Prim Care Clin Office Pract 34 (2007) 731759

Diagnosis and Management of Type 2 Diabetes and Prediabetes

Je Unger, MD
Chino Medical Group, Diabetes and Headache Intervention Center, 5475 Walnut Avenue, Chino, CA 91710, USA

Type 2 diabetes mellitus (T2DM) 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 of between 90% to 95% having T2DM [1]. For individuals born in the year 2000, the estimated lifetime risk for developing T2DM is 33% for males and 39% for females [2]. The risk for death among individuals who have diabetes mellitus is almost twice that of individuals who do not have diabetes of similar age [2]. A recent published report indicates that nearly 45% of newly diagnosed cases of diabetes among US children and adolescents are classied as T2DM [3]. The prevalence of T2DM among American children is expected to continue to increase and exceed that of T1DM over the next 10 years [3]. Non-Hispanic black individuals and Mexican-American individuals are 1.8 times and 1.7 times, respectively, more likely to have diabetes than non-Hispanic white individuals [2]. T2DM is a prominent comorbid condition associated with obesity, coronary artery disease, and mental illness [46]. Approximately 90% of patients who have 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 [7]. The development of T2DM diabetes is strongly inuenced by geneticsd 39% of patients who have T2DM have at least one parent who has the disease [8].
E-mail address: jungermd@aol.com 0095-4543/07/$ - see front matter 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pop.2007.07.007 primarycare.theclinics.com

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The lifetime risk for a rst-degree relative of a patient who has T2DM diabetes is 5 to 10 times higher than that of age- and weight-matched subjects without a family history of diabetes [9]. Among monozygotic twin pairs with one aected twin, T2DM eventually develops in 60% to 90% of unaffected twins [8]. First-degree relatives of patients who have T2DM often have impaired glucose tolerance, delayed rst-phase insulin response, and beta-cell dysfunction years before diabetes develops [10]. Successful management of T2DM requires an understanding of the pathophysiology of insulin resistance (IR), a strategy to promote lifestyle modications, 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 prevention of type 2 diabetes Screening for diabetes should be performed by a health care provider annually, beginning at age 30 for all patients at risk for developing type 2 diabetes as shown in Box 1. The easiest way to screen for diabetes is by obtaining a fasting plasma glucose (FPG) level (Fig. 1). Patients who have elevated FPGs (O126 mg/dL)

Box 1. Risk factors for prediabetes and diabetes mellitus [11] 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Family history of diabetes History of cardiovascular disease Overweight or obese (BMI >25 kg per m2) Sedentary lifestyle Latino/Hispanic, nonHispanic black, Asian American, Native American, or Pacic Islander ethnicity Previously identied impaired glucose tolerance or impaired fasting glucose History of hypertension Increased levels of triglycerides, low concentrations of high-density lipoprotein cholesterol, or both History of gestational diabetes History of delivery of an infant with a birth weight >9 pounds Polycystic ovary syndrome Psychiatric illness (bipolar depression, major depression, schizophrenia)

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Fasting Glucose Diabetes mellitus

126 mg/dL

2-Hour Glucose Challenge Diabetes mellitus

200 mg/dL

IFG
100 mg/dL 140 mg/dL

IGT

Normal

Normal

Fig. 1. Diagnosing diabetes. Patients with normal glycemia have fasting blood glucose levels of 100 mg per dL or less. A blood glucose level between 100 and 126 mg per dL suggests the presence of impaired fasting glucose (IFG). A fasting blood glucose higher than 126 is diagnostic of diabetes. Patients with multiple diabetes risk factors who have a normal fasting blood glucose level, should also undergo a 2-hour, 75-g glucose challenge. Blood glucose levels less than 140 mg per dL are considered normal. Glucose levels between 141 and 200 mg per dL are diagnostic of impaired glucose tolerance (IGT). A blood glucose higher than 200 mg per dL is diagnostic of diabetes. (Adapted from Unger J. Screening for type 2 diabetes in primary care. The Female Patient 2004;29:279.)

should be considered high risk and should be retested on a dierent day using a 75 g 2-hour glucose challenge. When the FPG is less than 126 mg per dL and a high index of suspicion exists for diabetes based on the patients risk factors (see Box 1), 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. Prediabetes is the term that describes those metabolic states that occur when blood glucose levels are elevated, but remain below levels that are established for the clinical diagnosis of T2DM. Prediabetes includes states of impaired fasting glucose (IFG) or impaired glucose tolerance (IGT). The 2-hour oral glucose tolerance test is more sensitive for diagnosing prediabetes than the FPG test, and is the recommended screening method for this condition; however, because performing the oral glucose tolerance test is not always practical in an ambulatory care setting, the FPG test may be used to identify patients who have IFG. In the absence of intervention, prediabetes often progresses to T2DM [12]. The hyperglycemia which begins in prediabetes and progresses in partnership with a deterioration of pancreatic b-cell dysfunction and heightened peripheral insulin resistance increases ones risk of cardiovascular complications [13,14]. Cardiovascular disease may develop years before the clinical onset of diabetes mellitus. When current glycemic goals are achieved early in the progression of the disease, b-cell function is preserved and the patient gains residual long-term benets in reducing vascular complications [15]. Results from large randomized controlled trials demonstrate the eectiveness of lifestyle interventions (with and without pharmacologic therapy)

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in preventing the progression of impaired glucose tolerance to T2DM [12,16]. The development of T2DM can be delayed or prevented by modest weight loss (5% to 7% of total body weight) and regular physical activity (eg, 30 minutes of walking, 5 days a week) [12,16]. Bariatric surgery may play a role in reducing ones risk of T2DM developing. A nonrandomized clinical trial consisting of 136 subjects who had IGT and severe obesity (O45 kg excess body weight) were followed up for 2 to 10 years [17]. Of the 109 of these individuals who underwent bariatric surgery, diabetes developed in only 1, in comparison with 6 new cases within the control group. The study authors concluded that surgical intervention in the severely obese, high-risk patients reduced the progression from IGT to diabetes more than 30 fold. The exact mechanisms by which bariatric surgery reverses hyperglycemia or improves ones risk of developing T2DM is uncertain; however, patients who have T2DM are decient producers of the incretin gut hormone, GLP-1. Individuals who have normal glucose tolerance will release GLP-1 in response to an oral glucose load. The GLP-1 then stimulates pancreatic b-cell production and release of endogenous insulin. Following bariatric surgery, endogenous levels of incretin hormones remain elevated for up to 20 years [18].

