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InternalMed_Harrison. To avoid exercise-related hyperor hypoglycemia, individuals with type 1 DM should (1) monitor blood glucose before, during, and after exercise; (2) delay exercise if blood glucose is >14 mmol/L (250 mg/ dL) and ketones are present; (3) if the blood glucose is <5.6 mmol/L (100 mg/dL), ingest carbohydrate before exercising; (4) monitor glu cose during exercise and ingest carbohydrate to prevent hypoglycemia; (5) decrease insulin doses (based on previous experience) before exercise and inject insulin into a nonexercising area; and (6) learn individual glucose responses to different types of exercise and increase food intake for up to 24 h after exercise, depending on intensity and duration of exercise. In individuals with type 2 DM, exercise-related hypoglycemia is less common but can occur in individuals taking either insulin or insulin secretagogues.


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InternalMed_Harrison. younger age in both type 1 and type 2 DM, routine screening for coronary artery disease has not been shown to be effective and is not recommended (Chap. 419). Untreated proliferative retinopathy is a relative contraindication to vigorous exercise, because this may lead to vitreous hemorrhage or retinal detachment. Optimal monitoring of glycemic control involves plasma glucose measurements by the patient and an assessment of long-term control by the physician (measurement of hemoglobin A1c [HbA1c] and review of the patient’s self-measurements of plasma glucose). These measurements are complementary: the patient’s measurements provide a picture of short-term glycemic control, whereas the HbA1c reflects average glycemic control over the previous 2–3 months.


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InternalMed_Harrison. Self-Monitoring of Blood Glucose Self-monitoring of blood glucose (SMBG) is the standard of care in diabetes management and allows the patient to monitor his or her blood glucose at any time. In SMBG, a small drop of blood and an easily detectable enzymatic reaction allow measurement of the capillary plasma glucose. Many glucose monitors can rapidly and accurately measure glucose (calibrated to provide plasma glucose value even though blood glucose is measured) in small amounts of blood (3–10 μL) obtained from the fingertip; alternative testing sites (e.g., forearm) are less reliable, especially when the blood glucose is changing rapidly (postprandially). A large number of blood glucose monitors are available, and the certified diabetes educator is critical in helping the patient select the optimal device and learn to use it properly. By combining glucose measurements with diet history, medication changes, and exercise history, the diabetes management team and patient can improve the


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InternalMed_Harrison. optimal device and learn to use it properly. By combining glucose measurements with diet history, medication changes, and exercise history, the diabetes management team and patient can improve the treatment program.


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InternalMed_Harrison. The frequency of SMBG measurements must be individualized and adapted to address the goals of diabetes care. Individuals with type 1


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InternalMed_Harrison. Diabetes Mellitus: Management and Therapies 2410 DM or individuals with type 2 DM taking multiple insulin injections each day should routinely measure their plasma glucose three or more times per day to estimate and select mealtime boluses of short-acting insulin and to modify long-acting insulin doses. Most individuals with type 2 DM require less frequent monitoring, although the optimal frequency of SMBG has not been clearly defined. Individuals with type 2 DM who are taking insulin should use SMBG more frequently than those on oral agents. Individuals with type 2 DM who are on oral medications should use SMBG as a means of assessing the efficacy of their medication and the impact of diet. Because plasma glucose levels fluctuate less in these individuals, one to two SMBG measurements per day (or fewer in patients who are on oral agents or are diet-controlled) may be sufficient. Most measurements in individuals with type 1 or type 2 DM should be performed prior to a meal and


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InternalMed_Harrison. per day (or fewer in patients who are on oral agents or are diet-controlled) may be sufficient. Most measurements in individuals with type 1 or type 2 DM should be performed prior to a meal and supplemented with postprandial measurements to assist in reaching postprandial glucose targets (Table 418-2). Devices for continuous glucose monitoring (CGM) have been approved by the U.S. Food and Drug Administration (FDA), and others are in various stages of development. These devices do not replace the need for traditional glucose measurements and require calibration with SMBG. This rapidly evolving technology requires substantial expertise on the part of the diabetes management team and the patient. Current CGM systems measure the glucose in interstitial fluid, which is in equilibrium with the blood glucose. These devices provide useful short-term information about the patterns of glucose changes as well as an enhanced ability to detect hypoglycemic episodes. Alarms notify the patient if


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InternalMed_Harrison. blood glucose. These devices provide useful short-term information about the patterns of glucose changes as well as an enhanced ability to detect hypoglycemic episodes. Alarms notify the patient if the blood glucose falls into the hypoglycemic range. Clinical experience with these devices is rapidly growing, and they are most useful in individuals with hypoglycemia unawareness, individuals with frequent hypoglycemia, or those who have not achieved glycemic targets despite major efforts. The utility of CGM in the intensive care unit (ICU) setting remains to be determined.


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InternalMed_Harrison. Assessment of Long-Term Glycemic Control Measurement of glycated hemoglobin (HbA1c) is the standard method for assessing long-term glycemic control. When plasma glucose is consistently elevated, there is an increase in nonenzymatic glycation of hemoglobin; this alteration reflects the glycemic history over the previous 2–3 months, because erythrocytes have an average life span of 120 days (glycemic level in the preceding month contributes about 50% to the HbA1c value). Measurement of HbA1c at the “point of care” allows for more rapid feedback and may therefore assist in adjustment of therapy.


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InternalMed_Harrison. HbA1c should be measured in all individuals with DM during their initial evaluation and as part of their comprehensive diabetes care. As the primary predictor of long-term complications of DM, the HbA1c should mirror, to a certain extent, the short-term measurements of SMBG. These two measurements are complementary in that recent intercurrent illnesses may impact the SMBG measurements but not the HbA1c. Likewise, postprandial and nocturnal hyperglycemia may not be detected by the SMBG of fasting and preprandial capillary plasma glucose but will be reflected in the HbA1c. In standardized assays, the HbA1c approximates the following mean plasma glucose values: an HbA1c of 6% = 7.0 mmol/L (126 mg/dL), 7% = 8.6 mmol/L (154 mg/dL), 8% = 10.2 mmol/L (183 mg/dL), 9% = 11.8 mmol/L (212 mg/dL), 10% = 13.4 mmol/L (240 mg/dL), 11% = 14.9 mmol/L (269 mg/dL), and 12% = 16.5 mmol/L (298 mg/dL). In patients achieving their glycemic goal, the ADA recommends measurement of the HbA1c at least twice per


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InternalMed_Harrison. = 13.4 mmol/L (240 mg/dL), 11% = 14.9 mmol/L (269 mg/dL), and 12% = 16.5 mmol/L (298 mg/dL). In patients achieving their glycemic goal, the ADA recommends measurement of the HbA1c at least twice per year. More frequent testing (every 3 months) is warranted when glycemic control is inadequate or when therapy has changed. Laboratory standards for the HbA1c test have been established and should be correlated to the reference assay of the Diabetes Control and Complications Trial (DCCT). Clinical conditions such hemoglobinopathies, anemias, reticulocytosis, transfusions, and uremia may interfere with the HbA1c result. The degree of glycation of other proteins, such as albumin, can be used as an alternative indicator of glycemic control when the HbA1c is inaccurate. The fructosamine assay (measuring glycated albumin) reflects the glycemic status over the prior 2 weeks.


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InternalMed_Harrison. Comprehensive care of type 1 and type 2 DM requires an emphasis on nutrition, exercise, and monitoring of glycemic control but also usually involves glucose-lowering medication(s). This chapter discusses classes of such medications but does not describe every glucose-lowering agent available worldwide. The initial step is to select an individualized, glycemic goal for the patient. Because the complications of DM are related to glycemic control, normoglycemia or near-normoglycemia is the desired, but often elusive, goal for most patients. Normalization or near-normalization of the plasma glucose for long periods of time is extremely difficult, as demonstrated by the DCCT and United Kingdom Prospective Diabetes Study (UKPDS). Regardless of the level of hyperglycemia, improvement in glycemic control will lower the risk of diabetes-specific complications (Chap. 419).


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InternalMed_Harrison. The target for glycemic control (as reflected by the HbA1c) must be individualized, and the goals of therapy should be developed in consultation with the patient after considering a number of medical, social, and lifestyle issues. The ADA calls this a patient-centered approach, and other organizations such as the IDF and American Association of Clinical Endocrinologists (AACE) also suggest an individualized glycemic goal. Important factors to consider include the patient’s age and ability to understand and implement a complex treatment regimen, presence and severity of complications of diabetes, known cardiovascular disease (CVD), ability to recognize hypoglycemic symptoms, presence of other medical conditions or treatments that might affect survival or the response to therapy, lifestyle and occupation (e.g., possible consequences of experiencing hypoglycemia on the job), and level of support available from family and friends.


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InternalMed_Harrison. In general, the ADA suggests that the goal is to achieve an HbA1c as close to normal as possible without significant hypoglycemia. In most individuals, the target HbA1c should be <7% (Table 418-2) with a more stringent target for some patients. For instance, the HbA1c goal in a young adult with type 1 DM may be 6.5%. A higher HbA1c goal may be appropriate for the very young or old or in individuals with limited life span or comorbid conditions. For example, an appropriate HbA1c goal in elderly individuals with multiple, chronic illnesses and impaired activities of daily living might be 8.0 or 8.5%. A major consideration is the frequency and severity of hypoglycemia, because this becomes more common with a more stringent HbA1c goal.


