸ However, unlike treatment with troglitazone, the beneficial effects of acarbose stopped as soon as the drug was discontinued. In addition, subjects in the trial experienced significant gastrointestinal (GI) side effects from the study drug, which limits its clinical usefulness.

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Small reductions in body mass may reduce the potential of T2DM developing in high-risk individuals. Orlistat, a gastrointestinal lipase inhibitor, reduces dietary fat absorption by approximately 30% and provides a pharmacologic means of promoting weight loss. The XENDOS study¹⁹ showed that orlistat plus lifestyle changes resulted in a 37% decrease in progression toward T2DM in patients with IGT.

Type 2 diabetes can be prevented or delayed by pharmacologic agents that affect glucose metabolism and facilitate weight loss (Table 4-4). In addition, drugs that do not directly affect weight or glucose management may delay the onset of T2DM (Table 4-5). Hypertensive patients are at almost 2.5 times higher risk of developing T2DM in comparison with normotensive individuals.²⁰ Several studies that evaluated cardiovascular outcomes in hypertensive patients treated with angiotensin-converting enzyme (ACE) inhibitors,^21,22 calcium channel blockers,^23,24 and angiotensin II receptor agents (ARBs)²⁵ noted a reduced incidence of new-onset T2DM. The Heart Outcomes Prevention Evaluation (HOPE) trial demonstrated that the ACE inhibitor ramipril reduced the incidence of macrovascular and microvascular complications in hypertensive individuals with and without T2DM.²¹ Post hoc analysis of 5,720 HOPE trial participants with vascular disease but without diabetes at study entry, followed up for a mean of 4.5 years, had a 40% reduction in the diagnosis of T2DM compared with placebo-treated patients.

Similar results were reported in the Captopril prevention project (CAPPP)²² and Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).²⁴ Although many clinical trials with antihypertensive agents have reported a positive effect on T2DM prevention, other investigations have not shown any benefit with similar drugs in delaying the onset of diabetes.^20,26 Thiazide diuretics and beta blockers may confer an increased risk of T2DM.^20,23 Speculations as to why ARBs and ACE inhibitors appear to reduce the risk of diabetes progression are listed in Table 4-6.

The Diabetes Reduction Assessment with Ramiprial and Rosiglitazone Medication (DREAM) study followed 5,269 subjects with IFG or IGT (prediabetes) for 3 years, evaluating their development of diabetes, death, and regression to normoglycemia. Participants were randomized to receive either placebo or ramipril 15 mg per day or to receive placebo or rosiglitazone 8 mg per day. The rosiglitazone cohort demonstrated a 60% reduction in the primary outcome of progression to diabetes or death compared with those given placebo and a 62% reduction in the rate of diabetes development alone. The DREAM trial investigators suggested that for every 1,000 people treated with rosiglitazone for about 3 years, 144 cases of diabetes will be prevented and 200 people with prediabetes will progress to normoglycemia. Although rosiglitazone may be associated with a slight increase in the risk of heart failure, especially in individuals with diastolic dysfunction, this study did suggest that patients with either IFG or IGT can benefit from chemoprevention. Although not FDA approved for use in treating prediabetes, TZDs should certainly be scrutinized as a therapeutic agent in patients at high risk for diabetes progression.^26a,b

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Statins may have beneficial effects on reducing progression to T2DM in addition to their lipid-lowering action. The West of Scotland Coronary Prevention Study (WOSCOP) reported a 30% reduction in new-onset T2DM in subjects treated with pravastatin.²⁷ The Heart Protection Study, however, demonstrated no difference in new-onset T2DM between subjects treated with simvastatin and placebo.²⁸

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Women with known coronary artery disease who were given hormone replacement therapy demonstrated a lower incidence of T2DM progression over a 4-year period in comparison with placebo-treated women in the Heart and Estrogen/Progestin Replacement Study (HERS).²⁹ However, hormone replacement therapy is not indicated for T2DM prevention because of an unfavorable risk of thrombolic disease developing.

Although one may infer a positive benefit on cardiovascular risk for patients using ACE inhibitor drugs or ARBs, their direct effect on delaying progression to diabetes might be questioned. Uncertainty exists with the ARBs and ACE inhibitors as to whether these drugs actually prevent new-onset diabetes or if the comparator drugs (beta-blockers and thiazide diuretics) are responsible for increasing the risk of diabetes. Long-term prospective clinical trials, such as NAVIGATOR, are necessary to address this issue.

The NAVIGATOR trial (Nateglide and Valsartan Impaired Glucose Tolerance Outcomes Research),³⁰ currently under way in 40 countries, will evaluate the use of the short-acting secretagogue nateglinide (Starlix) and ARB valsartan (Diovan) in preventing T2DM and cardiovascular events in patients with IGT. Subjects (ages 50 years and older) in the NAVIGATOR trial will have at least one cardiovascular risk factor as well as IGT. Of the 9,000 participants, 25% will be randomized to receive nateglinide, 60 mg TID, with valsartan, 160 mg daily; 25% will receive nateglinide and placebo; 25%, valsartan and placebo; and 25% will receive only placebo. Lifestyle-intervention strategies will also be evaluated in all groups. Patients will be advised to reduce their fat and caloric intake, exercise 150 minutes per week, and target a 7% baseline weight reduction if overweight. The study is scheduled to conclude in 2008. However, NAVIGATOR is an event-driven trial in that the study will not conclude until 1,374 subjects have at least one major adverse cardiovascular event such as acute myocardial infarction, acute coronary syndrome, stroke, hospitalization for heart failure, renal failure, or require coronary revascularization.

One of the most interesting statistics that has emerged from the NAVIGATOR trial involves the screening process that is used before randomization. Of the 9,000 subjects screened who had existing cardiovascular disease, 24% had unrecognized diabetes, and 30% had IGT. This suggests that the prevalence of unrecognized impaired glycemia is quite prominent in patients with cardiovascular disease.

Prevention and Reversal of Type 2 Diabetes with Surgical Intervention

Clinically severe obesity is defined as a BMI greater than 40 kg per m² or a BMI greater than 35 kg per m² in the presence of a serious comorbid condition such as hypoventilation, sleep apnea, diabetes, hypertension, cardiomyopathy, or musculoskeletal dysfunction. A BMI more than 40 kg per m²

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Approximately 40,000 bariatric operations are performed annually in the United States, primarily with the goal of reducing the comorbidities associated with clinically severe obesity.³⁶ The four main surgical procedures include the vertical band gastroplasty, roux-en-Y gastric bypass, biliopancreatic diversion, and adjustable silicone gastric banding.³³ The most popular procedure is the roux-en-Y gastric bypass, which produces weight reduction by restricting caloric intake (because of the reduction in the patient's gastric capacity) and inducing anorexia or early satiety. Gastric bypass operations may result in a 42% baseline weight reduction maintained for 11 years postoperatively.³⁷

Bariatric surgery may play a role in reducing one's risk of T2DM developing. A nonrandomized clinical trial consisting of 136 subjects with IGT and severe obesity (>45 kg excess body weight) were followed up for 2 to 10 years.³⁴ Of the 109 of these individuals who underwent bariatric surgery, in only one did diabetes develop, whereas in 6 subjects in the control group, diabetes developed. The authors concluded that surgical intervention in the severely obese, high-risk patients reduced the progression from IGT to diabetes by more than 30-fold.

The exact mechanisms for improvement in glycemia after gastric bypass surgery are uncertain. The resolution of diabetes after bariatric surgery is independent of weight loss alone, and exclusion of the foregut appears to play a necessary role. Excessive food intake in subjects with diabetes is thought to result in the production of incretin-antagonist hormones, leading to glucose intolerance and dysregulated insulin production.³¹ Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released from the small intestines in response to a mealtime stimulus. Once released, the incretin hormones reduce blood glucose levels in a glucose-dependent fashion (significant postprandial hyperglycemia triggers a greater incretin hormone response to re-establish normoglycemia). Patients with T2DM are GLP-1 deficient.³⁸ Gastric bypass may normalize GLP-1 levels, improving beta-cell response to an oral glucose or protein stimulus.

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Rapid presentation of nutrients into the more distal gut, as occurs after bariatric surgery, may also induce the production of pro-insulin hormones similar to GLP-1. GIP and GLP-1 have been noted to be elevated for 20 years after gastric bypass surgery.³⁹

Complications reported by bariatric surgery centers suggest a mortality rate of 1% and an early postoperative complication rate of 10%.⁴⁰ Postoperative complications include gastrointestinal leak, deep venous thrombosis, bleeding, anastomotic stricture, incisional or internal hernia, marginal ulceration, vitamin and protein malnutrition, gallstone formation, and wound infections. The more adept a surgeon is at performing gastric bypass procedures, the fewer complications the patient experiences.⁴¹ Postoperative patients must be evaluated frequently for deficiencies in calcium, iron, thiamine, folate, and B¹².

The majority of patients with T2DM (83%) or glucose intolerance (99%) will experience normalization of glucose, A1C, and insulin levels after bariatric surgery.⁴² Maintenance of normal metabolic parameters as well as persistence of weight loss has been described at 10 to 14 years after bypass surgery.⁴³ No randomized clinical trials have been performed to compare the benefits of intensive lifestyle intervention with the effects of bariatric surgery in improving glycemic control in clinically severe obese patients. However, surgery for clinically severe obesity provides a potential for cure in patients with T2DM and should be considered in all severe obese individuals with diabetes. Table 4-7 lists the indications for bariatric surgery.