Pathogenesis of type 2 diabetes T2DM is characterized by hyperglycemia, insulin resistance, and relative impairment of insulin secretion. The clinical features associated with T2DM are based on genetic and environmental inuences. Whether an individual remains euglycemic or advances toward the hyperglycemic pathway is ultimately determined by the ability of ones pancreatic b-cell to produce and secrete enough insulin to maintain normoglycemia. Unlike autoimmune type 1 diabetes (T1DM), the progression to T2DM occurs over a period of from 7 to 10 years. In the prediabetes states of IFG and IGT, pancreatic b-cell excrete increasing amounts of insulin in an attempt to maintain normal glycemia. This 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 b-cell insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting and postprandial hyperglycemia. At the time one is initially diagnosed as having T2DM, less than 50% of the b-cell mass remains functioning [19]. 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. An elevated plasma free fatty acid (FFA) level antagonizes

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insulin action and is the cornerstone of IR, reduced b-cell response to hyperglycemia, and b-cell death (apoptosis). Animal studies suggest that b-cell failure and death are preceded by an increase in plasma FFAs, accompanied by an accumulation of triglyceride within the b-cell [20]. IR is characterized by a reduction in the ability of insulins target tissues (skeletal muscle cells, adipocytes, and hepatocytes) to promote glucose use, which is 30% to 60% lower in diabetics than in normoglycemic subjects [21]. Insulin secretion and insulin sensitivity are interrelated. In T2DM, insulin secretion initially increases in response to IR, to maintain normal blood glucose regulation. At rst, 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 b-cell function and leads to worsening hyperglycemia. Improvement in glycemic control and weight reduction is often associated with improved b-cell function [16]. Insulin resistance can result in a 33% reduction in b-cell function over 4 years in some genetically susceptible individuals [22]. Endogenous insulin produced and secreted by the pancreatic b-cell regulates hepatic glucose production [21]. The amount of glucose released from the liver determines ones 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 in response to a hypoglycemic trigger from the pancreatic alpha cells located around the periphery of the islet. The protective mechanism of glucagon activates hepatic gluconeogenesis and glycogenolysis, thereby raising ambient plasma glucose levels. When released from the adrenal glands in response to stress or a threat, epinephrine also induces glycogenolysis. As prediabetes progresses toward b-cell failure, the reduced levels of circulating plasma insulin can no longer inhibit glucogenesis or glycogenolysis. When blood glucose levels cannot be maintained within the normal range of 70 to 140 mg per dL, postprandial and fasting hyperglycemia begins to develop. A reduction of 50% of ones b-cell function will result in persistent hyperglycemia regardless of ones fasting state. The increased hepatic glucose production in diabetes is coupled with the reduction of insulins ability to facilitate glucose transport into skeletal muscle cells, further intensifying the severity of the hyperglycemic state. Before initiating any metabolic eects in peripheral target tissues, insulin must bind to receptors. Although insulin receptor numbers are reduced in obese individuals, no reduction in insulin receptor activity occurs in hepatocytes or skeletal muscle cells of patients who have T2DM. This suggests that IR arises from intracellular postreceptor abnormalities, which may have genetic or environmental origins [21]. Patients who have T2DM therefore have diculty transporting glucose into the cell to be used as an energy source once insulin binds to the target receptor.

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Finally, insulin resistance is heightened by elevated levels of circulating FFA. In response to IR, lipotoxicity results in the mobilization of FFA from adipocytes. Adipocytes store and release FFA in response to the bodys need for an immediate energy source. When plasma glucose levels are diminished, such as during a prolonged fast or period of starvation, the FFAs supply energy in the form of ketone bodies. This alternative fuel is used primarily by the skeletal muscle and heart, ensuring that the central nervous system will lay claim to any remaining glucose as its obligatory energy source. Unregulated FFA release, however, promotes IR and impaired insulin secretion [21]. Whereas insulin promotes hepatic glucose storage, FFA has the opposite eect by promoting the breakdown of glycogen to glucose as an energy source. Insulin also favors hepatic storage of FFA and the production of triglycerides. As pancreatic b-cell functioning diminishes, insulin levels decrease. Rather than being stored as an energy source, FFA plasma levels increase, adding to ones IR.

Treatment of patients who have prediabetes Treatment of patients who have IFG or IGT is being openly debated. Patients who are identied as having prediabetes have a distinct advantage when compared with newly diagnosed T2DM patients who present to the clinicians oce for the rst time with symptomatic disease and an A1C of 11%. A treatment-na ve T2DM patient has already been exposed to the eects of chronic hyperglycemia and insulin resistance for 7 to 10 years before diagnosis, and has lost at least 50% of his pancreatic b-cell function. Although patients who have prediabetes have early signs of glucose intolerance, their b-cell function and mass remain, relatively intact. Lifestyle changes and pharmaceutical interventions can be introduced that can preserve the patients endogenous insulin production. Lifestyle intervention forms the cornerstone of for prediabetes management. Based upon the diabetes prevention program, patients should target a 5% to 7% reduction in total body weight and exercise 30 minutes daily 5 days per week [23]. Patients should be assessed for cardiovascular risk before beginning any moderate or intensive exercise program. The use of the insulin sensitizersdmetformin and the thiazolidinediones (TZDs)dhas been shown to be benecial in delaying the progression from prediabetes to diabetes [12,24]. In the Diabetes Prevention Program, metformin, 850 mg twice daily, reduced the relative risk of progression to type 2 diabetes by 31%. Metformin may additionally improve outcomes by inducing weight loss. Although conducted in women who had a history of gestational diabetes, the Troglitazone in the Prevention of Diabetes (TRIPOD) study demonstrated a 56% reduction in relative risk in progression of prediabetes to diabetes. Treatment was terminated prematurely because of