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InternalMed_Harrison. More stringent glycemic control (HbA1c of ≤6%) is not beneficial, and may be detrimental, in patients with type 2 DM and a high risk of CVD. Large clinical trials (UKPDS, Action to Control Cardiovascular Risk in Diabetes [ACCORD], Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE], Veterans Affairs Diabetes Trial [VADT]; Chap. 419) have examined glycemic control in type 2 DM in individuals with low risk of CVD, with high risk of CVD, or with established CVD and have found that more intense glycemic control is not beneficial and, in some patient populations, may have a negative impact on some outcomes. These divergent outcomes stress the need for individualized glycemic goals based on the following general guidelines: (1) early in the course of type 2 diabetes when the CVD risk is lower, improved glycemic control likely leads to improved cardiovascular outcome, but this benefit occurs more than a decade after the period of improved


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InternalMed_Harrison. of type 2 diabetes when the CVD risk is lower, improved glycemic control likely leads to improved cardiovascular outcome, but this benefit occurs more than a decade after the period of improved glycemic control; (2) intense glycemic control in individuals with established CVD or at high risk for CVD is not advantageous, and may be deleterious, over a follow-up of 3–5 years; an HbA1c goal <7.0% is not appropriate in this population; (3) hypoglycemia in such high-risk populations (elderly, CVD) should be avoided; and (4) improved glycemic control reduces microvascular complications of diabetes (Chap. 419) even if it does not improve macrovascular complications like CVD.


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InternalMed_Harrison. TYPE 1 DIABETES MELLITUS General Aspects The ADA recommendations for fasting and bedtime glycemic goals and HbA1c targets are summarized in Table 418-2. The goal is to design and implement insulin regimens that mimic physiologic insulin secretion. Because individuals with type 1 DM partially or completely lack endogenous insulin production, administration of basal insulin is essential for regulating glycogen breakdown, gluconeogenesis, lipolysis, and ketogenesis. Likewise, insulin replacement for meals should be appropriate for the carbohydrate intake and promote normal glucose utilization and storage.


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InternalMed_Harrison. Intensive Management Intensive diabetes management has the goal of achieving euglycemia or near-normal glycemia. This approach requires multiple resources, including thorough and continuing patient education, comprehensive recording of plasma glucose measurements and nutrition intake by the patient, and a variable insulin regimen that matches glucose intake and insulin dose. Insulin regimens usually include multiple-component insulin regimens, multiple daily injections (MDIs), or insulin infusion devices (each discussed below).


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InternalMed_Harrison. The benefits of intensive diabetes management and improved glycemic control include a reduction in the microvascular complications of DM and a reduction in diabetes-related complications. From a psychological standpoint, the patient experiences greater control over his or her diabetes and often notes an improved sense of well-being, greater flexibility in the timing and content of meals, and the capability to alter insulin dosing with exercise. In addition, intensive diabetes management prior to and during pregnancy reduces the risk of fetal malformations and morbidity. Intensive diabetes management is encouraged in newly diagnosed patients with type 1 DM because it may prolong the period of C-peptide production, which may result in better glycemic control and a reduced risk of serious hypoglycemia. Although intensive management confers impressive benefits, it is also accompanied by significant personal and financial costs and is therefore not appropriate for all individuals.


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InternalMed_Harrison. Insulin Preparations Current insulin preparations are generated by recombinant DNA technology and consist of the amino acid sequence of human insulin or variations thereof. In the United States, most insulin is formulated as U-100 (100 units/mL). Regular insulin formulated as U-500 (500 units/mL) is available and sometimes useful in patients with severe insulin resistance. Human insulin has been formulated with distinctive pharmacokinetics or genetically modified to more closely mimic physiologic insulin secretion. Insulins can be classified as short-acting or long-acting (Table 418-4). For example, one short-acting insulin formulation, insulin lispro, is an insulin analogue in which the 28th and 29th amino acids (lysine and proline) on the insulin B chain have been reversed by recombinant DNA technology. Insulin aspart and insulin glulisine are genetically modified insulin analogues with properties similar to lispro. All three of the insulin analogues have full biologic activity but


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InternalMed_Harrison. DNA technology. Insulin aspart and insulin glulisine are genetically modified insulin analogues with properties similar to lispro. All three of the insulin analogues have full biologic activity but less tendency for self-aggregation, resulting in more rapid absorption and onset of action and a shorter duration of action. These characteristics are particularly advantageous for allowing entrainment of insulin injection and action to rising plasma glucose levels following meals. The shorter duration of action also appears to be associated with a decreased number of hypoglycemic episodes, primarily because the decay of insulin action corresponds to the decline in plasma glucose after a meal. Thus, insulin aspart, lispro, or glulisine is preferred over regular insulin for prandial coverage. Insulin glargine is a long-acting biosynthetic human insulin that differs from normal insulin in that asparagine is replaced by glycine at amino acid 21, and two arginine residues are added to the C


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InternalMed_Harrison. Insulin glargine is a long-acting biosynthetic human insulin that differs from normal insulin in that asparagine is replaced by glycine at amino acid 21, and two arginine residues are added to the C terminus of the B chain. Compared to neutral protamine Hagedorn (NPH) insulin, the onset of insulin glargine action is later, the duration of action is longer (~24 h), and there is a less pronounced peak. A lower incidence of hypoglycemia, especially at night, has been reported with insulin glargine when compared to NPH insulin. The most recent evidence does not support an association between glargine and increased cancer risk. Insulin detemir has a fatty acid side chain that prolongs its action by slowing absorption and catabolism. Twice-daily injections of glargine or detemir are sometimes required to provide 24-h coverage. Regular and NPH insulin have the native insulin amino acid sequence.


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InternalMed_Harrison. Basal insulin requirements are provided by long-acting (NPH insulin, insulin glargine, or insulin detemir) insulin formulations. These TAblE 418-4 PRoPERTiES of inSulin PREPARATionSa Time of Action aInsulin preparations available in the United States; others are available in the United Kingdom and Europe. bGlargine and detemir have minimal peak activity. cDuration is dose-dependent (shorter at lower doses). dOther insulin combinations are available eDual: two peaks—one at 2–3 h and the second one several hours later. Source: Adapted from FR Kaufman: Medical Management of Type 1 Diabetes, 6th edition. Alexandria, VA: American Diabetes Association, 2012.


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InternalMed_Harrison. are usually prescribed with short-acting insulin in an attempt to mimic physiologic insulin release with meals. Although mixing of NPH and short-acting insulin formulations is common practice, this mixing may alter the insulin absorption profile (especially the short-acting insulins). For example, lispro absorption is delayed by mixing with NPH. The alteration in insulin absorption when the patient mixes different insulin formulations should not prevent mixing insulins. However, the following guidelines should be followed: (1) mix the different insulin formulations in the syringe immediately before injection (inject within 2 min after mixing); (2) do not store insulin as a mixture; (3) follow the same routine in terms of insulin mixing and administration to standardize the physiologic response to injected insulin; and (4) do not mix insulin glargine or detemir with other insulins. The miscibility of some insulins allows for the production of combination insulins that contain 70% NPH


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InternalMed_Harrison. to injected insulin; and (4) do not mix insulin glargine or detemir with other insulins. The miscibility of some insulins allows for the production of combination insulins that contain 70% NPH and 30% regular (70/30), or equal mixtures of NPH and regular (50/50). By including the insulin analogue mixed with protamine, several combinations have a short-acting and long-acting profile (Table 418-4). Although more convenient for the patient (only two injections/day), combination insulin formulations do not allow independent adjustment of short-acting and long-acting activity. Several insulin formulations are available as insulin “pens,” which may be more convenient for some patients. Insulin delivery by inhalation has recently been approved but is not yet available. Other insulins, such as one with a duration of action of several days, are under development but are not currently available in the United States.


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InternalMed_Harrison. Insulin Regimens Representations of the various insulin regimens that may be used in type 1 DM are illustrated in Fig. 418-1. Although the insulin profiles are depicted as “smooth,” symmetric curves, there is considerable patient-to-patient variation in the peak and duration. In all regimens, long-acting insulins (NPH, glargine, or detemir) supply basal insulin, whereas regular, insulin aspart, glulisine, or lispro insulin provides prandial insulin. Short-acting insulin analogues should be injected just before (<10 min) or just after a meal; regular insulin is given 30–45 min prior to a meal. Sometimes short-acting insulin analogues are injected just after a meal (gastroparesis, unpredictable food intake). A shortcoming of current insulin regimens is that injected insulin immediately enters the systemic circulation, whereas endogenous Diabetes Mellitus: Management and Therapies


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InternalMed_Harrison. FIGURE 418-1 Representative insulin regimens for the treatment of diabetes. For each panel, the y-axis shows the amount of insulin effect and the x-axis shows the time of day. B, breakfast; HS, bedtime; L, lunch; S, supper. *Lispro, glulisine, or insulin aspart can be used. The time of insulin injection is shown with a vertical arrow. The type of insulin is noted above each insulin curve. A. Multiple-component insulin regimen consisting of long-acting insulin (∧glargine or detemir) to provide basal insulin coverage and three shots of glulisine, lispro, or insulin aspart to provide glycemic coverage for each meal. B. Injection of two shots of long-acting insulin (NPH) and short-acting insulin analogue (glulisine, lispro, insulin aspart [solid red line], or regular insulin [green dashed line]). Only one formulation of short-acting insulin is used. C. Insulin administration by insulin infusion device is shown with the basal insulin and a bolus injection at each meal. The basal insulin


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InternalMed_Harrison. Only one formulation of short-acting insulin is used. C. Insulin administration by insulin infusion device is shown with the basal insulin and a bolus injection at each meal. The basal insulin rate is decreased during the evening and increased slightly prior to the patient awakening in the morning. Glulisine, lispro, or insulin aspart is used in the insulin pump.