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Case 2

This 45-year-old female patient was seen for her initial office visit with a 13-year history of diabetes. She was insulin-naive and had been taking Glucovance 5/500 twice daily over the previous 2-year period. Her baseline A1C was 9%, and she was symptomatic, complaining of urinary frequency, recurrent vaginitis, blurred vision, and fatigue. Her comorbidities included hypertension, proteinuria, hypothyroidism, and atherogenic dyslipidemia. She weighed 119 kg and had a BMI of 42 kg per m². Because her A1C was greater than 8.5% and she was symptomatic, the patient was started on a basal-bolus insulin regimen with preprandial lispro plus bedtime lantus. As soon as insulin therapy was initiated, the patient experienced a significant weight gain, requiring increasingly higher doses of insulin. The weight gain continued despite starting insulin pump therapy, exercising 5 days per week, and attending monthly diabetes education classes. Within 3 months of starting insulin, her A1C decreased to 7.2%, but her weight increased by 18 kg. Figure 4-3A demonstrates the severity of the IR she experienced while pumping more than 150 units of insulin daily.

After the patient's weight peaked at 144 kg with insulin pump therapy, she was referred for a bariatric surgical consult. The patient successfully completed a comprehensive presurgical evaluation and underwent a laparoscopic adjustable gastric-banding procedure. Ten months after her successful surgery, the patient recorded a weight loss of 47 kg. Her BMI decreased to 29.5 kg per m². Considerable improvement in metabolic parameters such as A1C, lipids, hypertension, and proteinuria were also noted at 9 months after surgery (Fig. 4-3C, chart). Figure 4-3B shows the improvement in her glucose levels after gastric bypass surgery.

The patient continues to use an insulin pump, with her basal rate reduced by 80% compared with her presurgical parameters. She provides bolus insulin based on her meal carbohydrate content. As a result of successful medical and surgical management of diabetes, her A1C has decreased from 7.7% before surgery to 5.7% 9 months after surgery.

Fifty percent to 70% of children and adolescents who are obese carry their obesity into adulthood, thus increasing their risks of developing serious and life-threatening conditions. This astounding risk increases to 80% if just one parent is obese.⁴⁴ Behavioral-therapy approaches to weight reduction have

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Pathogenesis of Type 2 Diabetes

Type 2 diabetes is characterized by hyperglycemia, IR, and relative impairment of insulin secretion. The clinical features associated with T2DM are based on genetic and environmental influences. Whether an individual remains euglycemic or advances toward the hyperglycemic pathway is ultimately determined by the ability of one's pancreatic beta cells to produce and secrete enough insulin to maintain normoglycemia.

The Cellular Mechanisms That Impair Insulin Secretion and Promote Insulin Resistance

The hallmark of the metabolic dysfunction associated with T2DM includes a reduction in insulin secretion as well as altered insulin action, resulting in hyperglycemia. Unlike autoimmune type 1 diabetes (T1DM), the progression to T2DM occurs over a period of from 7 to 10 years (Fig. 4-4). In the prediabetes states of impaired fasting glucose (IFG) and IGT, pancreatic beta cells excrete increasing amounts of insulin in an attempt to maintain normal glycemia. The higher insulin output is accompanied by reduced insulin activity in the liver, adipose tissue, and skeletal muscles, resulting in diminished intracellular glucose disposal. A further decline in beta-cell insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting and postprandial hyperglycemia. Patients proceed through a spectrum of abnormal glucose states, including IFG and IGT, until ultimately progressing to diabetes. At the time one is initially diagnosed as having T2DM, less than 50% of the beta-cell mass remains functioning⁴⁶ (Fig. 4-5).

Several hormones (insulin, glucagon, amylin, leptin, epinephrine, resistin, GLP-1, and adiponectin) must interact in unity to maintain a normal metabolic environment. Insulin plays a crucial role in modulating the metabolism of fats and protein while being the primary regulator of cellular uptake and the use of glucose. Insulin regulates glucose homeostasis in the liver, skeletal muscle, and adipose tissue.⁴⁷

An elevated plasma free fatty acid (FFA) level antagonizes insulin action and is the cornerstone of IR, reduced beta-cell response to hyperglycemia, and beta-cell apoptosis. Animal studies suggest that beta-cell failure and death are preceded by an increase in plasma FFAs, accompanied by an accumulation of triglyceride within the beta cell^48,49,50 (Fig. 4-6).

IR is characterized by a reduction in the ability of insulin's target tissues (skeletal muscle cells, adipocytes, and hepatocytes) to promote glucose

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Peroxisome proliferator activated receptors (PPARs) also play an important role in IR. When activated by prostaglandins and leukotrienes, PPAR-

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IR may be the best predictor of future T2DM risk. The likelihood that a patient has IR can be assessed by calculating the ratio of one's plasma triglycerides to HDL-C. A level greater than 3.5 is strongly associated with IR² (Case 1).

Insulin secretion and insulin sensitivity are interrelated. In T2DM, insulin secretion initially increases in response to IR, to maintain normal blood glucose regulation. At first, the insulin secretory defect is mild and selectively involves glucose-stimulated insulin secretion. Over time, insulin secretion deteriorates and becomes inadequate in response to glucose stimulation. Chronic hyperglycemia paradoxically impairs beta-cell function and leads to worsening hyperglycemia. Improvement in glycemic control and weight reduction is often associated with improved beta-cell function.⁵³

Insulin Resistance: The Link to the Hepatocyte

Endogenous insulin produced and secreted by the pancreatic beta cell regulates hepatic glucose production.⁵⁴ The amount of glucose released from the liver determines one's fasting (basal) plasma glucose level. Insulin directly inhibits glycogenolysis (the conversion of hepatic stored glycogen to glucose) and gluconeogenesis (the synthesis of glucose from noncarbohydrate sources).

Glucagon is secreted from the pancreatic alpha cells located around the periphery of the islet in response to a hypoglycemic trigger. The protective mechanism of glucagon activates hepatic gluconeogenesis and glycogenolysis, thereby raising ambient glucose levels. When released from the adrenal glands in response to stress or a threat, epinephrine also induces glycogenolysis.

Gluconeogenesis occurs primarily in hepatocytes, and to a smaller degree in the kidneys, to ensure that skeletal muscles, the central nervous system, and the heart all have an adequate supply of glucose as an energy source.

A doubling of insulin secretion in a nondiabetic individual reduces hepatic glucose production by 60%, effectively shutting down glycogenolysis. Higher levels of insulin secretion begin to inhibit gluconeogenesis.⁵⁵

As prediabetes progresses toward beta-cell failure, the reduced levels of circulating plasma insulin can no longer inhibit glucogenesis or glycogenolysis. As blood glucose levels can no longer be maintained within the range of 70 to 140 mg per dL, postprandial and fasting hyperglycemia begins to develop. When only 50% of the beta-cell mass remains functional, patients have persistent hyperglycemia regardless of their fasting state. The increased hepatic glucose production in diabetes is coupled with the reduction of insulin's ability to facilitate glucose transport into skeletal muscle cells, further intensifying the severity of the hyperglycemic state (Fig. 4-7).

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Pancreatic Beta-cell Receptor and Signaling Abnormalities Reduce Insulin Secretion

Within the beta cells, IR results from mutations affecting either the structure of the insulin receptor or any one of multiple intracellular insulin-signaling mechanisms. Ultimately, both intracellular glucose transport and delivery of insulin from the beta cell to the plasma are impaired. Environmental factors, such as lack of physical activity, obesity, age, and dietary factors, fuel the resultant hyperglycemia triggered by these genetic anomalies.

Although insulin receptor numbers are reduced in obese individuals, no reduction in insulin receptor activity occurs in liver or skeletal muscle in patients with T2DM. This suggests that IR arises from intracellular postreceptor abnormalities.⁵⁷ The insulin receptors in T2DM have decreased tyrosine kinase activity, resulting in postbinding defects in glucose transport mechanisms.⁵⁸ Alterations in the structure of the insulin receptor coupled with the

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Insulin secretion from the pancreas occurs in two phases. The first-phase insulin response represents an immediate release of insulin from the beta cells. Normally this insulin release occurs as beta cells excrete preformed insulin for 10 to 20 minutes after a glucose stimulus (Fig. 4-9). The second-phase insulin release will continue until the blood glucose level returns to normal, approximately 90 minutes after eating. First-phase insulin response is genetically predetermined and frequently abnormal in subjects with a first-degree relative with diabetes.⁶⁰ First-phase insulin response is also impaired because of the effects of chronic hyperglycemia on beta-cell function and postreceptor signaling, which promote intracellular glucose transport.^61,62 Direct beta-cell death resulting from an elevation in FFA levels will also impair first-phase insulin response.

Role of the Adipocyte in Promoting Both Insulin Resistance and Reduced Insulin Secretion

Lipotoxicity promotes IR, reduced insulin secretion, beta-cell death, and subsequent progression to T2DM. In response to IR, lipotoxicity results in the mobilization of FFA from adipocytes. Adipocytes store and release FFA in

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The two main types of adipose tissue are subcutaneous and visceral adipose tissue (VAT). Eighty percent of body fat is located in the subcutaneous adipose tissue, and 10% is located in VAT.⁶³ Ten percent of the body fat is located in perirenal and peritoneal adipose tissue. Visceral fat, which is prominent in

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Whereas insulin promotes hepatic glucose storage, FFA has the opposite effect by promoting the breakdown of glycogen to glucose as an energy source.⁶⁹ Insulin also favors hepatic storage of FFA and the production of

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Figures 4-8 and 4-11 summarize the pathogenesis of IR at the cellular level and the resulting reduction in insulin secretion in patients with T2DM.