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the withdrawal of troglitazone from the US market, yet persistent protective eects were observed more than 8 months after the drug was discontinued. Long-term clinical trial data are not yet available for the newer TZDs, but there is a reasonable expectation that the currently available medications in this drug class may provide similar benets. Until further clinical trial data become available, clinician judgment based upon individualized patient characteristics will determine the use of insulin sensitizers in prediabetes. The use of nonapproved pharmacologic therapy in patients who have prediabetes has not been advocated by the American Diabetes Association or the American Association of Clinical Endocrinologists [7,11]. Age-related dierences in response to therapy are important factors to consider, because weight loss in elderly patients, for example, may be deleterious. There is a general consensus that reducing postprandial hyperglycemia may decrease the risk of cardiovascular events in patients who have IGT as well as T1DM [15] and T2DM [25]. Studies of selected angiotensin-converting enzyme inhibitors (ramipril) and statins (pravastatin) have suggested that these drugs may also delay the progression of prediabetes to diabetes [26,27]. The Diabetes Reduction Assessment with Ramiprial and Rosiglitazone Medication (DREAM) study [28] followed 5269 subjects who had 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 1000 people treated with rosiglitazone for about 3 years, 144 cases of diabetes will be prevented and 200 people who have prediabetes will progress to normoglycemia. Although rosiglitazone may be associated with a slight increase in the risk of heart failure, especially in individuals who have diastolic dysfunction, this study did suggest that patients who have either IFG or IGT can benet from chemoprevention [28].

Management of type 2 diabetes The goals of pharmacologic intervention in T2DM are to normalize hyperglycemia, improve insulin sensitivity, preserve pancreatic b-cell, reduce hepatic glucose output, improve peripheral glucose use, and delay or prevent long-term complications. Many factors must be considered when designing treatment programs for patients who have T2DM, including  The age and gender of the patient  The length of time the patient has had T2DM

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 The individual patients 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 agents (incretin mimetics, dipeptidyl peptidase IV inhibitors [DPP-IV], insulin analogs, inhaled insulin, and combination drugs) has increased treatment options for T2DM while supplementing our traditional therapies. Whether used alone or in combination with other blood glucose-lowering interventions, the availability of these novel agents has provided an increased number of choices for practitioners and patients, and some degree of uncertainty regarding the most appropriate means of treating this ubiquitous disease. Regardless of the apparent complexity of the pharmacologic options, successful management of diabetes can be attained by integrating the following strategies into each patients treatment protocol: 1. Follow the national standards of care as published by the American Diabetes Association (http://care.diabetesjournals.org/content/vol30/ suppl_1/) and the American Association of Clinical Endocrinologists (http://www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf). 2. Although individualization of therapy is encouraged, treatment should, with rare exceptions, be intensied for all patients until the recommended glycemic targets have been attained. 3. Successful management of diabetes requires patient participation. Unlike other chronic disease states (eg, cancer, hypertension, or depression), patients who have diabetes must make multiple decisions on a daily basis on how maintain euglycemia. Not every decision made will result in a perfect outcome. Patients should be provided with the educational tools they will need to make appropriate management choices. Praise should always be provided to those who succeed. Those who are struggling to attain success should be re-educated and encouraged rather than criticized. As physicians, we must do our absolute best to nd ways to help our patients become successful at managing their diabetes. 4. Avoid referring to patients as being noncompliant. For those of us who believe they can do better at managing diabetes than our patients, we should ask yourselves, Can I check my blood sugar 4 times a day,

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correctly interpret the results, provide the proper amount of insulin based upon the severity of my insulin resistance at that particular time of the day, accurately count the amount of carbohydrates I will eat for the next meal, and inject the insulin 10 to 15 minutes before eating? Did I account for any increase in physical activity I plan to do within two hours after eating? If my blood sugar drops below 60, how can I reverse the hypoglycemia safely without eating an excessive amount of calories? Did I check my glucose level before I drove my kids to school today to make sure I was not hypoglycemic? Did I remember to check my blood glucose before and after exercise? Did I take my three blood pressure pills, my two cholesterol pills, and my aspirin today? Did I remember to call my pharmacy to get all of my prescription rells this month? Did I check my feet before I went to bed last night? When was the last time I went to see the eye doctor? The dentist? Do I wake up at 3 AM to check my blood glucose levels each night? Remember, your pancreas is very likely working normally, whereas your patient is using his or her brain as pancreas. Give them credit for what they are doing to help themselves. Treatment plans should be concordant or acceptable to both the patient and the prescriber. Treatment plans should also be exible. Patients should be informed that intensication and changes in the treatment strategy can be expected at each visit based upon whether or not target glycemic goals are being attained. 5. Home blood glucose monitoring is an essential component to successful management of T2DM. Table 1 [29] lists suggestions on how often patients should perform self-blood glucose monitoring. 6. Diabetes is a progressive disorder. As such, the easiest patients to manage are those who have prediabetes. Patients who have multiple endstage complications are extremely challenging. Therefore, practice aggressive and intensive management as soon as the diagnosis of IGT, IFG, or T2DM is made. Healthy lifestyle choices, self-blood glucose monitoring and regularly scheduled exercised should be strongly encouraged. Patients should be screened and treated for any other
Table 1 Optimal frequency of home blood glucose monitoring for patients with type 2 diabetes A1C level %7% R8.5% Frequency of testing Fasting and postabsorptive (bedtime) rst 7 days of each month Fasting, 10 AM (2 hours postprandial) and bedtime (postabsorptive) on Monday, Wednesday, and Sunday each week.