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InternalMed_Harrison. (Adapted from H Lebovitz [ed]: Therapy for Diabetes Mellitus. American Diabetes Association, Alexandria, VA, 2004.) insulin is secreted into the portal venous system. Thus, exogenous insulin administration exposes the liver to subphysiologic insulin levels. No insulin regimen reproduces the precise insulin secretory pattern of the pancreatic islet. However, the most physiologic regimens entail more frequent insulin injections, greater reliance on short-acting insulin, and more frequent capillary plasma glucose measurements. In general, individuals with type 1 DM require 0.5–1 U/kg per day of insulin divided into multiple doses, with ~50% of the insulin given as basal insulin.


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InternalMed_Harrison. Multiple-component insulin regimens refer to the combination of basal insulin and bolus insulin (preprandial short-acting insulin). The timing and dose of short-acting, preprandial insulin are altered to accommodate the SMBG results, anticipated food intake, and physical activity. Such regimens offer the patient with type 1 diabetes more flexibility in terms of lifestyle and the best chance for achieving near normoglycemia. One such regimen, shown in Fig. 418-1B, consists of basal insulin with glargine or detemir and preprandial lispro, glulisine, or insulin aspart. The insulin aspart, glulisine, or lispro dose is based on individualized algorithms that integrate the preprandial glucose and the anticipated carbohydrate intake. To determine the meal component of the preprandial insulin dose, the patient uses an insulin-tocarbohydrate ratio (a common ratio for type 1 DM is 1–1.5 units/10 g of carbohydrate, but this must be determined for each individual). To this insulin dose is added


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InternalMed_Harrison. the patient uses an insulin-tocarbohydrate ratio (a common ratio for type 1 DM is 1–1.5 units/10 g of carbohydrate, but this must be determined for each individual). To this insulin dose is added the supplemental or correcting insulin based on the preprandial blood glucose (one formula uses 1 unit of insulin for every 2.7 mmol/L [50 mg/dL] over the preprandial glucose target; another formula uses [body weight in kg] × [blood glucose – desired glucose in mg/dL]/1500). An alternative multiple-component insulin regimen consists of bedtime NPH insulin, a small dose of NPH insulin at breakfast (20–30% of bedtime dose), and preprandial short-acting insulin. Other variations of this regimen are in use but have the disadvantage that NPH has a significant peak, making hypoglycemia more common. Frequent SMBG (more than three times per day) is absolutely essential for these types of insulin regimens.


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InternalMed_Harrison. In the past, one commonly used regimen consisted of twice-daily injections of NPH mixed with a short-acting insulin before the morning and evening meals (Fig. 418-1B). Such regimens usually prescribe two-thirds of the total daily insulin dose in the morning (with about two-thirds given as long-acting insulin and one-third as short-acting) and one-third before the evening meal (with approximately one-half given as long-acting insulin and one-half as short-acting). The drawback to such a regimen is that it forces a rigid schedule on the patient, in terms of daily activity and the content and timing of meals. Although it is simple and effective at avoiding severe hyperglycemia, it does not generate near-normal glycemic control in individuals with type 1 DM. Moreover, if the patient’s meal pattern or content varies or if physical activity is increased, hyperglycemia or hypoglycemia may result. Moving the long-acting insulin from before the evening meal to bedtime may avoid nocturnal


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InternalMed_Harrison. pattern or content varies or if physical activity is increased, hyperglycemia or hypoglycemia may result. Moving the long-acting insulin from before the evening meal to bedtime may avoid nocturnal hypoglycemia and provide more insulin as glucose levels rise in the early morning (so-called dawn phenomenon). The insulin dose in such regimens should be adjusted based on SMBG results with the following general assumptions: (1) the fasting glucose is primarily determined by the prior evening long-acting insulin; (2) the pre-lunch glucose is a function of the morning short-acting insulin; (3) the pre-supper glucose is a function of the morning long-acting insulin; and (4) the bedtime glucose is a function of the pre-supper, short-acting insulin. This is not an optimal regimen for the patient with type 1 DM, but is sometimes used for patients with type 2 DM.


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InternalMed_Harrison. Continuous SC insulin infusion (CSII) is a very effective insulin regimen for the patient with type 1 DM (Fig. 418-1C). To the basal insulin infusion, a preprandial insulin (“bolus”) is delivered by the insulin infusion device based on instructions from the patient, who uses an individualized algorithm incorporating the preprandial plasma glucose and anticipated carbohydrate intake. These sophisticated insulin infusion devices can accurately deliver small doses of insulin (microliters per hour) and have several advantages: (1) multiple basal infusion rates can be programmed to accommodate nocturnal versus daytime basal insulin requirement; (2) basal infusion rates can be altered during periods of exercise; (3) different waveforms of insulin infusion with meal-related bolus allow better matching of insulin depending on meal composition; and (4) programmed algorithms consider prior insulin administration and blood glucose values in calculating the insulin dose. These devices require


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InternalMed_Harrison. matching of insulin depending on meal composition; and (4) programmed algorithms consider prior insulin administration and blood glucose values in calculating the insulin dose. These devices require instruction by a health professional with considerable experience with insulin-infusion devices and very frequent patient interactions with the diabetes management team. Insulin-infusion devices present unique challenges, such as infection at the infusion site, unexplained hyperglycemia because the infusion set becomes obstructed, or diabetic ketoacidosis if the pump becomes disconnected. Because most physicians use lispro, glulisine, or insulin aspart in CSII, the extremely short half-life of these insulins quickly leads to insulin deficiency if the delivery system is interrupted. Essential to the safe use of infusion devices is thorough patient education about pump function and frequent SMBG. Efforts to create a closed-loop system in which data from continuous glucose measurement


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InternalMed_Harrison. to the safe use of infusion devices is thorough patient education about pump function and frequent SMBG. Efforts to create a closed-loop system in which data from continuous glucose measurement regulate the insulin infusion rate are under way.


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InternalMed_Harrison. Other Agents That Improve Glucose Control The role of amylin, a 37-amino-acid peptide co-secreted with insulin from pancreatic beta cells, in normal glucose homeostasis is uncertain. However, based on the rationale that patients who are insulin deficient are also amylin deficient, an analogue of amylin (pramlintide) was created and found to reduce postprandial glycemic excursions in type 1 and type 2 diabetic patients taking insulin. Pramlintide injected just before a meal slows gastric emptying and suppresses glucagon but does not alter insulin levels. Pramlintide is approved for insulin-treated patients with type 1 and type 2 DM. Addition of pramlintide produces a modest reduction in the HbA1c and seems to dampen meal-related glucose excursions. In type 1 DM, pramlintide is started as a 15-μg SC injection before each meal and titrated up to a maximum of 30–60 μg as tolerated. In type 2 DM, pramlintide is started as a 60-μg SC injection before each meal and may be titrated up to a


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InternalMed_Harrison. a 15-μg SC injection before each meal and titrated up to a maximum of 30–60 μg as tolerated. In type 2 DM, pramlintide is started as a 60-μg SC injection before each meal and may be titrated up to a maximum of 120 μg. The major side effects are nausea and vomiting, and dose escalations should be slow to limit these side effects. Because pramlintide slows gastric emptying, it may influence absorption of other medications and should not be used in combination with other drugs that slow GI motility. The short-acting insulin given before the meal should initially be reduced to avoid hypoglycemia and then titrated as the effects of the pramlintide become evident. α-Glucosidase inhibitors are sometimes used with insulin in type 1 DM.


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InternalMed_Harrison. TYPE 2 DIABETES MELLITUS General Aspects The goals of glycemia-controlling therapy for type 2 DM are similar to those in type 1 DM. Whereas glycemic control tends to dominate the management of type 1 DM, the care of individuals with type 2 DM must also include attention to the treatment of conditions associated with type 2 DM (e.g., obesity, hypertension, dyslipidemia, CVD) and detection/management of DM-related complications (Fig. 418-2). Reduction in cardiovascular risk is of paramount importance because this is the leading cause of mortality in these individuals.


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InternalMed_Harrison. Type 2 DM management should begin with MNT (discussed above). An exercise regimen to increase insulin sensitivity and promote weight loss should also be instituted. Pharmacologic approaches to the management of type 2 DM include oral glucose-lowering agents, insulin, and other agents that improve glucose control; most physicians and patients prefer oral glucose-lowering agents as the initial choice. Any therapy that improves glycemic control reduces “glucose toxicity” to beta cells and improves endogenous insulin secretion. However, type 2 DM is a progressive disorder and ultimately requires multiple therapeutic agents and often insulin in most patients.


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InternalMed_Harrison. Glucose-Lowering Agents Advances in the therapy of type 2 DM have generated oral glucose-lowering agents that target different pathophysiologic processes in type 2 DM. Based on their mechanisms of action, glucose-lowering agents are subdivided into agents that increase insulin secretion, reduce glucose production, increase insulin sensitivity, enhance GLP-1 action, or promote urinary excretion of glucose (Table 418-5). Glucose-lowering agents other than insulin (with the exception of amylin analogue and α-glucosidase inhibitors) are ineffective in type 1 DM and should not be used for glucose management of severely ill individuals with type 2 DM. Insulin is sometimes the initial glucose-lowering agent in type 2 DM. BiGuanideS Metformin, representative of this class of agents, reduces hepatic glucose production and improves peripheral glucose utilization slightly (Table 418-5). Metformin activates AMP-dependent protein kinase and enters cells through organic cation transporters


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InternalMed_Harrison. FIGURE 418-2 Essential elements in comprehensive care of type 2 diabetes.