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Nonalcoholic Steatohepatitis (A Precursor to Type 2 Diabetes)

Seventy-five percent of patients with T2DM have evidence of nonalcoholic steatohepatitis (NASH).⁷⁰ This fatty liver infiltration has two presentations. Primary NASH is associated with metabolic syndrome, obesity, and T2DM. Secondary NASH develops after bariatric surgery; rapid weight loss in severe clinical obesity; pregnancy; total parenteral nutrition; and as an adverse event in patients using certain drugs such as amiodarone, warfarin, corticosteroids, tamoxifen, methotrexate, estrogen, and tetracycline. NASH is found in 18.5% of obese patients, compared with 2.7% of lean individuals.⁷¹ Most patients with fatty liver infiltration are asymptomatic. However, half of patients with NASH report persistent fatigue, malaise, or upper abdominal discomfort. Progression of NASH to cirrhosis or fibrosis can result in ascites, edema, jaundice, and fever. The diagnosis of NASH can be made only with a liver biopsy. The laboratory findings suggestive of NASH are noted in Table 4-8.

NASH develops in two stages. As peripheral resistance to insulin action begins in visceral fat, increasing lipolysis, the transport of FFA from adipose tissue to the liver is increased, resulting in steatosis.⁷² Next, oxidative stress and cytokine tumor necrosis factor (TNF) directly damage hepatic mitochondria, beginning an inflammatory process, hepatocellular degeneration, and fibrosis.⁷³

PPARs play an important role in defending the liver against FFA-induced toxicity by sensing elevated FFA levels and upregulating genetic programs to clear the FFAs.⁷⁰ PPARs cannot overcome the effects of hyperinsulinemia on increased lipolysis.

Currently, no widely accepted and U.S. Food and Drug Administration (FDA) approved pharmacologic approaches exist for NASH. Treatment should focus on normalizing risk factors considered to be involved in the etiology of NASH, as listed in Table 4-9. Thiazolidinediones improve insulin sensitivity by binding with the PPAR receptors. As genetic modulation is enhanced within adipose tissue, plasma FFA levels are reduced, thereby protecting the liver against NASH and improving IR. Both rosiglitazone⁷⁴ and pioglitazone⁷⁵ have been shown to improve alanine aminotransferase (ALT) levels and reduce hepatic fat content. Whether the improvements in liver disease are the result of improved peripheral insulin sensitivity or the direct anti-inflammatory effects these drugs may have on hepatocytes is uncertain. Metformin also shows promise as a NASH therapeutic agent. Metformin inhibits the action of TNF, which, as a cytokine, may directly promote hepatic steatosis and cell death. In one study, treatment of 14 NASH patients with metformin, 500 mg TID for 4 months, normalized transaminase levels, improved insulin sensitivity, and decreased liver volume in 50% of the patients.⁷⁶ Cytoprotective agents, adiponectin, antioxidants, iron-reduction therapy, and lipid-lowering medications are currently being investigated for the treatment of NASH.

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Role of Environmental Factors in the Pathogenesis of Type 2 Diabetes

Clearly, environmental factors, such as obesity, favor the progression of genetically susceptible individuals from a state of normal glycemia through IGT and into chronic hyperglycemia. Obesity causes peripheral resistance to insulin-mediated glucose uptake as well as a decrease in the sensitivity of pancreatic beta cells to hyperglycemia.⁷⁷ These metabolic abnormalities are largely reversed with moderate weight reduction. The mechanisms by which obesity induces IR include the following:

• Free fatty acids. The elevated FFA levels associated with obesity impair insulin secretion and inhibit insulin-stimulated glucose uptake in patients with T2DM.⁶⁸

• Tumor necrosis factor- . Studies in genetically altered obese animals have demonstrated an increase release of TNF- from adipocytes, which results in impairment of insulin action. Weight reduction in obese animals is associated with improvement in insulin activity and a decrease in TNF- gene expression.⁷⁸

• Adiponectin. A number of observations suggest that a deficiency of adiponectin, an adipocyte-derived hormone, plays a role in the development of IR and the progression towards T2DM (see Chapter 2).⁷⁹

• Resistin and leptin (adipocytokines). Leptin influences feeding behavior, energy balance, and body-fat stores, whereas resistin, as modulated through PPAR- receptors, antagonizes insulin action and impairs glucose tolerance. These hormones appear to link obesity with diabetes.⁸⁰

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  TABLE 4-10 Drugs That Induce Hyperglycemia

  Thiazide diureticsa Central beta-blockers Monoxidil Beta-blocking agentsb Protease inhibitors Atypical antipsychotic agents Corticosteroids Oral contraceptives Pentamidine Isoniazid L-Dopa Theophylline aEffects may be dose dependent, with hyperglycemia seen most commonly at higher doses. bIndividual beta-blocking agents have variable effects on insulin resistance. Carvedilol, with both beta- and alpha-blocking properties, may have favorable effects on insulin sensitivity and glucose tolerance when compared with metoprolol or atenolol.

• Pattern of fat distribution. Android (upper body) obesity has a much greater association with IR and IGT than does gynoid (lower body) obesity.

• Intrauterine development. Malnutrition during fetal or early life may lead to the expression of the thrifty genotype. Intrauterine growth restriction leading to low birth weight appears to be associated with an increased risk of adulthood IR, glucose intolerance, T2DM, dyslipidemia, and hypertension.⁸¹

• Drug-induced hyperglycemia. Many commonly used drugs have been associated with treatment-emergent hyperglycemia and diabetic ketoacidosis (Table 4-10). The specific causes for the induction of hyperglycemia in many of these agents is uncertain. High-risk patients, such as those requiring the use of corticosteroids, second-generation antipsychotics, or protease inhibitors, should be carefully monitored for treatment-emergent hyperglycemia (Table 4-11). Drugs should not be withheld from use simply because of their potential for inducing hyperglycemia. Patients in whom hyperglycemia develops when using agents such as corticosteroids, second-generation antipsychotics, or protease inhibitors should have their diabetes managed concurrently by using appropriate therapeutic modalities.

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Genetic Susceptibility for Type 2 Diabetes

The development of T2DM diabetes is strongly influenced by genetics. Thirty-nine percent of patients with T2DM have at least one parent with the disease.⁸² The lifetime risk for a first-degree relative of a patient with T2DM diabetes is 5 to 10 times higher than that of age- and weight-matched subjects without a family history of diabetes.⁸³ Among monozygotic twin pairs with one affected twin, T2DM eventually develops in 60% to 90% of unaffected twins.⁸² First-degree relatives of patients with T2DM often have impaired glucose tolerance, delayed first-phase insulin response, and beta-cell dysfunction years before diabetes develops.^84,85

Approximately 2% to 5% of patients with type 2 diabetes are first seen at a young age, have mild disease, and show autosomal dominant transmission. This condition was formerly called maturity-onset diabetes of the young (MODY). In the new classification, the MODY subtypes have been eliminated and replaced by specific descriptions of the known genetic defects. It is anticipated that other subtypes of type 1 and type 2 diabetes will become more clearly defined in the future. Six different genetic abnormalities have been identified. The currently recognized genetic defects of beta-cell function are described in Table 4-12.

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Pharmacologic Intervention for Type 2 Diabetes

When lifestyle interventions including weight reduction and exercise fail to reduce glycemia to the desirable range, oral antihyperglycemic agents should be initiated. Nine years after randomization, only 9% of obese patients with T2DM in the United Kingdom Prospective Diabetes Study (UKPDS)⁸⁶ were able to maintain an A1C less than 7%.

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Because of the progressive nature of the disease, nearly all patients with T2DM will eventually require insulin to treat their hyperglycemia. Additionally, T2DM is associated with metabolic abnormalities such as hypertension, hyperlipidemia, endothelial inflammation, and procoagulation, all of which increase one's risk of early cardiovascular morbidity and mortality. The assessment and management of these comorbid conditions are imperative. One can understand how T2DM is in no way a simple form of diabetes, as many patients are led to believe.

The goals of pharmacologic intervention in T2DM are to normalize hyperglycemia, improve insulin sensitivity, preserve beta-cell function, reduce hepatic glucose output, improve peripheral glucose utilization, and delay or prevent microvascular and microvascular complications. Many factors must be considered when designing treatment programs for patients with T2DM, including

• The age and gender of the patient

• The length of time the patient has had T2DM

• The individual patient's coexisting metabolic abnormalities (hyperlipidemia, hypertension, obesity, hypertension, infertility, thyroid disorder)

• The presence of microvascular or macrovascular complications

• A family history of microvascular or macrovascular complications

• Socioeconomic status

• Type of employment as well as work hours (sleep dysfunction or erratic sleep schedules may complicate the ability of the patient to achieve targeted A1C levels)

• Lifestyle variables: smoking, alcohol, or substance-abuse history, activity level, meal schedule

• Prior treatment successes and failures

• Presence and severity of diabetes-related symptoms

The development of new classes of blood glucose lowering medications to supplement the older therapies, such as lifestyle-directed interventions, insulin, sulfonylureas, and metformin, has increased the treatment options for T2DM. Whether used alone or in combination with other blood glucose lowering interventions, the availability of the newer agents has provided an increased number of choices for practitioners and patients and heightened uncertainty regarding the most appropriate means of treating this widespread disease.

Although the ADA does not provide guidelines on when oral hypoglycemic agents should be initiated, a consensus panel has suggested that an A1C of 7% or greater should serve as a call to action. Patients with A1Cs of 7% or greater should intensify their treatment regimens to achieve an A1C as close to the nondiabetic range ( 6%) as possible or, at a minimum, strive to lower their A1C to less than 7% (Table 4-13). Of course, clinical judgment based on the potential benefits and risks of intensification needs to be exercised for each patient. Patients with a short life expectancy, those at high risk of hypoglycemia (especially if they live alone), and individuals with history of medical comorbidities such as coronary artery disease or stroke may not be

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• Metformin should be initiated concurrent with lifestyle intervention at the time of the diagnosis. Because T2DM is a metabolic disorder in which the level of hyperglycemia mirrors the progressive failure of beta-cell function, lifestyle interventions fail to achieve and maintain targeted glycemic goals in most patients.