Data from Unger J. Assessing gylcemic control using home blood glucose monitoring, continuous glucose sensing, and glycated hemoglobin (A1C) testing. In: Unger J, editor. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 32162.

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metabolic abnormalities such as hypertension, hyperlipidemia, microalbuminuria and obesity. Unless contraindicated, patients should be started on low-dose aspirin and a statin to minimize their risk of cardiovascular disease. Pharmacologic intervention should be considered based upon our understanding of the variable and changing relationship between how much fasting and postprandial glucose levels impact ones A1C. The relative contribution of fasting glucose levels to overall glycemia is approximately 70% in patients who have A1C levels greater than 10.2% [25]. The contributions of fasting and postprandial glucose levels are approximately equal when A1C levels are between 7.3% and 8.4% [25]. In a more recent study using continuous glucose sensing, Monnier and colleagues [30] demonstrated that postbreakfast hyperglycemia is most often the initial metabolic abnormality noted in patients who have early T2DM. As the disease progresses, patients developed prolonged nocturnal hyperglycemia caused by excessive hepatic glucose production. Patients will then experience fasting hyperglycemia. Because postprandial hyperglycemia is linked with the development of cardiovascular disease, and fasting hyperglycemia marks the progression of T2DM, one should target fasting glucose concentrations primarily, and then focus on reducing postprandial (especially postbreakfast) glucose concentrations. Clearly, eective management of both fasting and postprandial hyperglycemia levels simultaneously should allow the patients to achieve their targeted A1C levels. Treatment options for newly diagnosed patients who have T2DM as well as those who are currently treated with oral and parenteral agents are listed in Table 2 [21]. The six available classes of oral agents target dierent 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 ones 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 benets of the dierent types of oral hypoglycemic agents. Some medications may increase weight or induce hypoglycemia, whereas others (metformin) must be held before undergoing certain diagnostic procedures. Insulin is the preferred drug for patients who have diabetes admitted to the hospital for acute illness. Insulin may also be necessary in special situations that complicate the management of T2DM, such as during the concomitant use of corticosteroids, for patients requiring surgery, for

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Table 2 Pharmacologic regimens for treating type 2 diabetes mellitus A1C level Pharmacologic choices Comment Monitor and titrate medication every 23 months. Adjust dose or begin combination therapy if A1C is R7%

Part I. Treatment-na ve patients 6%7% Metformin Sulfonulurea (SU) Meglitinide TZD DPP-IV inhibitors a-glucosidase inhibitor (AGI) 7%8% Oral agents  Secretagogue metformin  Secretagogue TZD  Secretagogue AGI  TZD metformin  DPP-IV metformin  DPP-IV TZD  SU metformin TZD Fixed combination drugs  Pioglitazone metformin  Rosiglitazone metformin  Rosiglitazone glimepiride  Pioglitazone glimepiride  Glyburide metformin Inhaled insulin  For prandial glycemic control as monotherapy  For prandial glycemic control in combination with long-acting insulin analog Basal insulin analogs  With any oral agent (preferably metformin)  With short-acting insulin analog for prandial glycemic control 8%10% Initiate and intensify combination therapies (oral agents or oral agents insulin) listed above Normalize both fasting and postprandial glucose hyperglycemia Consider premixed insulin analogs if A1C is !9.5%, given once, twice, or three times daily with or without oral agents [21]. O10% Initiate insulin therapy Basal bolus insulin  Prandial rapid acting insulin analog long-acting insulin analog  Inhaled insulin long-acting insulin analog

Intensify therapy as soon as AIC rises O7% Check status of glutamic acid decarboxylase (GAD)-65 autoantibodies. If positive, patient has latent autoimmune diabetes of adulthood (LADA). These patients should be placed on intensive insulin therapy [21] Doses of medications and treatment protocols should be based upon results of patients self-blood glucose testing. Always suggest using insulin pens as a preferred method of insulin delivery.

Frequent home blood glucose monitoring is essential. Patients who are symptomatic should be placed on insulin therapy. Test GAD antibody status as above. Premixed insulins should be reserved for patients who eat three regularly scheduled meals daily.

Patients may be placed on oral agents if their A1Cs improve and if they recover some of their pancreatic beta cell function over time.

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742 Table 2 (continued ) A1C level Pharmacologic choices

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Comment

Part II. Patients with T2DM currently treated pharmacologically O7% All combination therapies listed above are also appropriate for patients who are receiving ongoing therapy for T2DM, but whose A1C is above the recommended treatment target. Add exenatide to an oral agent  Exenatide metformin  Exenatide metformin SU  Exenatide TZD  Exanatide SU Add pramlintide to prandial insulin Begin insulin replacement therapy for patients on maximum oral combination therapies or on oral exenatide whose A1C levels are O7% (as listed above for treatment-na ve patients). Continue metformin to minimize O8.5% Begin physiologic insulin weight gain and cardiovascular replacement therapy risk. (basal-bolus insulin protocol)  Multiple daily injections  Inhaled insulin for prandial glucose control long acting insulin analog  Continuous subcutaneous insulin infusion (insulin pump therapy)

patients who have restricted oral intake, or in those patients who become pregnant while taking oral agents. The pharmacologic agents used to treat patients who have T2DM are summarized in Table 3 [21].