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InternalMed_Harrison. (polymorphisms of these may influence the response to metformin). 2413 Recent evidence indicates that metformin’s mechanism for reducing hepatic glucose production is to antagonize glucagon’s ability to generate cAMP in hepatocytes. Metformin reduces fasting plasma glucose (FPG) and insulin levels, improves the lipid profile, and promotes modest weight loss. An extended-release form is available and may have fewer gastrointestinal side effects (diarrhea, anorexia, nausea, metallic taste). Because of its relatively slow onset of action and gastrointestinal symptoms with higher doses, the initial dose should be low and then escalated every 2–3 weeks based on SMBG measurements. Metformin is effective as monotherapy and can be used in combination with other oral agents or with insulin. The major toxicity of metformin, lactic acidosis, is very rare and can be prevented by careful patient selection. Vitamin B12 levels are ~30% lower during metformin treatment. Metformin should not be used


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InternalMed_Harrison. toxicity of metformin, lactic acidosis, is very rare and can be prevented by careful patient selection. Vitamin B12 levels are ~30% lower during metformin treatment. Metformin should not be used in patients with renal insufficiency (glomerular filtration rate [GFR] <60 mL/min), any form of acidosis, unstable congestive heart failure (CHF), liver disease, or severe hypoxemia. Some feel that that these guidelines are too restrictive and prevent individuals with mild to moderate renal impairment from being safely treated with metformin. The National Institute for Health and Clinical Excellence in the United Kingdom suggests that metformin be used at a GFR >30 mL/min, with a reduced dose when the GFR is <45 mL/min. Metformin should be discontinued in hospitalized patients, in patients who can take nothing orally, and in those receiving radiographic contrast material. Insulin should be used until metformin can be restarted.


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InternalMed_Harrison. inSulin SecretaGoGueS—aGentS tHat affect tHe atp-SenSitive K+ cHannel Insulin secretagogues stimulate insulin secretion by interacting with the ATP-sensitive potassium channel on the beta cell (Chap. 417). These drugs are most effective in individuals with type 2 DM of relatively recent onset (<5 years) who have residual endogenous insulin production. First-generation sulfonylureas (chlorpropamide, tolazamide, tolbutamide) have a longer half-life, a greater incidence of hypoglycemia, and more frequent drug interactions, and are no longer used. Second-generation sulfonylureas have a more rapid onset of action and better coverage of the postprandial glucose rise, but the shorter half-life of some agents may require more than once-a-day dosing. Sulfonylureas reduce both fasting and postprandial glucose and should be initiated at low doses and increased at 1to 2-week intervals based on SMBG. In general, sulfonylureas increase insulin acutely and thus should be taken shortly before a meal;


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InternalMed_Harrison. glucose and should be initiated at low doses and increased at 1to 2-week intervals based on SMBG. In general, sulfonylureas increase insulin acutely and thus should be taken shortly before a meal; with chronic therapy, though, the insulin release is more sustained. Glimepiride and glipizide can be given in a single daily dose and are preferred over glyburide, especially in the elderly. Repaglinide, nateglinide, and mitiglinide are not sulfonylureas but also interact with the ATP-sensitive potassium channel. Because of their short half-life, these agents are given with each meal or immediately before to reduce meal-related glucose excursions.


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InternalMed_Harrison. Insulin secretagogues, especially the longer acting ones, have the potential to cause hypoglycemia, especially in elderly individuals. Hypoglycemia is usually related to delayed meals, increased physical activity, alcohol intake, or renal insufficiency. Individuals who ingest an overdose of some agents develop prolonged and serious hypoglycemia and should be monitored closely in the hospital (Chap. 420). Most sulfonylureas are metabolized in the liver to compounds (some of which are active) that are cleared by the kidney. Thus, their use in individuals with significant hepatic or renal dysfunction is not advisable. Weight gain, a common side effect of sulfonylurea therapy, results from the increased insulin levels and improvement in glycemic control. Some sulfonylureas have significant drug interactions with alcohol and some medications including warfarin, aspirin, ketoconazole, α-glucosidase inhibitors, and fluconazole. A related isoform of ATP-sensitive potassium channels is present


InternalMed_Harrison

InternalMed_Harrison. interactions with alcohol and some medications including warfarin, aspirin, ketoconazole, α-glucosidase inhibitors, and fluconazole. A related isoform of ATP-sensitive potassium channels is present in the myocardium and the brain. All of these agents except glyburide have a low affinity for this isoform. Despite concerns that this agent might affect the myocardial response to ischemia and observational studies suggesting that sulfonylureas increase cardiovascular risk, studies have not shown an increased cardiac mortality with glyburide or other agents in this class.


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InternalMed_Harrison. Diabetes Mellitus: Management and Therapies aExamples are approved for use in at least one country, but may not be available in the United States or all countries. Examples may not include all agents in the class. bHbA1c reduction (absolute) depends partly on starting HbA1c. cUsed for treatment of type 2 diabetes. dUsed in conjunction with insulin for treatment of type 1 diabetes. Cost of agent: *low, **moderate, ***high, ****variable. Note: Some agents used to treat type 2 DM are not included in table (see text). Abbreviations: ACE, angiotensin-converting enzyme; CHF, congestive heart failure; CV, cardiovascular; GI, gastrointestinal; HbA1c, hemoglobin A1c.


InternalMed_Harrison

InternalMed_Harrison. insulin secreTagogues—agenTs THaT enHance glP-1 recePTor signaling peptidase IV [DPP-IV]). Thus, exenatide has prolonged GLP-1-like “Incretins” amplify glucose-stimulated insulin secretion (Chap. 417). action and binds to GLP-1 receptors found in islets, the gastrointesti-Agents that either act as a GLP-1 receptor agonist or enhance endog-nal tract, and the brain. Liraglutide, another GLP-1 receptor agonist, enous GLP-1 activity are approved for the treatment of type 2 DM is almost identical to native GLP-1 except for an amino acid substitu(Table 418-5). Agents in this class do not cause hypoglycemia because tion and addition of a fatty acyl group (coupled with a γ-glutamic acid of the glucose-dependent nature of incretin-stimulated insulin secre-spacer) that promote binding to albumin and plasma proteins and protion (unless there is concomitant use of an agent that can lead to long its half-life. GLP-1 receptor agonists increase glucose-stimulated hypoglycemia—sulfonylureas, etc.).


InternalMed_Harrison

InternalMed_Harrison. plasma proteins and protion (unless there is concomitant use of an agent that can lead to long its half-life. GLP-1 receptor agonists increase glucose-stimulated hypoglycemia—sulfonylureas, etc.). Exenatide, a synthetic version of insulin secretion, suppress glucagon, and slow gastric emptying. These a peptide initially identified in the saliva of the Gila monster (exen-agents do not promote weight gain; in fact, most patients experience din-4), is an analogue of GLP-1. Unlike native GLP-1, which has a modest weight loss and appetite suppression. Treatment with these half-life of >5 min, differences in the exenatide amino acid sequence agents should start at a low dose to minimize initial side effects (nausea render it resistant to the enzyme that degrades GLP-1 (dipeptidyl being the limiting one). GLP-1 receptor agonists, available in twice daily, daily, and weekly injectable formulations, can be used as combination therapy with metformin, sulfonylureas, and thiazolidinediones. Some


InternalMed_Harrison

InternalMed_Harrison. one). GLP-1 receptor agonists, available in twice daily, daily, and weekly injectable formulations, can be used as combination therapy with metformin, sulfonylureas, and thiazolidinediones. Some patients taking insulin secretagogues may require a reduction in those agents to prevent hypoglycemia. The major side effects are nausea, vomiting, and diarrhea. Some formulations carry a black box warning from the FDA because of an increased risk of thyroid C-cell tumors in rodents and are contraindicated in individuals with medullary carcinoma of the thyroid or multiple endocrine neoplasia. Because GLP-1 receptor agonists slow gastric emptying, they may influence the absorption of other drugs. Whether GLP-1 receptor agonists enhance beta cell survival, promote beta cell proliferation, or alter the natural history of type 2 DM is not known. Other GLP-1 receptor agonists and formulations are under development.


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InternalMed_Harrison. DPP-IV inhibitors inhibit degradation of native GLP-1 and thus enhance the incretin effect. DPP-IV, which is widely expressed on the cell surface of endothelial cells and some lymphocytes, degrades a wide range of peptides (not GLP-1 specific). DPP-IV inhibitors promote insulin secretion in the absence of hypoglycemia or weight gain and appear to have a preferential effect on postprandial blood glucose. The levels of GLP-1 action in the patient are greater with the GLP-1 receptor agonists than with DPP-IV inhibitors. DPP-IV inhibitors are used either alone or in combination with other oral agents in type 2 DM. Reduced doses should be given to patients with renal insufficiency. Initial concerns about the pancreatic side effects of GLP-1 receptor agonists and DPP-IV inhibitors (pancreatitis, possible premalignant lesions) appear to be unfounded.


InternalMed_Harrison

InternalMed_Harrison. α-GlucoSidaSe inHiBitorS α-Glucosidase inhibitors reduce postprandial hyperglycemia by delaying glucose absorption; they do not affect glucose utilization or insulin secretion (Table 418-5). Postprandial hyperglycemia, secondary to impaired hepatic and peripheral glucose disposal, contributes significantly to the hyperglycemic state in type 2 DM. These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen. Therapy should be initiated at a low dose with the evening meal and increased to a maximal dose over weeks to months. The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to the large bowel and can be reduced somewhat by gradual upward dose titration. α-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia. Simultaneous treatment with bile acid resins and


InternalMed_Harrison

InternalMed_Harrison. somewhat by gradual upward dose titration. α-Glucosidase inhibitors may increase levels of sulfonylureas and increase the incidence of hypoglycemia. Simultaneous treatment with bile acid resins and antacids should be avoided. These agents should not be used in individuals with inflammatory bowel disease, gastroparesis, or a serum creatinine >177 μmol/L (2 mg/dL). This class of agents is not as potent as other oral agents in lowering the HbA1c but is unique because it reduces the postprandial glucose rise even in individuals with type 1 DM. If hypoglycemia from other diabetes treatments occurs while taking these agents, the patient should consume glucose because the degradation and absorption of complex carbohydrates will be retarded.