• Metformin is an excellent choice as the initial pharmacologic therapy because of its effect on glycemia, absence of weight gain or induction of hypoglycemia, generally well accepted side effect profile, low cost, and broad-based formulary acceptance.

• When metformin is initiated as monotherapy, titrate to the maximum effective dose over 1 to 2 months as tolerated. Supplement with additional glucose-lowering drugs in the setting of persistent hyperglycemia.

• When adding a second agent to metformin, consider which agent will most likely allow the patient to achieve his or her targeted A1C level.

• Consider initiating insulin therapy for patients having an A1C greater than 8.5 %, especially if they have symptomatic hyperglycemia.

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One should be mindful that the consensus guidelines shown in Figure 4-12 do not specifically mention which patients should be treated with incretin mimetic agents or dipeptidyl peptidase IV (DPP-IV) inhibitors. When initiating insulin therapy, should the oral agents be maintained or discontinued? Is inhaled insulin an appropriate bridge therapy for patients taking oral agents? Which patients might respond to novel treatment regimens, such as basal insulin analogues plus prandial doses of pramlintide or exenatide? PCPs have many treatment options for their patients. Although the means to intensify T2DM therapy may be unique for each patient, the ultimate goals for all patients are similar:

• Achieve and maintain normal glycemia.

• Once type 2 diabetes is diagnosed, begin lifestyle intervention and metformin.

• Rapidly add other medications to a patient's treatment regimen when glycemic targets are not achieved or sustained.

• Insulin should be added sooner (as opposed to later) to the patient's treatment regimen if the A1C cannot be maintained below 7% on oral agents or if the patient has symptomatic hyperglycemia.^86a

In 2006, The American Association of Clinical Endocrinologists (AACE) published a Road Map, which is an effective tool for managing patients in

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The level to which the A1C should actually be targeted for patients with T2DM may become less controversial once the results from the Action to Control Cardiac Risk in Diabetes (ACCORD) trial are revealed.

The ACCORD trial is a multicenter trial funded by the National Heart and Lung Institute designed to determine whether intensive glycemic control, treatment to increase HDL-C and lower triglycerides, and intensive blood pressure control reduce cardiovascular events in patients with T2DM.⁸⁸ More than 10,000 patients with diabetes at high risk for cardiovascular disease will be recruited and followed up for 4 to 8 years. The results of the study will be available in 2007. The primary outcomes of the ACCORD trial include the following:

• Blood sugar. ACCORD will determine whether reducing blood glucose to a goal closer to normal than called for in current guidelines reduces cardiovascular risk. The targeted A1C will be less than 6%.

• Blood pressure. The blood pressure part of the trial will evaluate the effects of reducing blood pressure in the context of good blood glucose control. ACCORD will determine whether reducing systolic blood pressure to less than 120 mm Hg will reduce cardiovascular risk better than the usually targeted level of less than 140 mm Hg.

• Lipids. This part of the study will look at the cardiovascular end points associated with reducing LDL-C and triglyceride levels, and increasing HDL-C, compared with an intervention that reduces only LDL-C, all in the context of good blood glucose control. Fibrates will be used to reduce triglycerides and increase HDL levels, whereas statins will be used to reduce LDL-C levels.

Oral Hypoglycemic Agents

Until the 1990s, prescribers in the United States had only two drug-therapy classes to choose from to control hyperglycemia associated with T2DM: insulins and sulfonylureas. The introduction of metformin (a biguanide, in 1995), acarbose (an glucosidase inhibitor, in 1995), and troglitazone (a thiazolidinedione, in 1997) in the United States gave clinicians the opportunity to treat

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The six available classes of oral agents target different metabolic defects associated with T2DM. Each drug promotes improved glycemia when used alone or in combination therapy. Initiation of an oral agent should be guided by the targeted metabolic defect that must be managed at any given time.

Once oral hypoglycemic therapy is initiated, patients must become active participants in diabetes self-management. Contrary to the belief held by many patients, T2DM is certainly not a mild form of diabetes. Blood glucose self-monitoring, medical nutrition therapy, enhancing one's active lifestyle, and professional surveillance to determine if the targeted metabolic goals are being achieved are all necessary to lessen the impact associated with diabetes-related complications. Patients should be aware of the potential risks and clinical benefits of the different types of oral hypoglycemic agents. Some medications may increase weight or induce hypoglycemia, whereas others must be held before undergoing certain diagnostic procedures. The continued use of oral hypoglycemic agents in the acute hospital setting may be detrimental.⁹⁰ Insulin is the preferred drug for patients with diabetes admitted to the hospital for acute illness. Insulin may also be necessary in certain situations that complicate the management of T2DM, such as during the concomitant use of corticosteroids, for patients requiring surgery, for patients with restricted oral intake, or in those patients who become pregnant while taking oral agents.

Sulfonylureas

The first oral agents for treating T2DM were initially marketed in 1957 as sulfonylureas. Although the first-generation sulfonylureas (orinase, tolinase, and diabinese) can improve hyperglycemia, potential drug interactions resulting in hypoglycemia make these drugs less attractive than the second-generation drugs. The second-generation sulfonylureas (glipizide and glyburide) were first introduced in 1984, and glimepiride followed in 1996. During the 11-year period from 1990 to 2001, a 3.9-fold increase (from 23.4 million to nearly 92 million) occurred in the dispensing of outpatient prescriptions for oral antidiabetic drugs.⁹¹ Only 21.5 million prescriptions were dispensed in 1986.⁹² This rapid increase in prescriptions coincides with the increase in the incidence of T2DM diabetes in the United States.

Sulfonylureas are known as secretagogues because their binding to pancreatic beta-cell receptors results in an increase in insulin production and secretion through a complex series of intracellular events. Once bound to the sulfonylurea (SUR) receptor on the pancreatic beta-cell plasma membrane,

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All sulfonylureas may not be equal in regard to efficacy and side-effect profile. Glimepiride has been shown to improve first- and second-phase insulin output,⁹⁴ whereas other sulfonylureas are thought to improve only second-phase insulin response. Glimepiride has been shown in a European study to have many fewer incidents of hypoglycemia than glibenclamide, a European sulfonylurea.⁹⁵ Although long-term therapy with any sulfonylurea can result in weight gain, a meta-analysis study of more than 14,000 patients demonstrated far less weight gain with glimepiride in comparison with other sulfonylureas.⁹⁶

Glimepiride may have a different mechanism of action than that of other sulfonylureas. Glimepiride improves hyperglycemia by improving the efficiency of the intracellular glucose transporter protein known as GLUT4.⁹⁷ Glucose is cleared from the bloodstream by a family of facilitative transporters (GLUTs), which catalyze the transport of glucose down its concentration gradient and into cells of target tissues, primarily striated muscle and adipocytes. GLUT4 transporter proteins are sequestered into specialized storage vesicles that remain within the cell's interior under fasting conditions. As postprandial glucose levels increase, the subsequent increase in circulating insulin activates intracellular signaling cascades that move (translocate) GLUT4 storage compartments to the plasma membrane (Fig. 4-8). As plasma insulin levels decline, GLUT4 transporters are moved away from the cell membrane and back into intracellular storage compartments. Alterations in GLUT4 translocation will result in inadequate insulin release in response to hyperglycemia.⁹⁸ Glimepiride may be insulin sparing. Subjects taking glimepiride have been shown to have lower fasting plasma insulin and C-peptide (a measure of endogenous insulin secretion) than do those taking glyburide.⁹⁷

Treatment with sulfonylureas generally results in a 1% to 2% reduction in A1C levels.^99,100 Sulfonylureas are effective agents as monotherapy or in combination with other oral agents and insulin, which have different mechanisms of action.¹⁰¹ Side effects of sulfonylureas include weight gain,¹⁰² which could be significant when used in patients who are already struggling with obesity. Hypoglycemia risk becomes a factor as patients' overall glycemic control approaches normal targets. Elderly patients may be at increased risk of developing hypoglycemia when initially placed on sulfonylureas.¹⁰³ Long-acting sulfonylureas such as chlorpropamide and glyburide are more likely to cause hypoglycemia.¹⁰⁴

Sulfonylureas should be initiated at low doses and increased weekly until target fasting blood glucose levels are less than 110 mg per dL. For best efficacy, sulfonylureas should be given 1 hour before breakfast (to improve first-phase insulin release) and/or at bedtime (to reduce overnight hepatic glucose production).⁵

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Patients first seen with newly diagnosed type 2 diabetes and blood glucose levels more than 300 mg per dL could be started on glipizide XL, 20 mg at bedtime, and monitored for glycemic improvement. Usually blood glucose levels and diabetes-related symptoms improve dramatically within 3 to 4 days. After 2 weeks, assuming glucose control is improved, the dose of the glipizide can be reduced and metformin initiated. Another option would be to continue the same high-dose glipizide while adding metformin to the treatment regimen.⁵ Long-duration hyperglycemia can induce beta-cell toxicity, which may not respond to low-dose secretagogue therapy. Higher-dose sulfonylureas might therefore be more appropriate in these patients.

Case 3

A 43-year-old Hispanic woman with a history of gestational diabetes at the time of her last pregnancy (12 years ago) appears in the emergency department complaining of thirst, fatigue, blurred vision, weight loss, and frequent urination for 7 days. She denies any other significant medical history, other than having had a C-section for her last pregnancy 5 years ago because of failure to progress in labor. The baby's weight at birth was 9 pounds 4 ounces. On examination, the patient is not in any distress. Blood pressure is 138/92, pulse is 78, temperature is 98.6 , respirations are 16, BMI is 32 kg per m², and her waist circumference is 41 inches.