Treatment targets and potential risks of therapeutic agents The primary goals of diabetes management are to minimize short- and long-term complications. This can best be accomplished by targeting fasting and postprandial blood glucose levels to fall within the ranges suggested by the American Diabetes Association and the American Association of Clinical Endocrinologists (Table 4). Although treatment must be individualized, most patients should be intensively managed so that they may be successful in achieving these goals. Exceptions may be made for elderly patients, those who live alone, or individuals who have had a recent myocardial infarction

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or stroke. Induction of hypoglycemia in these patients could have devastating consequences. Many patients believe that because they do not have to take insulin, their disease is less severe than their injecting counterparts. Nothing can be further from the truth. Diabetes should be considered a toxic metabolic state regardless of the etiology of diabetes or the age at which the patient is affected. Patients who have T2DM have a two to four times higher increased risk of cardiovascular events than those who have normal glycemia [31]. Yet for every 1% reduction in A1C, one can expect a 35% reduction in microvascular complications and a 14% reduction in macrovascular risk [19]. Most importantly, patients who are able to achieve an A1C of less than 7% should expect to live 5 years longer and experience 15 years of free of complications when compared with those who have A1Cs greater than 7% [32]. With all the new and powerful pharmacologic agents we have at our disposal, controversy still exists regarding their specic risks and benets. A recently published meta-analysis of 42 studies reported an increased risk of myocardial infarction (odd ratio 1.43) and cardiovascular death (odds ratio 1.64) in patients taking rosiglitazone compared with control patients [33]; however, the authors also discussed some important limitations with their data: (1) they did not have access to the original source data, and consequently were unable to perform either time-to-end analyses or calculations of dose-response relationships from the data they did obtain; (2) the trials they analyzed were not powered to explore cardiovascular outcomes as a primary or secondary endpoint; (3) some of the adverse events they reported were ambiguous, and some cardiovascular events may even have been misclassied; and (4) the actual number of adverse events was small. When compared with the number of patients taking rosiglitazone, the risk of having a cardiovascular event in patients who have an inherent elevated risk for cardiovascular disease appears to be very small. Denitive resolution regarding the magnitude and statistical and clinical signicance of these ndings will require a more sensitive time-toevent (life-table) analysis and the nal results of the ongoing phase 3 trial (RECORD) to evaluate cardiovascular outcomes in patients receiving rosiglitazone; the latter are expected in 2009. Interim analysis of the results of the RECORD trial with 4447 patients after 3.75 years of follow-up shows no statistically signicant increased risk of myocardial infarction, cardiac death, or all-cause mortality in individuals receiving rosiglitazone [34]. This has been called an inconclusive study because of the limited number of cardiac events observed to date. To date, TZDs do not appear to be associated with an increased risk of cardiovascular disease [34]. TZDs appear to be safe when used as indicated, in patients who have T2DM who do not have clinical evidence of New York Heart Association Class III or IV cardiac disease [35,36].

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Table 3 Oral hypoglycemic agents for treating type 2 diabetes Drug class and generic (brand) name Sulfonylureas Initial dose Maximum dose Mechanism of action By binding to sulfonylurea receptors on the surface of pancreatic b-cells, these agents cause the voltage-dependent potassium adenosine triphosphate channels to close, which facilitates cell-membrane depolarization, calcium entry into the cell, and insulin secretion [21]. 12 mg/d 8 mg/d Comments Lower A1C 1%2% [21] May be used as monotherapy or in combination with other oral agents, exenatide and insulin Best taken at bedtime or 1 hour before breakfast. Cheapest oral hypoglycemics on the market Can administer with breakfast, rst main meal of the day, or at bedtime Have an eect on both fasting and postprandial glucose levels

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Glimepiride (Amaryl)

Glipizide (Glucotrol) Glipzide XL (Glucotrol XL) Glyburide (Micronase, Glynase, Diabeta)

5 mg daily 2.5 mg daily in elderly patients 10 mg/daily 1.255 mg daily

20 mg twice a day

20 mg daily as a single dose 20 mg in 12 divided doses

Can be taken as a single dose at bedtime Glynase (micronized glyburide doses are 312 mg/day)

Meglitinides

Stimulate a rapid but short-lived release of insulin from pancreatic b-cells that lasts 1 to 2 hours. Mechanism of action similar to sulfonylureas. Elderly patients and patients not previously treated with hypoglycemic agents or patients with an A1C !8% use 0.5 mg 3 times a day. Patients previously treated with hypoglycemic agents, or those with A1C O8% use 12 mg three times a day. 120 mg 3 times a day 60 mg 3 times a day in elderly patients 16 mg/day

Repaglinide (Prandin)

Hypoglycemia less common than with sulfonylureas Should be taken 15 minutes before meals More costly than sulfonylureas Target postprandial hyperglycemia Administer 15 minutes before meals Dose may vary based on size of meal Best used with metformin

TYPE 2 DIABETES AND PREDIABETES

Nateglinide (Starlix)

120 mg 3 times a day

Take 1530 minutes before each meal Primary mechanism of action is the reduction of hepatic glucose production Associated with weight loss and minimal incidence of hypoglycemia Lowers A1C by 1%2% Nonglycemic benets include lowering of LDL cholesterol, triglycerides, and plasminogen activator inhibitor 1 levels

Metformin

745

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Table 3 (continued ) Drug class and generic (brand) name Initial dose Maximum dose Mechanism of action Comments Can restore fertility in patients who have PCOS (see article by Dr. Futterweit elsewhere in this issue) Can delay onset of diabetes in some high-risk patients Administer with food to avoid gastrointestinal (GI) side eects. Slow upward dose titration advised. Hold drug for 24 hours before and after any IV contrast study Maximum eective dosage is 2 g/day Use with caution if serum creatinine is O1.5 mg/dL (men) or 1.4 mg/dL (women), or in patients who have congestive heart failure, liver disease, or alcohol abuse. Obtain serum creatinine before initiating therapy with metformin.