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InternalMed_Harrison. tHiazolidinedioneS Thiazolidinediones (Table 418-5) reduce insulin resistance by binding to the PPAR-γ (peroxisome proliferator–activated receptor γ) nuclear receptor (which forms a heterodimer with the retinoid X receptor). The PPAR-γ receptor is found at highest levels in adipocytes but is expressed at lower levels in many other tissues. Agonists of this receptor regulate a large number of genes, promote adipocyte differentiation, reduce hepatic fat accumulation, and promote fatty acid storage. Thiazolidinediones promote a redistribution of fat from central to peripheral locations. Circulating insulin levels decrease with use of the thiazolidinediones, indicating a reduction in insulin resistance. Although direct comparisons are not available, the two currently available thiazolidinediones appear to have similar efficacy. The prototype of this class of drugs, troglitazone, was withdrawn from the U.S. market after reports of hepatotoxicity and an association with an idiosyncratic


InternalMed_Harrison

InternalMed_Harrison. appear to have similar efficacy. The prototype of this class of drugs, troglitazone, was withdrawn from the U.S. market after reports of hepatotoxicity and an association with an idiosyncratic liver reaction that sometimes led to hepatic failure. Although rosiglitazone and pioglitazone do not appear to induce the liver abnormalities seen with troglitazone, the FDA recommends measurement of liver function tests prior to initiating therapy.


InternalMed_Harrison

InternalMed_Harrison. Rosiglitazone raises low-density lipoprotein (LDL), high-density 2415 lipoprotein (HDL), and triglycerides slightly. Pioglitazone raises HDL to a greater degree and LDL a lesser degree but lowers triglycerides. The clinical significance of the lipid changes with these agents is not known and may be difficult to ascertain because most patients with type 2 DM are also treated with a statin.


InternalMed_Harrison

InternalMed_Harrison. Thiazolidinediones are associated with weight gain (2–3 kg), a small reduction in the hematocrit, and a mild increase in plasma volume. Peripheral edema and CHF are more common in individuals treated with these agents. These agents are contraindicated in patients with liver disease or CHF (class III or IV). The FDA has issued an alert that rare patients taking these agents may experience a worsening of diabetic macular edema. An increased risk of fractures has been noted in women taking these agents. Thiazolidinediones have been shown to induce ovulation in premenopausal women with polycystic ovary syndrome. Women should be warned about the risk of pregnancy because the safety of thiazolidinediones in pregnancy is not established.


InternalMed_Harrison

InternalMed_Harrison. Concerns about increased cardiovascular risk associated with rosiglitazone led to considerable restrictions on its use and to the FDA issuing a “black box” warning in 2007. However, based on new information, the FDA has revised its guidelines and categorizes rosiglitazone similar to other drugs for type 2 DM. Because of a possible increased risk of bladder cancer, pioglitazone is part of an ongoing FDA safety review.


InternalMed_Harrison

InternalMed_Harrison. (Table 418-5) lower the blood glucose by selectively inhibiting this co-transporter, which is expressed almost exclusively in the proximal, convoluted tubule in the kidney. This inhibits glucose reabsorption, lowers the renal threshold for glucose, and leads to increased urinary glucose excretion. Thus, the glucose-lowering effect is insulin independent and not related to changes in insulin sensitivity or secretion. Because these agents are the newest class to treat type 2 DM (Table 418-5), clinical experience is limited. Due to the increased urinary glucose, urinary or vaginal infections are more common, and the diuretic effect can lead to reduced intravascular volume. As part of the FDA approval of canagliflozin in 2013, postmarketing studies for cardiovascular outcomes and for monitoring bladder and urinary cancer risk are under way.


InternalMed_Harrison

InternalMed_Harrison. Bile acid–binding resins Evidence indicates that bile acids, by signaling through nuclear receptors, may have a role in metabolism. Bile acid metabolism is abnormal in type 2 DM. The bile acid–binding resin colesevelam has been approved for the treatment of type 2 DM (already approved for treatment of hypercholesterolemia). Because bile acid–binding resins are minimally absorbed into the systemic circulation, how bile acid–binding resins lower blood glucose is not known. The most common side effects are gastrointestinal (constipation, abdominal pain, and nausea). Bile acid–binding resins can increase plasma triglycerides and should be used cautiously in patients with a tendency for hypertriglyceridemia. The role of this class of drugs in the treatment of type 2 DM is not yet defined.


InternalMed_Harrison

InternalMed_Harrison. Bromocriptine A formulation of the dopamine receptor agonist bromocriptine (Cycloset) has been approved by the FDA for the treatment of type 2 DM. However, its role in the treatment of type 2 DM is uncertain. insulin THeraPy in TyPe 2 dm Insulin should be considered as the initial therapy in type 2 DM, particularly in lean individuals or those with severe weight loss, in individuals with underlying renal or hepatic disease that precludes oral glucose-lowering agents, or in individuals who are hospitalized or acutely ill. Insulin therapy is ultimately required by a substantial number of individuals with type 2 DM because of the progressive nature of the disorder and the relative insulin deficiency that develops in patients with long-standing diabetes. Both physician and patient reluctance often delay the initiation of insulin therapy, but glucose control and patient well-being are improved by insulin therapy in patients who have not reached the glycemic target.


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InternalMed_Harrison. Diabetes Mellitus: Management and Therapies 2416 Because endogenous insulin secretion continues and is capable of providing some coverage of mealtime caloric intake, insulin is usually initiated in a single dose of long-acting insulin (0.3–0.4 U/kg per day), given in the evening (NPH) or just before bedtime (NPH, glargine, detemir). Because fasting hyperglycemia and increased hepatic glucose production are prominent features of type 2 DM, bedtime insulin is more effective in clinical trials than a single dose of morning insulin. Glargine given at bedtime has less nocturnal hypoglycemia than NPH insulin. Some physicians prefer a relatively low, fixed starting dose of long-acting insulin (5–15 units) or a weight-based dose (0.2 units/kg). The insulin dose may then be adjusted in 10% increments as dictated by SMBG results. Both morning and bedtime long-acting insulin may be used in combination with oral glucose-lowering agents. Initially, basal insulin may be sufficient, but often


InternalMed_Harrison

InternalMed_Harrison. as dictated by SMBG results. Both morning and bedtime long-acting insulin may be used in combination with oral glucose-lowering agents. Initially, basal insulin may be sufficient, but often prandial insulin coverage with multiple insulin injections is needed as diabetes progresses (see insulin regimens used for type 1 DM). Other insulin formulations that have a combination of short-acting and long-acting insulin (Table 418-4) are sometimes used in patients with type 2 DM because of convenience but do not allow independent adjustment of short-acting and long-acting insulin dose and often do not achieve the same degree of glycemic control as basal/bolus regimens. In selected patients with type 2 DM, insulin-infusion devices may be considered.


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InternalMed_Harrison. cHoice of initial GlucoSe-loWerinG aGent The level of hyperglycemia and the patient’s individualized goal (see “Establishment of Target Level of Glycemic Control”) should influence the initial choice of therapy. Assuming that maximal benefit of MNT and increased physical activity has been realized, patients with mild to moderate hyperglycemia (FPG <11.1–13.9 mmol/L [200–250 mg/dL]) often respond well to a single, oral glucose-lowering agent. Patients with more severe hyperglycemia (FPG >13.9 mmol/L [250 mg/dL]) may respond partially but are unlikely to achieve normoglycemia with oral monotherapy. A stepwise approach that starts with a single agent and adds a second agent to achieve the glycemic target can be used (see “Combination therapy with glucose-lowering agents,” below). Insulin can be used as initial therapy in individuals with severe hyperglycemia (FPG <13.9–16.7 mmol/L [250–300 mg/dL]) or in those who are symptomatic from the hyperglycemia. This approach is based on the


InternalMed_Harrison

InternalMed_Harrison. can be used as initial therapy in individuals with severe hyperglycemia (FPG <13.9–16.7 mmol/L [250–300 mg/dL]) or in those who are symptomatic from the hyperglycemia. This approach is based on the rationale that more rapid glycemic control will reduce “glucose toxicity” to the islet cells, improve endogenous insulin secretion, and possibly allow oral glucose-lowering agents to be more effective. If this occurs, the insulin may be discontinued.


InternalMed_Harrison

InternalMed_Harrison. Insulin secretagogues, biguanides, α-glucosidase inhibitors, thiazolidinediones, GLP-1 receptor agonists, DPP-IV inhibitors, SLGT2 inhibitors, and insulin are approved for monotherapy of type 2 DM. Although each class of oral glucose-lowering agents has advantages and disadvantages (Table 418-5), certain generalizations apply: (1) insulin secretagogues, biguanides, GLP-1 receptor agonists, and thiazolidinediones improve glycemic control to a similar degree (1–2% reduction in HbA1c) and are more effective than α-glucosidase inhibitors, DPP-IV inhibitors, and SLGT2 inhibitors; (2) assuming a similar degree of glycemic improvement, no clinical advantage to one class of drugs has been demonstrated; any therapy that improves glycemic control is likely beneficial; (3) insulin secretagogues, GLP-1 receptor agonists, DPP-IV inhibitors, α-glucosidase inhibitors, and SLGT2 inhibitors begin to lower the plasma glucose immediately, whereas the glucose-lowering effects of the biguanides and


InternalMed_Harrison

InternalMed_Harrison. GLP-1 receptor agonists, DPP-IV inhibitors, α-glucosidase inhibitors, and SLGT2 inhibitors begin to lower the plasma glucose immediately, whereas the glucose-lowering effects of the biguanides and thiazolidinediones are delayed by weeks; (4) not all agents are effective in all individuals with type 2 DM; (5) biguanides, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors, thiazolidinediones, and SLGT2 inhibitors do not directly cause hypoglycemia; (6) most individuals will eventually require treatment with more than one class of oral glucose-lowering agents or insulin, reflecting the progressive nature of type 2 DM; and (7) durability of glycemic control is slightly less for glyburide compared to metformin or rosiglitazone.