Her baseline laboratory values are as follows:

• Blood glucose, 387 mg per dL

• Na⁺, 138 mmol per L

• K⁺, 4.6 mmol per L

• Blood urea nitrogen (BUN), 20 mg per dL

• Creatinine, 1.1 mg per dL

• Chloride, 104 mmol per L

• Carbon dioxide, 25 mmol per L

• Urine ketones, trace +

• Serum ketones, negative

• A1C, 9.2% (ADA target, <7%)

Liver function tests

• ALT, 72 U per L (normal range, 2 to 60)

• Aspartate aminotransferase (AST), 61 U per L (normal range, 2 to 50)

Lipid panel

• Triglycerides, 335 mg per dL

• HDL-C, 32 mg per dL

• LDL-C, 130 mg per dL

• Total cholesterol, 224 mg per dL

• Non HDL-C, 192 (target, <130)

Thyroid studies: Normal

CBC: Normal

The patient was diagnosed as having T2DM with comorbidities including obesity, hypertension, NASH, and an atherogenic dyslipidemia. She was advised to take glipizide XL, 20 mg at bedtime, and to begin home blood glucose monitoring, fasting and at bedtime, until seen by her PCP in 2 weeks. The table shows the results of her blood glucose monitoring.

When evaluated on 9/12, she is no longer symptomatic and has gained 1 pound over the past week. The decision is made to decrease the glipizide XL to 10 mg at bedtime and to begin metformin, 500 mg, with breakfast and dinner. On her return in 9 weeks, a point-of-service A1C documents a decrease in her baseline level to 7.1%. Her blood pressure is 124/72, and her BMI is 30 kg per m². The patient has been attending group diabetes education classes, has joined a ladies-only workout center, and is exercising 30 minutes, 5 days weekly. Repeated liver function studies revealed that her transaminase levels had normalized, most likely because of her 10-pound weight reduction. Her non HDL-C is now 126 mg per dL. The patient was advised to continue her metformin and to begin monitoring her blood glucose level, fasting and 2 hours after supper (her largest meal of the day), on 3 days each week until her next visit. Because her metabolic condition appears to be stabilized, renal function studies will be performed, including a spot urine for microalbuminuria and a glomerular filtration rate (GFR) determination. An ophthalmology consult will be scheduled for the patient.

Of interest is the fact that although this patient had gestational diabetes, she gave birth to a son weighing 10 pounds. When asked by the PCP how much her 12-year-old now weighs, she did not hesitate in saying his weight was well over 160 pounds. His pediatrician had been concerned that the boy was becoming clinically obese. The PCP mentions that her son is at high risk for developing T2DM as an adolescent, which could result in significant cardiovascular risk when he reaches his 20s (see Chapter 2). Lifestyle interventions that were beneficial for the patient should also be used by the son to reduce the chance of diabetes and cardiovascular disease developing.

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The use of sulfonylureas may improve the chance of microvascular complications developing.⁴⁶ However, no outcome data from prospective clinical trials have been published demonstrating a reduction in macrovascular risk associated with the use of sulfonylureas. Some^105,106 but not all^107,108 retrospective analyses have demonstrated worse cardiovascular outcomes in patients taking sulfonylureas compared with those taking metformin or TZDs (Table 4-14).

Meglitinides

Although patients with T2DM may have high fasting insulin levels and a reduction in insulin action, a blunted or absent first-phase insulin response to a glycemic challenge is also present. Most sulfonylureas (except glimepiride) increase pancreatic beta-cell insulin secretion as well as plasma insulin concentrations, yet fail to improve first-phase insulin release. The meglitinides do increase early insulin response, allowing improved postprandial glycemic control.¹⁰⁹ Drugs in this class include nateglinide (Starlix) and repaglinide (Prandin). Both agents are rapid-acting insulin secretagogues. When the drugs are taken 15 minutes before a meal, postprandial glucose excursions can be minimized. This is important because significant postprandial hyperglycemia has been associated with cardiovascular morbidity.^110,111,112 In randomized placebo-controlled clinical trials, repaglinide appears to reduce

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Meglitinides are more expensive than sulfonylureas. Both repaglinide and nateglinide are approved for use as monotherapy and in combination with TZDs and metformin. Although long-term outcome data are unavailable for this drug class, their effects on improving diabetes-related complications are likely to be at least similar to those observed with sulfonylureas.

-Glucosidase Inhibitors

-Glucosidase inhibitors (AGIs) block the action of -glucosidase enzymes at the brush border of the intestine. The inhibition slows the breakdown of dietary oligosaccharides and disaccharides. The delayed digestion of carbohydrates decreases postprandial glucose concentrations.¹¹⁸ The two members of this drug class include acarbose (Precose) and miglitol (Glyset). In placebo-controlled trials, AGIs have been shown to reduce AIC levels by only 0.5% to 1.0%^{119,120,121,122} and are therefore considered less effective than other oral agents. AGIs are approved for use as monotherapy and in combination with sulfonylureas and metformin.

The use of AGIs in managing diabetes has been limited in the United States because of the side effects, which include abdominal bloating, cramping, and flatulence. Patients will frequently discontinue use of these drugs because of these uncomfortable side effects. The use of acarbose has been shown to reduce the incidence of T2DM by 25% over a 3.3-year period compared with placebo, regardless of age, sex, or BMI.¹⁸ In post hoc analysis of data from the Study to Prevent Non Insulin-Dependent Diabetes Mellitus trial (Stop NIDDM), acarbose was observed to have an impressive effect on risk of myocardial infarction, supporting the view that postprandial hyperglycemia has a greater influence on cardiovascular events than does fasting glucose.¹²³

Metformin

Metformin, a biguanide, is commonly referred to as an insulin sensitizer because glucose levels improve without stimulation of insulin secretion. Metformin acts by decreasing hepatic glucose production, decreasing glucose absorption, and increasing glucose uptake into skeletal muscle.^124,125 As circulating glucose levels are reduced, peripheral IR at the skeletal muscle site and adipose tissue may also improve. At the molecular level, metformin appears

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Metformin as monotherapy has numerous beneficial effects on metabolic parameters and diabetes prevention. In the DPP, patients with IGT or impaired fasting glucose receiving metformin, 850 mg twice daily, had a 31% reduction in progression toward diabetes. Those individuals randomized to lifestyle intervention (exercising 150 minutes per week and weight loss of 7% of baseline body weight) had a reduction of 58%. Metformin was found to be most effective in reducing progression toward diabetes¹² in subjects younger than 45 as well as in individuals with a BMI greater than 35 kg per m². The diagnosis of the primary outcome, diabetes, was based either on a 75-g oral glucose tolerance test (OGTT) with FPG or 2-hour glucose exceeding 125 or 199 mg per dL, respectively, or on 6-month FPG, exceeding 125 mg per dL. Metformin was particularly effective in decreasing diabetes among individuals with FPG exceeding 110 mg per dL, whereas the lifestyle intervention was similarly effective in persons above and below this level. Half of those treated with metformin experienced GI side effects, and some reduced the dose to 850 mg once daily. No evidence indicates whether combined lifestyle metformin treatment would have an additive benefit. Patients with prediabetes who are unable to or unwilling to participate in lifestyle-intervention programs might benefit from pharmacologic therapy using metformin.

Metformin has been shown to improve inflammatory markers linked to cardiovascular risk. The drug reduces triglyceride levels by 10% to 30%,¹²⁷ LDL-C and total cholesterol by 5% to 10%,¹²⁸ while having no significant influence on HDL-C levels.¹²⁹ Metformin has no effect on blood pressure.¹²⁷ Levels of fibrinogen¹³⁰ and CRP¹³¹ are also lower in metformin-treated patients.

The UKPDS showed that obese patients using metformin as monotherapy had a lower risk of myocardial infarction and stroke when compared with subjects taking metformin with a sulfonylurea.¹⁰⁵ Although the risk of vascular disease was slightly higher when metformin was used in combination with a sulfonylurea, most authorities believe these numbers to be statistically insignificant.¹³²

In placebo-controlled trials,^133,134,135 metformin consistently lowers A1C by 1% to 2%, similar to secretagogues. Metformin is approved for use alone or in combination with all other antidiabetic agents, as well as exenatide and pramlintide. Patients with polycystic ovary syndrome who take metformin have improved ovulatory function and show a reduction in parameters suggestive of IR¹³⁶.

Extended-release metformin (Glucophage XR, Fortamet, Glumetza) offers the option of giving the drug as a single daily dose with the largest meal of the day. Improvements in glycemic control have been shown to be similar in patients taking once-daily extended-release metformin or the traditional twice-daily dosing schedule, whereas the gastrointestinal side effects were equal in both groups over a 24-week period.¹³⁷

Gastrointestinal side effects of metformin are common and can be minimized by slow-dose titration and by taking the medication while in the process of eating. Because of the rare risk of lactic acidosis (characterized by

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In the first 14 months after metformin was released in the United States, the FDA received confirmation of 47 cases of metformin-associated lactic acidosis, with a 42% mortality rate.¹³⁹ More than 90% of patients in whom lactic acidosis developed had a relative or absolute contraindication for using metformin. In elderly patients, the GFR may the best way to evaluate renal function and predict one's increased risk of metformin treatment-emergent lactic acidosis developing. Serum creatinine levels overestimate the GFR by up to 19%.¹⁴⁰ A GFR calculator is available at the National Kidney Foundation Web site: http://www.kidney.org/professionals/kls/gfr_calculator.cfm. A GFR of 60 mL per minute or less for more than 3 months is considered diagnostic of chronic renal failure.¹⁴¹ Metformin should not be used in these individuals.