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Metformin (Glucophage)

Metformin XL (Fortamet) Metformin XR (Glucophage XR)

500 mg twice a day or 850 mg once daily in the morning with food 5001000 mg once daily 5001000 mg once daily

2550 mg in three divided doses with meals 2500 mg once daily 15002500 mg once daily

Take with main meal

Metformin XR (Glumetza)

500 mg once daily

10002000 mg 12 times daily

Metformin oral suspension (Riomet)

500 mg (5 cc) twice a day

2550 mg (25.5 mL) per day

a glucosidase inhibitors

Use slow titration to avoid GI side eects: 25 mg once daily for 2 weeks, then 25 mg twice daily for 2 weeks, then 25 mg 3 times daily for 8 weeks. Maximum dose is 100 mg 3 times daily.

Delays carbohydrate absorption from the gut, thereby minimizing postprandial hyperglycemia

Take with main meal 500 twice daily with food. Increase 500 mg/d weekly or 850 mg daily every 2 weeks, to maximum of 2550 mg/d Start with single 1000-mg dose at evening meal. Can increase to maximum of 2000 mg either once daily or 1000 mg twice daily Can use for children, patients with diculty swallowing, or those in nursing homes with feeding tubes Administer with rst bite of each main meal Side eects are signicant and eect adherence. They include abdominal cramping and atulence. Must use pure glucose to reverse drug-induced hypoglycemia Reduce A1C 0.6%1.3% Do not use in patients who have inammatory bowel disease (continued on next page)

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Table 3 (continued ) Drug class and generic (brand) name Acarbose (Precose) Miglitol (Glyset) Thiazolidinediones Initial dose 25 mg daily 25 mg daily Maximum dose 100 mg 3 times a day 100 mg 3 times a day Enhances insulin sensitivity Thiazolidinediones are pharmacological ligands for a nuclear receptor known as peroxisome proliferator-activated receptor g. When activated, this receptor binds to response elements on DNA and alters transcription of various genes that regulate carbohydrate and lipid metabolism Decrease in glucose may not begin for 4 weeks after drug initiation Reduce A1C 1.5%1.6% Side eects include weight gain and edema Maximum ecacy may not be apparent for 6 months after drug initiation Nonglycemic eects include:  Lowering blood pressure  Improving endothelial function Raise HDL cholesterol Lower triglycerides Enhance brinolysis Reduces C-reactive protein levels by 30% May prevent pancreatic beta cell death Contraindications:  ALT O2.5 upper limits of normal  Hepatic disease  Alcohol abuse  NYHA Class III or IV Mechanism of action Comments

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Pioglitazone (Actos) Rosiglitazone (Avandia)

15 mg daily with or without food 2 mg twice daily or 4 mg once daily, with or without food

45 mg daily 4 mg twice daily or 8 mg once daily Stabilize endogenous GLP-1 at physiological concentrations, and induce insulin secretion in a glucose-dependent manner No signicant side eects. Reduce dose in patients with renal insuciency. Unlike incretin mimemtics, will not result in weight loss Reduce A1C 0.8%

Dipeptidyl-peptidase 4 inhibitor (DPP-IV inhibitors)

TYPE 2 DIABETES AND PREDIABETES

Sitagliptin (Januvia)

100 mg daily with or without food If creatinine clearance is 3050 mL/min/1.73 m2, reduce dosage to 50 mg daily. If creatinine clearance is !30 mL/min/1.73 m2, reduce dosage to 25 mg daily 15 mg/500 mg or 15 mg/850 mg once or twice daily with food

100 mg daily

Combination drugs Pioglitazone metformin (Actosplusmet)

Same

Indicated for patients with T2DM not adequately controlled on either pioglitazone or metformin alone.

Rosiglitazone metformin (Avandamet) Rosiglitazone glimepiride (Avandaryl)

2 mg/500 mg twice daily with food 4 mg/1 mg or 4 mg/2 mg once daily

4 mg/1000 mg twice daily with food 8 mg (rosi)/4 mg (glim) daily

Administer with rst meal of the day (continued on next page)

749

Table 3 (continued ) Drug class and generic (brand) name Glyburide metformin (Glucovance) Initial dose 1.25 mg/250 mg once or twice daily with food Maximum dose 5 mg/500 mg (two pills twice daily) with food Mechanism of action Comments Starting doses should not exceed daily doses of glyburide or metformin already taken; dose increases can be made at 2-week intervals. Indicated for patients with T2DM inadequately controlled by diet and exercise alone. Starting doses should not exceed daily doses of glyburide or metformin already taken; dose increases can be made at 2-week intervals. Indicated for patients with T2DM inadequately controlled by diet and exercise alone. Not recommended for patients with renal insuciency Gut incretin hormone which is decient in patients with T2DM. Stimulates release of insulin from pancreatic beta-cells Most common side eect is nausea, which can be minimized if patients are informed to limit fatty food

750

Glipizide metformin (Metaglip)

2.5 mg/25 mg once or twice daily with food

5 mg/500 mg (two pills twice daily with food)

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Sitagliptin metformin (Janumet) Parenteral agents Exenatide (Byetta)

50 mg/500 mg twice daily with food

50 mg/1000 mg twice daily with food

5 micrograms twice daily administered within 60 minutes of breakfast and dinner. After 1 month, if patient is tolerating this

10 micrograms twice daily administered within 60 minutes of breakfast and dinner

dose, increase to the 10 microgram dose.

in a glucose dependent fashion. Reduces postprandial hyperglycemia by lowering pancreatic alpha cell glucagon production. In animal models, stimulates beta cell growth and prevents apoptosis. Improves gastric emptying. As a neuroendocrine hormone, reduces appetite and often results in weight reduction.