InternalMed_Harrison

InternalMed_Harrison. Considerable clinical experience exists with metformin and sulfonylureas because they have been available for several decades. It is assumed that the α-glucosidase inhibitors, GLP-1 agonists, DPP-IV inhibitors, thiazolidinediones, and SLGT2 inhibitors will reduce DM-related complications by improving glycemic control, but longterm data are not yet available. The thiazolidinediones are theoretically attractive because they target a fundamental abnormality in type 2 DM, namely insulin resistance. However, all of these agents are currently more costly than metformin and sulfonylureas. Patient with type 2 diabetes Individualized glycemic goal Medical nutrition therapy, increased physical activity, weight loss + metformin


InternalMed_Harrison

InternalMed_Harrison. Patient with type 2 diabetes Individualized glycemic goal Medical nutrition therapy, increased physical activity, weight loss + metformin Insulin + metformin Reassess HbA1c Reassess HbA1c Reassess HbA1c Combination therapy -metformin + second agent Combination therapy -metformin + two other agents FIGURE 418-3 Glycemic management of type 2 diabetes. See text for discussion of treatment of severe hyperglycemia or symptomatic hyperglycemia. Agents that can be combined with metformin include insulin secretagogues, thiazolidinediones, α-glucosidase inhibitors, DPP-IV inhibitors, GLP-1 receptor agonists, SLGT2 inhibitors, and insu-lin. HbA1c, hemoglobin HbA1c.


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InternalMed_Harrison. Treatment algorithms by several professional societies (ADA/ European Association for the Study of Diabetes [EASD], IDF, AACE) suggest metformin as initial therapy because of its efficacy, known side effect profile, and low cost (Fig. 418-3). Metformin’s advantages are that it promotes mild weight loss, lowers insulin levels, and improves the lipid profile slightly. Based on SMBG results and the HbA1c, the dose of metformin should be increased until the glycemic target is achieved or maximum dose is reached. If metformin is not tolerated, then initial therapy with an insulin secretagogue or DPP-IV inhibitor is reasonable.


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InternalMed_Harrison. comBination tHerapy WitH GlucoSe-loWerinG aGentS A number of combinations of therapeutic agents are successful in type 2 DM (metformin + second oral agent, metformin + GLP-1 receptor agonist, or metformin + insulin), and the dosing of agents in combination is the same as when the agents are used alone. Because mechanisms of action of the first and second agents should be different, the effect on glycemic control is usually additive. There are little data to support the choice of one combination over another combination. Medication costs vary considerably (Table 418-5), and this often factors into medication choice. Several fixed-dose combinations of oral agents are available, but evidence that they are superior to titration of single agent to a maximum dose and then addition of a second agent is lacking. If adequate control is not achieved with the combination of two agents (based on reassessment of the HbA1c every 3 months), a third oral agent or basal insulin should be added (Fig.


InternalMed_Harrison

InternalMed_Harrison. agent is lacking. If adequate control is not achieved with the combination of two agents (based on reassessment of the HbA1c every 3 months), a third oral agent or basal insulin should be added (Fig. 418-3). Treatment approaches vary considerably from country to country. For example, α-glucosidase inhibitors are used commonly in South Asian patients (Indian), but infrequently in the United States or Europe. Whether this reflects an underlying difference in the disease or physician preference is not clear.


InternalMed_Harrison

InternalMed_Harrison. Treatment with insulin becomes necessary as type 2 DM enters the phase of relative insulin deficiency (as seen in long-standing DM) and is signaled by inadequate glycemic control with one or two oral glucose-lowering agents. Insulin alone or in combination should be used in patients who fail to reach the glycemic target. For example, a single dose of long-acting insulin at bedtime is often effective in combination with metformin. In contrast, insulin secretagogues have little utility once insulin therapy is started. Experience using incretin therapies and insulin is limited. As endogenous insulin production falls further, multiple injections of long-acting and short-acting insulin regimens are necessary to control postprandial glucose excursions. These insulin regimens are identical to the long-acting and short-acting combination regimens discussed above for type 1 DM. Because the hyperglycemia of type 2 DM tends to be more “stable,” these regimens can be increased in 10% increments


InternalMed_Harrison

InternalMed_Harrison. long-acting and short-acting combination regimens discussed above for type 1 DM. Because the hyperglycemia of type 2 DM tends to be more “stable,” these regimens can be increased in 10% increments every 2–3 days using the fasting blood glucose results. Weight gain and hypoglycemia are the major adverse effects of insulin therapy. The daily insulin dose required can become quite large (1–2 units/kg per day) as endogenous insulin production falls and insulin resistance persists. Individuals who require >1 unit/kg per day of long-acting insulin should be considered for combination therapy with metformin or a thiazolidinedione. The addition of metformin or a thiazolidinedione can reduce insulin requirements in some individuals with type 2 DM, while maintaining or even improving glycemic control. Insulin plus a thiazolidinedione promotes weight gain and is associated with peripheral edema. Addition of a thiazolidinedione to a patient’s insulin regimen may necessitate a reduction in the


InternalMed_Harrison

InternalMed_Harrison. Insulin plus a thiazolidinedione promotes weight gain and is associated with peripheral edema. Addition of a thiazolidinedione to a patient’s insulin regimen may necessitate a reduction in the insulin dose to avoid hypoglycemia. Patients requiring large doses of insulin (>200 units/day) can be treated with a more concentrated form of insulin, U-500.


InternalMed_Harrison

InternalMed_Harrison. Whole pancreas transplantation (performed concomitantly with a renal transplant) may normalize glucose tolerance and is an important therapeutic option in type 1 DM with end-stage renal disease, although it requires substantial expertise and is associated with the side effects of immunosuppression. Pancreatic islet transplantation has been plagued by limitations in pancreatic islet supply and graft survival and remains an area of clinical investigation. Many individuals with longstanding type 1 DM still produce very small amounts of insulin or have insulin-positive cells within the pancreas. This suggests that beta cells may slowly regenerate but are quickly destroyed by the autoimmune process. Thus, efforts to suppress the autoimmune process and to stimulate beta cell regeneration are being tested both at the time of diagnosis and in years after the diagnosis of type 1 DM. Closed-loop pumps that infuse the appropriate amount of insulin in response to changing glucose levels are


InternalMed_Harrison

InternalMed_Harrison. being tested both at the time of diagnosis and in years after the diagnosis of type 1 DM. Closed-loop pumps that infuse the appropriate amount of insulin in response to changing glucose levels are potentially feasible now that CGM technology has been developed. Bi-hormonal pumps that deliver both insulin and glucagon are under development. New therapies under development for type 2 DM include activators of glucokinase, inhibitors of 11 β-hydroxysteroid dehydrogenase-1, GPR40 agonists, monoclonal antibodies to reduce inflammation, and salsalate.


InternalMed_Harrison

InternalMed_Harrison. Bariatric surgery for obese individuals with type 2 DM has shown considerable promise, sometimes with dramatic resolution of the diabetes or major reductions in the needed dose of glucose-lowering therapies (Chap. 416). Several large, unblinded clinical trials have demonstrated a much greater efficacy of bariatric surgery compared to medical management in the treatment of type 2 DM; the durability of the diabetes reversal or improvement is uncertain. The ADA clinical guidelines state that bariatric surgery should be considered in individuals with DM and a body mass index >35 kg/m2.


InternalMed_Harrison

InternalMed_Harrison. As with any therapy, the benefits of efforts directed toward glycemic control must be balanced against the risks of treatment (Table 418-5). Side effects of intensive treatment include an increased frequency of serious hypoglycemia, weight gain, increased economic costs, and greater demands on the patient. In the DCCT, quality of life was very similar in 2417 the intensive and standard therapy groups. The most serious complication of therapy for DM is hypoglycemia, and its treatment with oral glucose or glucagon injection is discussed in Chap. 420. Severe, recurrent hypoglycemia warrants examination of treatment regimen and glycemic goal for the individual patient. Weight gain occurs with most (insulin, insulin secretagogues, thiazolidinediones) but not all (metformin, α-glucosidase inhibitors, GLP-1 receptor agonists, DPP-IV inhibitors) therapies. The weight gain is partially due to the anabolic effects of insulin and the reduction in glucosuria. As a result of recent controversies


InternalMed_Harrison

InternalMed_Harrison. GLP-1 receptor agonists, DPP-IV inhibitors) therapies. The weight gain is partially due to the anabolic effects of insulin and the reduction in glucosuria. As a result of recent controversies about the optimal glycemic goal and concerns about safety, the FDA now requires information about the cardiovascular safety profile as part of its evaluation of new treatments for type 2 DM.


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InternalMed_Harrison. Individuals with type 1 or type 2 DM and severe hyperglycemia (>16.7 mmol/L [300 mg/dL]) should be assessed for clinical stability, including mentation and hydration. Depending on the patient and the rapidity and duration of the severe hyperglycemia, an individual may require more intense and rapid therapy to lower the blood glucose. However, many patients with poorly controlled diabetes and hyperglycemia have few symptoms. The physician should assess if the patient is stable or if diabetic ketoacidosis or a hyperglycemic hyperosmolar state should be considered. Ketones, an indicator of diabetic ketoacidosis, should be measured in individuals with type 1 DM when the plasma glucose is >16.7 mmol/L (300 mg/dL), during a concurrent illness, or with symptoms such as nausea, vomiting, or abdominal pain. Blood measurement of β-hydroxybutyrate is preferred over urine testing with nitroprusside-based assays that measure only acetoacetate and acetone.