Lactic acidosis is subtle in onset. Symptoms include malaise, myalgias, respiratory distress, fatigue, and abdominal discomfort. As the acidosis intensifies, patients will become hypothermic, hypotensive, and drug-resistant bradyarrhythmias may develop. Despite the warnings regarding treatment-emergent lactic acidosis associated with the use of metformin, 22% to 54% of patients taking the drug have an absolute or relative contraindication to its use.^138,142 Hospitalized patients taking metformin often do not have the drug discontinued despite having at least one risk factor for lactic acidosis developing.¹⁴³ A recent review of patients discharged from the hospital with a diagnosis of congestive heart failure and diabetes found that 11% were given a prescription for metformin.¹⁴⁴ Most experts on diabetes management believe that metformin should not be used in the acute hospital setting.

The use of iodinated contrast material for studies including intravenous pyelography, intravenous cholangiography, angiography, and computed tomography (CT) scanning may induce acute renal failure, resulting in lactic acidosis in metformin-treated patients. Metformin should be temporarily stopped immediately before the planned procedure and withheld for 48 hours once the procedure is completed. The patient's renal status should always be reassessed before resuming metformin.

Thiazolidinediones

The two TZDs currently available are pioglitazone and rosiglitazone. Thiazolidinediones act (a) by stimulating the PPAR- receptor, which promotes insulin-sensitizing effects on skeletal muscle and adipose tissue; and (b) by inhibiting hepatic gluconeogenesis. Stimulation of the PPAR receptors modulates the activity of the cell's genes and helps to regulate both carbohydrate and lipid

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TZDs enhance the effects of insulin on the liver, thereby reducing hepatic glucose production (gluconeogenesis and glycogenolysis).¹⁴⁶ FFA suppression by TZDs can improve insulin sensitivity while preserving pancreatic beta-cell function. TZDs suppress both fasting and postprandial levels of FFA, which can significantly improve IR affecting the liver and skeletal muscles.^146,147

Adiponectin also plays an important role in the modulation of glucose and lipid metabolism. Low levels of circulating adiponectin have been linked with human obesity¹⁴⁸ as well as IR and dyslipidemia.¹⁴⁹ Plasma adiponectin levels are significantly lower in patients with T2DM but can be increased rapidly when TZDs are initiated.¹⁵⁰ In addition, plasma adiponectin levels in diabetes patients with evidence of coronary artery disease (CAD) are lower than those in diabetes patients without CAD, suggesting that adiponectin may be cardioprotective as well as endothelial cell protective.¹⁵¹

Studies of skeletal muscle function in mice have suggested that adiponectin improves FFA transport and oxidation. Lower levels of circulating FFA improve IR. In the liver, low levels of adiponectin have been shown to reduce FFA transport,¹⁵¹ which in turn worsens IR (Fig. 4-11).

The exact means by which TZDs improve plasma levels of adiponectin may involve the ability of PPAR- to enhance the expression of adipocyte genes responsible to increase the production of adiponectin.¹⁵²

PPAR- activation by TZDs promotes the differentiation of small adipocytes into larger adipocytes, resulting in weight gain and an absolute increase in adipose cell mass. As a result, patients who use TZDs may experience modest weight gain in association with improvement in their blood glucose and lipid levels. TZDs have been postulated to improve insulin sensitivity by redistributing fat from visceral to subcutaneous adipose tissue.¹⁵³ PPAR- is expressed at highest concentrations in adipose tissue and at much lower concentrations in liver and muscle,¹⁵⁴ suggesting that the primary action of TZDs is on adipose tissue.

IR occurs in association with a number of metabolic abnormalities that improve when TZDs are added to the therapeutic regimen. For example, patients with IR tend to have a predominance of small, dense, atherogenic LDL particles that are susceptible to oxidation, an important step in the atherosclerotic process. TZDs increase the ratio of large, buoyant LDL to small, dense LDL particles, reducing the degree of atherogenesis.^155,156 Small, dense LDL particles easily lodge themselves into vessel walls that have been damaged by inflammation, where they become oxidized. Large, buoyant LDL particles are too hefty to become wedged within the vessel walls and instead simply bounce through the blood vessels, causing minimal harm. Although lipid profiles tend to improve with the use of TZDs, patients older than 40 with diabetes should still be provided with statins.¹⁵⁷

Pioglitazone may decrease the concentration of conjugated oral contraceptives (COCs). Therefore, patients taking pioglitazone and COCs should

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In summary, activation of PPAR- results in higher expression of adiponectin from adipose tissue, reducing plasma levels of FFA, thereby improving IR and redistributing fat from metabolically active VAT to metabolically inactive subcutaneous fat. In diabetes, as FFA levels increase, IR worsens, within both the liver and the skeletal muscle sites, causing the pancreatic beta cells to produce more endogenous insulin. Individuals with a genetic predisposition for diabetes cannot produce and secrete enough endogenous insulin to maintain euglycemia. TZDs appear to improve IR by directly affecting PPAR- activation in adipose tissue, hepatocytes, and skeletal muscle cells. The metabolic effects of the TZDs are displayed in Table 4-15.

The two currently marketed TZDs (pioglitazone and rosiglitazone) are equipotent in reducing A1C levels, typically in the same range as metformin and sulfonylureas. These agents are approved as monotherapy and in combination with other agents, including metformin, sulfonylureas, and insulin. Side effects include weight gain (range, 0.9 2.6 kg) and edema. The weight gain tends to occur early and is not associated with a prolonged upward trend. TZDs should not be used in patients with advanced heart-failure symptoms (New York Heart Association class III or IV).¹⁶⁰

No comparative head-to-head trials show that one TZD is superior to the other. Because of the unique features of the TZDs, patients must be assessed individually to determine which agent might be most appropriate.¹⁶¹ Subtle differences between the two drugs are apparent. For example, pioglitazone is associated with the most weight gain, whereas rosiglitazone causes a more significant increase in LDL-C and triglyceride levels.

Patients with diabetes are twice as likely to have hypertension as are those individuals with normoglycemia.¹⁶² The UKPDS blood pressure substudy revealed a significant reduction in microvascular and macrovascular complications when blood pressure is controlled in patients with diabetes.¹⁶³ Rosiglitazone decreases systolic and diastolic blood pressure by 5 to 6 mm Hg in patients with T2DM,¹⁶⁴ which may provide another mechanism by which long-term diabetes-related complication rates may be reduced. Pioglitazone appears to have a similar effect on both systolic and diastolic blood pressure reduction in patients with T2DM.¹⁶⁵

A direct correlation exists between IR, T2DM, and increased levels of plasminogen activator inhibitor type-1 (PAI-1). Elevation of PAI-1 inhibits fibrinolysis, thereby increasing one's risk of arterial thrombosis. Higher A1C levels correlate with higher PAI-1 levels.¹⁶⁶ Patients with suboptimal diabetes control therefore are at higher risk of vascular thrombosis. Whereas sulfonylureas increase PAI-1 levels, TZDs in combination with sulfonylureas appear to decrease PAI-1 activity by more than 33%.¹⁶⁷ TZDs may play a critical role in reducing endothelial damage by improving fibrinolytic activity, leading to lowered cardiovascular risk in patients with T2DM.

CRP is an independent marker of vascular inflammation. Elevated CRP levels are associated with an increased cardiovascular risk as well as IR.

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The current available clinical data show that no hepatotoxicity occurs with the two marketed TZDs. However, patients using TZDs should have liver function tests performed on initiation of the drug. TZDs should not be started if a patient has evidence of active liver disease or if the ALT levels are greater than 2.5 times the upper limits of normal. Patients with normal liver function tests should have an ALT performed every 2 months for the first year, followed by periodic testing. If at any time during treatment with a TZD, the ALT levels exceed 3 times the upper limits of normal, complete liver function testing should be repeated immediately. If on repeated testing, the ALT remains 3 or more times the upper limits of normal, the drug should be discontinued. Liver enzymes should also be checked if a patient experiences symptoms suggesting hepatic dysfunction while taking the TZDs.¹⁷⁰

Use of TZDs should begin early in the course of diabetes treatment and, in most patients, be considered cornerstone therapy. TZDs improve insulin sensitivity, hyperglycemia, and pancreatic beta-cell function. Lipid profiles, vascular dynamics, inflammatory markers, fibrinolysis, blood pressure, and endothelial cell function are all positively affected with TZD therapy. TZDs have also been useful in delaying the onset of diabetes in high-risk patients (TRIPOD Study)¹⁶ while improving the likelihood of ovulation in patients with PCOS.

The A Diabetes Outcome Progression Trial (ADOPT) evaluated the efficacy of a thiazolidinedione (rosiglitazone), metformin, and glyburide as initial treatments for patients newly diagnosed with T2DM.^170a The 4,360 patients treated in this randomized placebo controlled trial were treated for a median period of 4 years. The primary outcome was the time to monotherapy failure (defined as a confirmed FPG >180 mg/dL). Secondary outcomes included levels of FPG and A1C, insulin sensitivity, and beta-cell function. Patients randomized to the rosiglitazone arm demonstrated a 32% risk of treatment failure compared with metformin and a 63% reduction in risk of failure compared with glyburide over 4 years. Rosiglitazone was associated with weight gain. On average, patients gained 6.9 kg compared with metformin and 2.5 kg compared with glyburide. Cardiovascular events were similar in the rosiglitazone and metformin arms but lower in the glyburide arm. Rosiglitazone was most effective, probably because of its effects on insulin sensitivity and beta-cell function. The use of rosiglitazone early in diabetes is preferable to glyburide because rosiglitazone was substantially more effective.