consumption during the rst month of drug use. Lowers A1C by 1.1%. Weight reduction is signicant. Many patients will loose over 10 lbs in 2 years. Weight loss is more profound in those individuals who are most obese. Weight loss will continue as long as patient remains on the drug. Exenatide works primarily on reducing postprandial hyperglycemia; however, weight loss can have an eect on lowering fasting glucose levels as well. Do not use if creatinine clearance is !30 mL/min/1.73 m2 Indicated for patients on a sulfonylurea, metformin, or a combination of the two who have not achieved adequate glycemic control. May also be used with a TZD with or without metformin in patients with T2DM inadequately controlled on their oral agents. (continued on next page)

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Table 3 (continued ) Drug class and generic (brand) name Pramlintide (Symlin) Initial dose For T2DM initiate at 60 micrograms injected 1015 minutes before each meal. Maximum dose Maximum recommended dose is 120 micrograms injected 1015 minutes before each meal. Mechanism of action Reduces postprandial hyperglycemia by lowering pancreatic alpha-cell glucagon release. As a neuroendocrine hormone, reduces appetite. Improves gastric emptying. Reduces oxidative stress, which can induce long-term diabetes-related complications [21,44] Comments Unlike exenatide, does NOT work in a glucose-dependent fashion; therefore, patients may develop hypoglycemia on this drug. Patients should ONLY use pramlintide if they are using concomitant insulin therapy. When starting pramlintide, reduce the prandial insulin dose by 50%. Although the maximum recommended dose for patients with T2DM is 120 micrograms, patients who are tolerating the drug will may try to increase the drug further, stopping at the point where they begin to feel either appetite suppression or nausea.

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Insulin

See text

Data from AACE diabetes mellitus guidelines. Endocr Pract 2007;13 (Suppl 1):1634; and Unger J. Managing type 2 diabetes in adults. In: Unger J. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 11891.

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Table 4 Recommended treatment targets for patients with type 2 diabetes American Diabetes Association recommendations !7% 90130 mg/dL !180 mg/dL American Association of Clinical Endocrinologists recommendations %6.5% !110 mg/dL !140 mg/dL

Parameter A1C Preprandial plasma glucosea Postprandial plasma glucoseb

a

Preprandial glucose levels include fasting glucose as well as any glucose level obtained before eating a meal. b Postprandial glucose levels are obtained 12 hours after eating. Data from ACE/ACE consensus conference on the implementation of outpatient management of diabetes mellitus: consensus conference recommendations. Endocr Pract 2006;12(Suppl 1):8; and American Diabetes Association. Clinical practice recommendations. Diabetes Care 2007;30(Suppl 1):S10.

Initiating insulin in patients who have type 2 diabetes Patients who are either unable to achieve their targeted A1C with the use of oral agents at maximum doses with or without parenteral augmentation (exenatide) or those patients who remain symptomatic while on such therapies should be transitioned to insulin. Many physicians and patients may feel that insulin initiation is synonymous with the beginning of a more serious phase of ones disease state; however, as when less than 80% of pancreatic b-cell function remains, there is little likelihood that oral agents will successfully lower fasting or postprandial glucose levels into their normal therapeutic ranges. Therefore, the initiation of insulin simply marks the forward progression of ones chronic state of hyperglycemia. Eventually, if one lives long enough, insulin replacement therapy will be required to maintain euglycemia. Several options are available for transitioning patients to insulin therapy. Although no one treatment strategy works for every patient, several unique and simple protocols are discussed below, each of which may be easily initiated within the primary care setting. Treat-to-trial protocol Patients who have an A1C of less than 9% who have had T2DM for usually less than 7 years might be successful at lowering their A1C to target (! 7%) by simply using a single dose of basal analog insulin (glargine or detemir) combined with metformin alone in combination with another sulfonylurea [37,38]. Studies have demonstrated that approximately 60% of patients who have T2DM having an A1C greater than 8.5% can attain an A1C less than 7% using such a protocol. Although the initial published studies suggested using 10 units of basal insulin as a starting dose and increasing the dose weekly based upon the average fasting blood glucose levels, most

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physicians tend to take a much more aggressive approach. The author has found success in the following treat-to-target protocol:  Initial basal insulin dose (glargine or detemir) is determined using the following formula: Initial basal insulin dose patients weight in kilograms =2 0:4 Thus, a 100 kg patient would require an initial starting dose of 100 0.4 40 units, which is given at a consistent time each evening before bedtime.  Check the fasting blood glucose level each morning  Increase the dose of basal insulin by 2 to 3 units every 2 to 3 days until all fasting glucose levels for 7 consecutive days are !110 mg/dL  If any single fasting glucose level is !60 mg/dL, decrease the dose of basal insulin by 2 units and discontinue the insulin dose titration. All-to-target regimen If the patient is using greater than 70 units of basal insulin and the A1C remains between 7.5% and 8.5%, consider adding an injection of fast-acting insulin analog targeting postprandial hyperglycemia for the largest meal of the day. In most cases, this would include dinner. The patient would continue using the treat-to-target regimen as above. Metformin would be continued, but the patient would be asked to discontinue the sulfonylurea if they are taking one. The dose of the dinner time (evening) insulin would be determined as below: Note that carbohydrate counting is not necessary using this regimen. Patients can simply estimate the size of the meal while adding or subtracting insulin as needed:  0.1 units (u)/kg given 10 minutes before the meal. (glulisine can be given up to 20 minutes after the conclusion of a meal). Thus a 100 kg man would require 10 units of insulin for dinner.  The dose of the insulin can be adjusted simply according to the size of the meal: -For very large meals, add 23 units -For moderate sized meals, add 2 units -For small meals, subtract 12 units  If the A1C does not reach the target of !7% within 3 months, use a similar dosing strategy and target breakfast. Repeat the A1C again after 3 months. If still O7%, use the same protocol and target breakfast, lunch, and dinner. You have now transitioned the patient into a basal-bolus regimen. Predictive 303 protocol This protocol has been shown to be eective in allowing insulin na ve patients to adjust their own dose of basal insulin within primary care