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InternalMed_Harrison. Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS) are acute, severe disorders directly related to diabetes. DKA was formerly considered a hallmark of type 1 DM, but also occurs in individuals who lack immunologic features of type 1 DM and who can sometimes subsequently be treated with oral glucose-lowering agents (these obese individuals with type 2 DM are often of Hispanic or African-American descent). HHS is primarily seen in individuals with type 2 DM. Both disorders are associated with absolute or relative insulin deficiency, volume depletion, and acid-base abnormalities. DKA and HHS exist along a continuum of hyperglycemia, with or without ketosis. The metabolic similarities and differences in DKA and HHS are highlighted in Table 418-6. Both Diabetes Mellitus: Management and Therapies aLarge changes occur during treatment of DKA. bAlthough plasma levels may be normal or high at presentation, total-body stores are usually depleted.


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InternalMed_Harrison. Diabetes Mellitus: Management and Therapies aLarge changes occur during treatment of DKA. bAlthough plasma levels may be normal or high at presentation, total-body stores are usually depleted. 2418 disorders are associated with potentially serious complications if not promptly diagnosed and treated.


InternalMed_Harrison

InternalMed_Harrison. DIABETIC KETOACIDOSIS Clinical Features The symptoms and physical signs of DKA are listed in Table 418-7 and usually develop over 24 h. DKA may be the initial symptom complex that leads to a diagnosis of type 1 DM, but more frequently, it occurs in individuals with established diabetes. Nausea and vomiting are often prominent, and their presence in an individual with diabetes warrants laboratory evaluation for DKA. Abdominal pain may be severe and can resemble acute pancreatitis or ruptured viscus. Hyperglycemia leads to glucosuria, volume depletion, and tachycardia. Hypotension can occur because of volume depletion in combination with peripheral vasodilatation. Kussmaul respirations and a fruity odor on the patient’s breath (secondary to metabolic acidosis and increased acetone) are classic signs of the disorder. Lethargy and central nervous system depression may evolve into coma with severe DKA but should also prompt evaluation for other reasons for altered mental status (e.g.,


InternalMed_Harrison

InternalMed_Harrison. classic signs of the disorder. Lethargy and central nervous system depression may evolve into coma with severe DKA but should also prompt evaluation for other reasons for altered mental status (e.g., infection, hypoxemia). Cerebral edema, an extremely serious complication of DKA, is seen most frequently in children. Signs of infection, which may precipitate DKA, should be sought on physical examination, even in the absence of fever. Tissue ischemia (heart, brain) can also be a precipitating factor. Omission of insulin because of an eating disorder, mental health disorders, or an unstable psychosocial environment may sometimes be a factor precipitating DKA.


InternalMed_Harrison

InternalMed_Harrison. Pathophysiology DKA results from relative or absolute insulin deficiency combined with counterregulatory hormone excess (glucagon, catecholamines, cortisol, and growth hormone). Both insulin deficiency and glucagon excess, in particular, are necessary for DKA to develop. The decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis, and ketone body formation in the liver, as well as increases in substrate delivery from fat and muscle (free fatty acids, amino acids) to the liver. Markers of inflammation (cytokines, C-reactive protein) are elevated in both DKA and HHS


InternalMed_Harrison

InternalMed_Harrison. The combination of insulin deficiency and hyperglycemia reduces the hepatic level of fructose-2,6-bisphosphate, which alters the activity of phosphofructokinase and fructose-1,6-bisphosphatase. Glucagon excess decreases the activity of pyruvate kinase, whereas insulin deficiency increases the activity of phosphoenolpyruvate carboxykinase. These changes shift the handling of pyruvate toward glucose synthesis and away from glycolysis. The increased levels of glucagon and catecholamines in the face of low insulin levels promote glycogenolysis. Insulin deficiency also reduces levels of the GLUT4 glucose transporter, which impairs glucose uptake into skeletal muscle and fat and reduces intracellular glucose metabolism.


InternalMed_Harrison

InternalMed_Harrison. Ketosis results from a marked increase in free fatty acid release from adipocytes, with a resulting shift toward ketone body synthesis in the liver. Reduced insulin levels, in combination with elevations in catecholamines and growth hormone, increase lipolysis and the mAnifESTATionS of DiAbETiC kEToACiDoSiS Shortness of breath Abdominal tenderness (may edema/possibly coma Infarction (cerebral, coronary, mesenteric, peripheral) Abbreviation: UTI, urinary tract infection.


InternalMed_Harrison

InternalMed_Harrison. Abbreviation: UTI, urinary tract infection. release of free fatty acids. Normally, these free fatty acids are converted to triglycerides or very-low-density lipoprotein (VLDL) in the liver. However, in DKA, hyperglucagonemia alters hepatic metabolism to favor ketone body formation, through activation of the enzyme carnitine palmitoyltransferase I. This enzyme is crucial for regulating fatty acid transport into the mitochondria, where beta oxidation and conversion to ketone bodies occur. At physiologic pH, ketone bodies exist as ketoacids, which are neutralized by bicarbonate. As bicarbonate stores are depleted, metabolic acidosis ensues. Increased lactic acid production also contributes to the acidosis. The increased free fatty acids increase triglyceride and VLDL production. VLDL clearance is also reduced because the activity of insulin-sensitive lipoprotein lipase in muscle and fat is decreased. Hypertriglyceridemia may be severe enough to cause pancreatitis.


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InternalMed_Harrison. DKA is often precipitated by increased insulin requirements, as occurs during a concurrent illness (Table 418-7). Failure to augment insulin therapy often compounds the problem. Complete omission or inadequate administration of insulin by the patient or health care team (in a hospitalized patient with type 1 DM) may precipitate DKA. Patients using insulin-infusion devices with short-acting insulin may develop DKA, because even a brief interruption in insulin delivery (e.g., mechanical malfunction) quickly leads to insulin deficiency.


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InternalMed_Harrison. Laboratory Abnormalities and Diagnosis The timely diagnosis of DKA is crucial and allows for prompt initiation of therapy. DKA is characterized by hyperglycemia, ketosis, and metabolic acidosis (increased anion gap) along with a number of secondary metabolic derangements (Table 418-6). Occasionally, the serum glucose is only minimally elevated. Serum bicarbonate is frequently <10 mmol/L, and arterial pH ranges between 6.8 and 7.3, depending on the severity of the acidosis. Despite a total-body potassium deficit, the serum potassium at presentation may be mildly elevated, secondary to the acidosis. Total-body stores of sodium, chloride, phosphorus, and magnesium are reduced in DKA but are not accurately reflected by their levels in the serum because of hypovolemia and hyperglycemia. Elevated blood urea nitrogen (BUN) and serum creatinine levels reflect intravascular volume depletion. Interference from acetoacetate may falsely elevate the serum creatinine measurement. Leukocytosis,


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InternalMed_Harrison. blood urea nitrogen (BUN) and serum creatinine levels reflect intravascular volume depletion. Interference from acetoacetate may falsely elevate the serum creatinine measurement. Leukocytosis, hypertriglyceridemia, and hyperlipoproteinemia are commonly found as well. Hyperamylasemia may suggest a diagnosis of pancreatitis, especially when accompanied by abdominal pain. However, in DKA the amylase is usually of salivary origin and thus is not diagnostic of pancreatitis. Serum lipase should be obtained if pancreatitis is suspected.


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InternalMed_Harrison. The measured serum sodium is reduced as a consequence of the hyperglycemia (1.6-mmol/L [1.6-meq] reduction in serum sodium for each 5.6-mmol/L [100-mg/dL] rise in the serum glucose). A normal serum sodium in the setting of DKA indicates a more profound water deficit. In “conventional” units, the calculated serum osmolality (2 × [serum sodium + serum potassium] + plasma glucose [mg/dL]/ 18 + BUN/2.8) is mildly to moderately elevated, although to a lesser degree than that found in HHS (see below).


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InternalMed_Harrison. In DKA, the ketone body, β-hydroxybutyrate, is synthesized at a threefold greater rate than acetoacetate; however, acetoacetate is preferentially detected by a commonly used ketosis detection reagent (nitroprusside). Serum ketones are present at significant levels (usually positive at serum dilution of ≥1:8). The nitroprusside tablet, or stick, is often used to detect urine ketones; certain medications such as captopril or penicillamine may cause false-positive reactions. Serum or plasma assays for β-hydroxybutyrate are preferred because they more accurately reflect the true ketone body level.


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InternalMed_Harrison. The metabolic derangements of DKA exist along a spectrum, beginning with mild acidosis with moderate hyperglycemia evolving into more severe findings. The degree of acidosis and hyperglycemia do not necessarily correlate closely because a variety of factors determine the level of hyperglycemia (oral intake, urinary glucose loss). Ketonemia is a consistent finding in DKA and distinguishes it from simple hyperglycemia. The differential diagnosis of DKA includes starvation ketosis, alcoholic ketoacidosis (bicarbonate usually >15 meq/L), and other forms of increased anion-gap acidosis (Chap. 66).


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InternalMed_Harrison. The management of DKA is outlined in Table 418-8. After initiating IV fluid replacement and insulin therapy, the agent or event that precipitated the episode of DKA should be sought and aggressively treated. If the patient is vomiting or has altered mental status, a nasogastric tube should be inserted to prevent aspiration of gastric contents. Central to successful treatment of DKA is careful monitoring and frequent reassessment to ensure that the patient and the metabolic derangements are improving. A comprehensive flow sheet should record chronologic changes in vital signs, fluid intake and output, and laboratory values as a function of insulin administered.


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InternalMed_Harrison. After the initial bolus of normal saline, replacement of the sodium and free water deficit is carried out over the next 24 h (fluid deficit is often 3–5 L). When hemodynamic stability and adequate urine output are achieved, IV fluids should be switched to 0.45% saline depending on the calculated volume deficit. The change to 0.45% saline helps to reduce the trend toward hyperchloremia later in the course of DKA. Alternatively, initial use of lactated Ringer’s IV solution may reduce the hyperchloremia that commonly occurs with normal saline.