Despite the positive effects of rosiglitazone on modest improvements in long-term glycemia, one must also weigh the drug's long-term adverse effects, such as weight gain, fluid retention, and even a higher incidence of extremity fractures. Even with the data supporting long-term efficacy with rosiglitazone, metformin still remains the logical choice as initial therapy for T2DM.^170b

The pharmacologic actions of all oral hypoglycemic agents are compared in Tables 4-16 and 4-17. Issues related to possible cardiovascular risk that may be associated with the use of oral hypoglycemic agents are addressed in Table 4-14.

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Combination Therapies

Although monotherapy may be effective initially in the treatment of T2DM, a more intensified management strategy is often needed to maintain optimal glycemic control within 5 years of drug initiation.⁵⁵ Data from the UKPDS demonstrated a relation between the progressive decline in beta-cell function and the inability of oral hypoglycemic agents to maintain a therapeutic A1C

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When combination therapy is initiated, always consider using drugs with different mechanisms of action. Side effects of combination drug therapy may become problematic. For example, weight gain can be significant when insulin is combined with a TZD or a secretagogue.

Several single-dose combination drugs are also available for use in patients with T2DM (sulfonylurea plus metformin, sulfonylurea plus a TZD, and metformin with a TZD) (Table 4-16). Combination drugs do have some advantages over the necessity to use two different existing drugs. Most combination agents cost the same as or less than the retail value of their individual drug components, and in some cases, combination drugs are considerably less expensive than the sum of the individual components.¹⁷³ For example, the use of the combination drug Metaglip costs $50 less per month in California than if a patient were to fill two individual prescriptions for metformin and glyburide. The same is true when one compares the cost of Avandamet with the cost of rosiglitazone plus metformin. Patient adherence to diabetes-treatment regimens may improve when a single drug is used for glycemic control, rather than two.

Combining agents from different therapeutic classes appears to have additive benefits on glucose control. Typically, the A1C reduction resembles the effect of the added individual agent when used as monotherapy. These drugs do not appear to work in a synergistic manner, and their ability to affect different metabolic parameters remains a great area of interest.

Most important, the use of a combination drug shortly after one is diagnosed as having diabetes may increase the clinical inertia toward diabetes therapy intensification.

Parenteral Agents

In 2005, two novel therapeutic agents were introduced that offer a means of providing safe and effective physiologic diabetes management to patients (see Chapter 12). Clinicians can now simulate human GLP-1 action by using a synthetic GLP-1 incretin mimetic hormone (exenatide). GLP-1 is secreted from enteroendocrine cells located in the ileum and colon in response to a meal. The incretin effect, which is GLP-1 dependent, refers to the difference in insulin secretion from the beta cells when glucose is administered orally versus intravenously. Intravenous glucose produces a much smaller endogenous insulin response than does an identical oral glucose challenge. Patients with IGT and T2DM are GLP-1 deficient. When administered before a meal in patients with type 2 diabetes, exenatide restores first-phase insulin response, reduces postprandial glucagon levels, increases insulin release from the beta cells, improves gastric

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Amylin is a peptide hormone that is secreted with insulin from the pancreatic beta cells and is deficient in patients with diabetes. Amylin inhibits glucagon secretion, delays gastric emptying, and decreases appetite. Pramlintide, a synthetic version of amylin, possesses pharmacokinetic and pharmacodynamic properties similar to those of native amylin in patients with both T1DM and T2DM. Both drugs improve A1C levels and favor weight loss rather than weight gain.¹⁷⁵

Because diabetes is a progressive disease, over time most patients will need to be transitioned to exogenous insulin therapy. Many simple protocols allow patients to achieve an A1C of 7% or lower by using basal insulin as monotherapy¹⁷⁶ or in a combination of oral agents.¹⁷⁷ Single or multiple daily doses of mixed insulin analogues can also be used as monotherapy or in combination with oral agents.^178,179 Preprandial inhaled insulin may be used with oral hypoglycemic agents or in conjunction with a basal insulin. Patients who are still unable to achieve successfully and safely the targeted A1C, or those experiencing significant glycemic variability, may require intensification of their regimen by using either multiple daily injections of insulin or insulin pump therapy, possibly combined with either pramlintide or exenatide.

Dipeptidyl Peptidase IV Inhibitors

Although native incretin hormones have a powerful effect on glucose regulation, their release in response to an oral glucose stimulus is tempered by rapid degradation from DPP-IV. Thus, as soon as GLP-1 is released from the intestinal L cells, one's own endogenous enzyme systems will act to neutralize the hormone's glycemic effects. Deficiencies in GLP-1 secretion can be treated with exogenous GLP-1 formulations (such as exenatide), which mimic the human characteristics of GLP-1 yet are immune to rapid DPP-IV degradation. One could also use medications that directly inhibit the actions of DPP-IV, thereby allowing endogenous GLP-1 to have a more profound glucodynamic effect after meals are consumed.

DPP-IV inhibitors are orally administered drugs that improve glycemic control by preventing the rapid degradation of incretin hormones, thereby resulting in postprandial increases in levels of biologically active intact GLP-1.

Sitagliptin (Januvia) was approved for the treatment of type 2 diabetes in the United States on October 17, 2006. Sitagliptin was approved for use either as monotherapy or as combination therapy when added to either metformin or a thiazolidinedione. The usual dose is 100 mg daily; however, patients with renal impairment may require a reduction in dose to either 50 mg or 25 mg.

In a 24-week randomized, placebo-controlled trial, sitagliptin 100 mg lowered A1C 0.8%, reduced fasting plasma glucose levels 21 mg/dL, and decreased 2-hour postprandial glucose level 54 mg/dL when compared with

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An open-label trial in poorly controlled patients (mean baseline A1C = 8.8%) demonstrated a significant mean placebo-subtracted reduction in A1C of 2.1% with sitagliptin (100 mg per day) plus metformin (2 g per day) as initial therapy. Also, in the primary analysis of the study, sitagliptin plus metformin provided substantial mean placebo-subtracted reductions of PPG (mean reduction of 117 mg/dL) and FPG levels (mean reduction of 70 mg/dL). Initial co-administration of sitagliptin plus metformin led to 66% of patients achieving the ADA-recommended A1C goal level of less than 7% compared with 38.4% of patients on metformin alone. Modest weight loss was observed in the groups receiving sitagliptin plus metformin or metformin alone (-20.6 to -21.3 kg from baseline). All doses of sitagliptin plus metformin were generally well tolerated.¹⁸¹

Vildagliptin (Galvus) should be approved by the FDA in 2007 for use in T2DM. However, the specific indications for using vildagliptin remain uncertain. When added to metformin, vildagliptin appears to improve beta-cell secretion of insulin. The main effect was observed already within the initial 12-week treatment and was sustained throughout the 52-week study period.¹⁸²

Although the DPP-IV drugs offer clinicians yet another treatment option for managing patients with T2DM, several questions should be addressed prior to initiating therapy with these agents:

• Will the patient be able to achieve the A1C target of 7% when these drugs are used alone or in combination with other agents?

• When using DPP-IV drugs in combination with a TZD, the cost of daily therapy could be prohibitive for many patients. Could one achieve the same benefits at a lower cost using time-proven drug therapies such as metformin plus a sulfonylurea?

• Would a patient be better starting basal insulin therapy and continuing with oral agents rather than starting therapy with a DPP-IV inhibitor?

• Considering that few individuals actually lose weight on the DPP-IV drugs, would a patient be better off injecting incretin mimetic (such as exenatide), which should result in a similar A1C reduction (1.1%) yet significantly more weight reduction?

• Perhaps the best candidates for a DPP-IV would be individuals with newly diagnosed T2DM who have A1C levels lower than 8% and who are not excessively overweight (BMI <30 kg/mL²).

Treatment Recommendations for Patients with Type 2 Diabetes

Striving to normalize glucose levels is reasonable in the majority of our patients with both T1DM and T2DM. The AACE has published a road map suggesting treatment regimens one might consider prescribing for patients based

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Specialists and PCPs intensify diabetes management in different ways.¹⁸³ Although PCPs are not afraid to add a second or third oral agent to a patient's treatment regimen, diabetes specialists are aggressive with insulin management. Patients with an A1C greater than 8.5% are 5 times more likely to be placed on insulin by a specialist than by a PCP. Patients who consult specialists for poorly controlled diabetes are more likely to be successfully managed to a targeted A1C by the specialist than by the primary care provider.¹⁸⁰ However, fewer than 50% of patients with poor glycemic control receive intensification of their glucose-lowering regimen by either specialists or a PCP. By familiarizing themselves with the ADA and AACE clinical practice guidelines, PCPs may also become more successful in treating patients to target, rather than having them struggle through long periods of failure.

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Case 4

Patrick is a 49-year-old man initially seen by a family physician for a complete physical. His doctor noted that he had a fasting blood glucose of 133 mg per dL. He was placed on glyburide, 5 mg at bedtime, when his A1C increased to 7%. However, when first evaluated at the diabetes center, he had not taken any medication for 4 months and was asymptomatic. His family history is significant because his younger brother has type 1 diabetes. Over the past 5 years, he was taking lisinopril, 10 mg daily, for hypertension. When first evaluated, the patient admitted to doing no exercise. He did not smoke or drink.

Examination results were as follows:

Physical exam:

• Weight, 96 kg

• BMI, 29 kg per m²

• Blood pressure, 122/94 mm Hg

• Waist circumference, 38 inches

• Pertinent physical findings: no evidence of peripheral sensory neuropathy or cardiac disease.