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settings. Over 5000 patients who have poorly controlled T2DM were randomized to either self-adjust their basal insulin regimen based on a simple regimen or to have the medical sta dose their insulin based upon the community standard of care [39]. The patients who were insulin na ve were found to be just as adept at lowering their fasting blood glucose levels and A1Cs as were the medical sta, suggesting that insulin adjustments are not very dicult to incorporate into ones daily routine. The US Predictive 303 Trial used insulin detemir as the basal insulin of choice [39].  The initial dose of basal insulin averaged 0.4 u/kg.  Fasting blood glucose levels should be obtained daily, and the basal insulin should be ajdusted according to the protocol listed in Table 5.  Patients may continue to use their prescribed oral agents while adjusting the dose of their basal insulin. 1,2,3 protocol for premixed insulin analogs Premixed insulin analogs might be useful for patients having a baseline A1C between 8.5% and 10%. Candidates who might be successful users of premixed insulin analogs include those who eat three meals daily and keep a regular scheduled routine of work and physical activity. The mixed insulin analogs lower postprandial glucose levels as well as improve fasting glucose levels. The analogs are preferred over the human premixed insulins because of their more predictable rates of absorption and less frequent induction of hypoglycemia [4042]. In a 48-week, multicenter, open-label trial [43], patients who had T2DM and who were not achieving targets on oral agents (with or without oncedaily basal insulin therapy with neutral protamine Hagedorn [NPH] or glargine) were titrated with Aspart Mix 70/30 to target plasma glucose levels. The study included 100 patients and was conducted in three separate phases. In phase 1, patients initiated treatment with Aspart Mix 70/30 once before supper. Dosing frequency was increased to twice-daily in phase 2, and to three-times daily in phase 3 at 16 and 32 weeks, respectively, if patients did not achieve an A1C of less than 6.5%. Patients completed end-of-study when they achieved A1C less than or equal to 6.5% or 48 weeks, whichever came rst. At the end of the trial, 77% of patients achieved A1C levels of

Table 5 Basal insulin adjustment Average fasting blood glucose over 3 days ! 80 mg/dL 80110 mg/dL O 10 mg/dL Adjust basal insulin dose 3 units (3) No change (0) 3 units (3)

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less than 7.0%, and 60% of patients attained an A1C level of less than or equal to 6.5% through once, twice or three-times daily dosing of Aspart Mix 70/30 [43]. The 1,2, 3 protocol is described below:  Begin by dosing Aspart Mix 70/30 12 units 1015 units before dinner.  Increase dose of Aspart Mix 70/30 by 2 units every 2 days until the prebreakfast glucose level is %110 mg/dL.  Check the A1C after 3 months. If not less than 6.5%, add a second injection of Aspart Mix 70/30, beginning with 6 units given 1015 minutes before breakfast. Continue monitoring the AM glucose readings and adjusting the dinner dose of insulin as before.  Increase the breakfast dose 2 units every 2 days if the dinner glucose readings are averaging R110 mg/dL.  Check A1C after 3 months.  If the A1C remains O6.5%, begin using a lunchtime dose of Aspart Mix 70/30, starting with 4 units injected 1015 minutes before eating. Monitor a 2-hours postlunch blood glucose level. Increase the lunchtime dose of Aspart Mix every 2 days by 2 units until the postlunch glucose levels are %140 mg/dL.  Check A1C after 3 months. If not 7%, other treatment options should be considered.

Summary Eective treatment of T2DM requires early initiation of appropriate therapies, frequent monitoring, and reassessment to make certain that therapeutic goals are being attained. T2DM is a progressive disease. Exposure to chronic hyperglycemia can cause macrovascular and microvascular complications, many of which may already be apparent when a patient is initially diagnosed as having T2DM. As b-cell unction deteriorates and insulin resistance intensies, patients will nd that their oral pharmacologic therapy is becoming less eective at minimizing the eects of their chronic hyperglycemia. Eventually, most all patients will require exogenous insulin therapy to normalize both fasting and postprandial hyperglycemia. PCPs, as a group, manage over 90% of all patients who have T2DM. As such, we must have a better understanding of our role as patient educators, advocates, and medical providers for patients suering from this complex metabolic disorder. We must never forget that simply achieving an A1C of close to 7% is not considered acceptable. A patient who does not have diabetes has an A1C of 6.1%. We should therefore do everything in our power to help our patients achieve the lowest and safest A1C possible.

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[39] Meneghini L, Koehnen C, Weng W, et al. The usage of a simplied self-titration dosing guideline for insulin detemir in patients with type 2 diabetesdresults of the 303 algorithm study. Presented (abstract # 197-OR) at the 67th annual meeting of the American Diabetes Association. Chicago (IL), June 2326, 2007. [40] Unger J. Physiologic insulin replacement therapy. In: Unger J, editor. Diabetes management in primary care. Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 192264. [41] Hermansen K, Colombo M, Storgaard H, et al. Improved postprandial glycemic control with biphasic insulin aspart relative to biphasic insulin lispro and biphasic human insulin in patients with type 2 diabetes. Diabetes Care 2002;25:8838. [42] Bretzel RG, Arnold S, Medding J, et al. A direct ecacy and safety comparison of insulin aspart, humansoluble insuling, and human premix insulin (70/30) in patients with type 2 diabetes. Diabetes Care 2004;27:10237. [43] Garber AJ, Wahlen J, Wahl T, et al. Attainment of glycaemic gols in type 2 diabetes with once-, twice-, or thrice-daily dosing with biphasic insulin aspart 70/30 (the 1-2-3 study). Diabetes Obes Metab 2006;8(1):5866. [44] Ceriello A, Piconi L, Quagliaro L, et al. Eects of pramlintide on postprandial glucose excursions and measures of oxidative stress in patients with type 1 diabetes. Diabetes Care 2005;28:6327.