• Exercise stress test, normal

  TABLE 4-18 Treatment Algorithm for Management of Type 2 Diabetes

  Patient A1C Level Author Suggestions AACE Guidelines for Treatment-naive Patients AACE Guidelines for Currently Treated Patients 6% 7% Lifestyle intervention Wt. reduction Exercise 30 min 5 d/wk Achieve FPG <110 mg/dL Achieve 2-h PPG <140 mg/dL Monitor BG levels fasting and bedtime 1st 7 days monthly Begin metformin 500 mg BID if FPG levels begin to exceed 110 mg/dL or 2 h postprandial glucose levels exceed 140 mg/dL Target A1C 7% Monitor other metabolic parameters (lipids, blood pressure, renal function) and treat them to target 6% 7% A1C Monotherapy or combination therapy with preferred drugs: metformin, TZD, AGI Goals: FPG <110 mg/dL, 2-h PPG <140 mg/dL, A1C 6.5% 6% 6.5% Adjust therapy as needed to meet AACE FPG and PPG targets using monotherapy or combination therapy Keep A1C <6.5% 7% 8% Begin combination therapy with one component being metformin. A DPP-IV inhibitor may also be considered as monotherapy. Titrate doses of oral agents Consider exenatide or Exubera Consider basal insulin analogue + oral agent Monitor blood glucose fasting and at bedtime >3 days weekly Recheck A1C in 4 mo Monitor metabolic parameters Continue exercise program Add to monotherapy: meglitinides, AGI, metformin, TZd, SUs Consider premixed insulin analogues or rapidacting insulin analogues for postprandial hyperglycemia 6.5 8.5% Maximize combination therapy Maximize insulin therapy: if FPG elevated add basal insulin if PPG elevated add bolus insulin if elevated FPG + PPG add basalbolus or premixed insulin therapy Add incretin mimetic to patients on SU or metformin 8% 9% Basal insulin analogue + oral agents Exenatide + orals Mixed analogues Basal insulin analogue + Exubera Basal insulin titrated to fasting glucose target <100 mg/dL Basal insulin titrated to treat fasting glucose target + add prandial insulin targeting largest meal of the day (usually supper) Combine therapies to address FPG and PPG: Metformin TZD SU Glargine Rapid-acting analogue Premixed analogues NPH insulin Other approved combinations >8.5 Basal-bolus insulin Premixed insulin analogues 9% 10% Start insulin. Target FPG at first. When A1C <8.5% begin adjusting insulin doses to target PPG levels Use basal-bolus insulin or mixed-dose analogues Combine therapies to address FPG and PPG: Metformin TZD SU Glargine Rapid-acting analogue Premixed analogues NPH insulin Other approved combinations >10% General measures should include the following: Reduce carbohydrate intake Inject analogue insulin 15 30 min prior to meals Strongly consider using pramlintide, which should also be injected 15 min prior to meals Consider using continuous glucose sensor or an insulin pump with augmented sensor to help reduce glycemic variability Basal-bolus insulin (rapidacting insulin analogue + glargine or detemir Insulin pump therapy pramlintide exenatide Blood glucose monitoring fasting, postprandial, and at bedtime Consider specialty referral if no response to treatment Basal-bolus insulin (rapidacting insulin analogue + glargine or detemir Premixed insulin analogues AACE, American Association of Clinical Endocrinologists; AGI, -glucosidase inhibitor; BG, blood glucose; FPG, fasting plasma glucose; PPG, postprandial glucose; SU, sulfonylurea;. TZD, thiazolidinedione; Wt., weight. Adapted from American College of Endocrinology. ACE road map to achieve glycemic goals: treated patients (type 2). Available at: http://www.aace.com/meetings/consensus/odimplementation/roadmap.pdf Accessed May 19, 2006.

Laboratory studies:

• A1C, 6.9%

• Total cholesterol (TC), 205 mg per dL

• HDL-C, 30 mg per dL

• LDL-C, 113 mg per dL

• Triglycerides, 310 mg per dL

• Urinalysis: showed 2+ glucose, -2 protein.

• Thyroid, liver, and blood chemistry tests were all normal.

Patrick was advised to begin home blood glucose monitoring, fasting and at bedtime, on Monday, Wednesday, and Sunday for 2 weeks. He was also encouraged to begin an exercise program by walking 30 minutes daily, 5 days per week. Low-dose aspirin, 81 mg, at bedtime was prescribed, and the antihypertensive medication was continued. He attended the group's monthly diabetes group education programs.

On his return 2 months later, Patrick's home blood glucose meter was downloaded. His average fasting glucose (28 readings) was 136 mg per dL, and his bedtime readings (30 readings) averaged 178 mg per dL. He had no readings greater than 200 mg per dL and was diagnosed as having IGT. Lifestyle intervention was stressed once again. Six months after his diagnosis of IGT, he returned for follow-up, having lost 8.5 kg. His physical and laboratory findings were as follows:

• Weight, 91.3 kg

• BMI, 27 kg per m²

• Blood pressure, 142/88

• A1C, 5.9%

• TC, 195 mg per dL

• HDL-C, 34 mg per dL

• LDL-C, 108 mg per dL

• Triglycerides, 255 mg per dL

• 24-hour urine for albumin, 108 mg per 24 hours (normal, 30 mg per 24 h)

Because of the reduced A1C, the patient was advised to continue home blood glucose monitoring, fasting and at bedtime, during the first 7 days of each month. He was started on Niaspan +1 g at dinner to be taken with the low-dose aspirin in an attempt to improve his atherogenic dyslipidemia (low HDL-C and elevated triglycerides). A statin was also prescribed because he was a high-risk cardiovascular disease patient older than 40 years with an LDL-C greater than 100 mg per dL. After his lisinopril dose was increased to 40 mg daily, a dry, hacking cough developed. The ACE inhibitor was discontinued, and he was started on valsartan, 160 mg daily (an ARB), for the hypertension and proteinuria.

At his next visit, 6 months later, Patrick admitted to feeling a bit more fatigued than usual, especially after eating large meals. He continued his exercise program and was following a modified Atkins Diet. Although his weight had not increased since the last visit, his point-of-service A1C test had risen from 5.9% to 6.8%. His home blood glucose monitoring downloads showed an average fasting glucose of 156 mg per dL, whereas the 2-hour postdinner readings were averaging 187 mg per dL. However, this time, 30% of his postprandial glucose readings were between 200 and 260 mg per dL. Patrick was started on a twice-daily metformin plus rosiglitazone combination drug (Avandamet).

Three months later, Patrick's A1C increased to 7.7%. His blood glucose meter downloads revealed that although his fasting glucose levels were fairly well controlled (10% of fasting glucoses were more than 110 mg per dL), his postprandial glucose levels remained elevated. Repaglinide, 4 mg taken 30 minutes before each meal, was prescribed. Fortunately his lipid profile had stabilized on the niacin and statin combination:

• TC, 194 mg per dL

• HDL-C, 45 mg per dL

• LDL-C, 74 mg per dL

• Triglycerides, 132 mg per dL

At his follow-up appointment 4 months later, Patrick's A1C decreased to 7.2%. Despite his increasingly rigorous training program and dietary modifications, his weight returned to baseline of 96 kg. Thinking that the TZD component of his therapy in addition to the secretagogue might be responsible for his weight gain, Patrick asked to discontinue the TZD. His physician advised Patrick of the nonglycemic benefits associated with TZDs and encouraged continuation of the drug. Feeling a bit uncomfortable with his weight, Patrick opted to stop the TZD. He was continued on metformin, 500 mg BID, and repaglinide, 4 mg TID, Niaspan, 1 g plus the statin at bedtime with low dose-aspirin, and valsartan, 160 mg daily.

Eighteen months after his initial diagnosis of IGT, Patrick's A1C increased again to 8.0%. His average blood glucose level was 223 mg per dL. His lipid profile and blood pressure remained at target. Since stopping the TZD 5 months earlier, his weight had decreased 1.8 kg. Because the last two A1C levels were above the ADA-recommended target, intensification of the diabetes regimen was discussed.

Patrick opted to begin treatment with bedtime basal insulin while continuing his twice-daily dose of metformin, 500 mg. The basal insulin dose was initiated at 10 U and adjusted weekly by the patient using a fixed dose-adjustment chart provided by his physician, targeting fasting blood glucose levels less than 100 mg per dL. Three months after starting his new diabetes regimen, Patrick had been successfully titrated to a basal insulin dose of 22 units at bedtime while on metformin BID. Although he recorded two blood glucose levels of 58 and 61 mg per dL before eating dinner 1 week that he had the flu, he had no documented episodes of nocturnal hypoglycemia. His point-of-service A1C was 6.7%, and he had lost 2 kg since starting his insulin regimen. Patrick understands that further intensification of his diabetes regimen may be necessary in the future. Patrick's home blood glucose meter downloads are presented in Figure 4-13.

Summary

Type 2 diabetes is a progressive disease, the pathophysiology of which is dependent on the ability of the pancreatic beta cells to produce enough insulin to maintain normoglycemia. Impaired insulin action at sites that include the liver, adipose tissue, and skeletal muscle limit the ability of insulin to bind with receptors, so that intracellular glucose transport is reduced. Postreceptor signaling defects further limit intracellular glucose transport and secretion of insulin from the pancreatic beta cells. The resultant glucose toxicity is cytotoxic to beta cells and minimizes the storage of FFAs within the adipose tissue. FFAs are beta-cell toxins and also worsen IR.

Management of patients with T2DM should combine lifestyle intervention with pharmacotherapy. Intervention should be aggressive to minimize beta-cell apoptosis in the short term and reduce the long-term risk of diabetes-related complications. As most patients with T2DM will eventually require insulin therapy, physicians should not hesitate to discuss this possibility during the early stages of the disease. Doing so will likely make the transition from oral agents to injectable therapy more acceptable to the patient.

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