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InternalMed_Harrison. A bolus of IV (0.1 units/kg) short-acting insulin should be administered immediately (Table 418-8), and subsequent treatment should provide continuous and adequate levels of circulating insulin. IV administration is preferred (0.1 units/kg of regular insulin per hour) because it ensures rapid distribution and allows adjustment of the infusion rate as the patient responds to therapy. In mild episodes of DKA, short-acting insulin can be used SC. IV insulin mAnAgEmEnT of DiAbETiC kEToACiDoSiS 1. Confirm diagnosis (↑ plasma glucose, positive serum ketones, metabolic acidosis). 2. Admit to hospital; intensive care setting may be necessary for frequent monitoring or if pH <7.00 or unconscious. 3. Assess: Serum electrolytes (K+, Na+, Mg2+, Cl−, bicarbonate, phosphate) Acid-base status—pH, HCO3−, PCO2, β-hydroxybutyrate Renal function (creatinine, urine output) 4.


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InternalMed_Harrison. 3. Assess: Serum electrolytes (K+, Na+, Mg2+, Cl−, bicarbonate, phosphate) Acid-base status—pH, HCO3−, PCO2, β-hydroxybutyrate Renal function (creatinine, urine output) 4. Replace fluids: 2–3 L of 0.9% saline over first 1–3 h (10–20 mL/kg per hour); subsequently, 0.45% saline at 250–500 mL/h; change to 5% glucose and 0.45% saline at 150–250 mL/h when plasma glucose reaches 250 mg/dL (13.9 mmol/L). 5. Administer short-acting insulin: IV (0.1 units/kg), then 0.1 units/kg per hour by continuous IV infusion; increase twoto threefold if no response by 2–4 h. If the initial serum potassium is <3.3 mmol/L (3.3 meq/L), do not administer insulin until the potassium is corrected. 6. Assess patient: What precipitated the episode (noncompliance, infection, trauma, pregnancy, infarction, cocaine)? Initiate appropriate workup for precipitating event (cultures, CXR, ECG). 7.


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InternalMed_Harrison. 6. Assess patient: What precipitated the episode (noncompliance, infection, trauma, pregnancy, infarction, cocaine)? Initiate appropriate workup for precipitating event (cultures, CXR, ECG). 7. Measure capillary glucose every 1–2 h; measure electrolytes (especially K+, bicarbonate, phosphate) and anion gap every 4 h for first 24 h. 8. Monitor blood pressure, pulse, respirations, mental status, fluid intake and output every 1–4 h. 9. Replace K+: 10 meq/h when plasma K+ <5.0–5.2 meq/L (or 20–30 meq/L of infusion fluid), ECG normal, urine flow and normal creatinine documented; administer 40–80 meq/h when plasma K+ <3.5 meq/L or if bicarbonate is given. If initial serum potassium is >5.2 mmol/L (5.2 meq/L), do not supplement K+ until the potassium is corrected. 10. See text about bicarbonate or phosphate supplementation. 11.


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InternalMed_Harrison. 10. See text about bicarbonate or phosphate supplementation. 11. Continue above until patient is stable, glucose goal is 8.3–13.9 mmol/L (150–250 mg/dL), and acidosis is resolved. Insulin infusion may be decreased to 0.05–0.1 units/kg per hour. 12. Administer long-acting insulin as soon as patient is eating. Allow for a 2–4 hour overlap in insulin infusion and SC insulin injection. Abbreviations: CXR, chest x-ray; ECG, electrocardiogram. Source: Adapted from M Sperling, in Therapy for Diabetes Mellitus and Related Disorders, American Diabetes Association, Alexandria, VA, 1998; and AE Kitabchi et al: Diabetes Care 32:1335, 2009.


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InternalMed_Harrison. Source: Adapted from M Sperling, in Therapy for Diabetes Mellitus and Related Disorders, American Diabetes Association, Alexandria, VA, 1998; and AE Kitabchi et al: Diabetes Care 32:1335, 2009. should be continued until the acidosis resolves and the patient is 2419 metabolically stable. As the acidosis and insulin resistance associated with DKA resolve, the insulin infusion rate can be decreased (to 0.05–0.1 units/kg per hour). Long-acting insulin, in combination with SC short-acting insulin, should be administered as soon as the patient resumes eating, because this facilitates transition to an outpatient insulin regimen and reduces length of hospital stay. It is crucial to continue the insulin infusion until adequate insulin levels are achieved by administering long-acting insulin by the SC route. Even relatively brief periods of inadequate insulin administration in this transition phase may result in DKA relapse.


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InternalMed_Harrison. Hyperglycemia usually improves at a rate of 4.2–5.6 mmol/L (75–100 mg/dL) per hour as a result of insulin-mediated glucose disposal, reduced hepatic glucose release, and rehydration. The latter reduces catecholamines, increases urinary glucose loss, and expands the intravascular volume. The decline in the plasma glucose within the first 1–2 h may be more rapid and is mostly related to volume expansion. When the plasma glucose reaches 13.9 mmol/L (250 mg/dL), glucose should be added to the 0.45% saline infusion to maintain the plasma glucose in the 8.3–13.9 mmol/L (150–250 mg/dL) range, and the insulin infusion should be continued. Ketoacidosis begins to resolve as insulin reduces lipolysis, increases peripheral ketone body use, suppresses hepatic ketone body formation, and promotes bicarbonate regeneration. However, the acidosis and ketosis resolve more slowly than hyperglycemia. As ketoacidosis improves, β-hydroxybutyrate is converted to ace toacetate. Ketone body levels may appear


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InternalMed_Harrison. regeneration. However, the acidosis and ketosis resolve more slowly than hyperglycemia. As ketoacidosis improves, β-hydroxybutyrate is converted to ace toacetate. Ketone body levels may appear to increase if measured by laboratory assays that use the nitroprusside reaction, which only detects acetoacetate and acetone. The improvement in acidosis and anion gap, a result of bicarbonate regeneration and decline in ketone bodies, is reflected by a rise in the serum bicarbonate level and the arterial pH. Depending on the rise of serum chloride, the anion gap (but not bicarbonate) will normalize. A hyperchloremic acidosis (serum bicarbonate of 15–18 mmol/L [15–18 meq/L]) often follows successful treatment and gradually resolves as the kidneys regenerate bicarbonate and excrete chloride.


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InternalMed_Harrison. Potassium stores are depleted in DKA (estimated deficit 3–5 mmol/kg [3–5 meq/kg]). During treatment with insulin and fluids, various factors contribute to the development of hypokalemia. These include insulin-mediated potassium transport into cells, resolution of the acidosis (which also promotes potassium entry into cells), and urinary loss of potassium salts of organic acids. Thus, potassium repletion should commence as soon as adequate urine output and a normal serum potassium are documented. If the initial serum potassium level is elevated, then potassium repletion should be delayed until the potassium falls into the normal range. Inclusion of 20–40 meq of potassium in each liter of IV fluid is reasonable, but additional potassium supplements may also be required. To reduce the amount of chloride administered, potassium phosphate or acetate can be substituted for the chloride salt. The goal is to maintain the serum potassium at >3.5 mmol/L (3.5 meq/L).


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InternalMed_Harrison. Despite a bicarbonate deficit, bicarbonate replacement is not usually necessary. In fact, theoretical arguments suggest that bicarbonate administration and rapid reversal of acidosis may impair cardiac function, reduce tissue oxygenation, and promote hypokalemia. The results of most clinical trials do not support the routine use of bicarbonate replacement, and one study in children found that bicarbonate use was associated with an increased risk of cerebral edema. However, in the presence of severe acidosis (arterial pH <7.0), the ADA advises bicarbonate (50 mmol/L [meq/L] of sodium bicarbonate in 200 mL of sterile water with 10 meq/L KCl per hour for 2 h until the pH is >7.0). Hypophosphatemia may result from increased glucose usage, but randomized clinical trials have not demonstrated that phosphate replacement is beneficial in DKA. If the serum phosphate is <0.32 mmol/L (1 mg/dL), then phosphate supplement should be considered and the serum calcium monitored. Hypomagnesemia may


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InternalMed_Harrison. that phosphate replacement is beneficial in DKA. If the serum phosphate is <0.32 mmol/L (1 mg/dL), then phosphate supplement should be considered and the serum calcium monitored. Hypomagnesemia may develop during DKA therapy and may also require supplementation.


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InternalMed_Harrison. Diabetes Mellitus: Management and Therapies 2420 With appropriate therapy, the mortality rate of DKA is low (<1%) and is related more to the underlying or precipitating event, such as infection or myocardial infarction. Venous thrombosis, upper gastrointestinal bleeding, and acute respiratory distress syndrome occasionally complicate DKA. The major nonmetabolic complication of DKA therapy is cerebral edema, which most often develops in children as DKA is resolving. The etiology of and optimal therapy for cerebral edema are not well established, but overreplacement of free water should be avoided. Following treatment, the physician and patient should review the sequence of events that led to DKA to prevent future recurrences. Foremost is patient education about the symptoms of DKA, its precipitating factors, and the management of diabetes during a concurrent illness. During illness or when oral intake is compromised, patients should (1) frequently measure the capillary blood glucose;


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InternalMed_Harrison. factors, and the management of diabetes during a concurrent illness. During illness or when oral intake is compromised, patients should (1) frequently measure the capillary blood glucose; (2) measure urinary ketones when the serum glucose is >16.5 mmol/L (300 mg/dL); (3) drink fluids to maintain hydration; (4) continue or increase insulin; and (5) seek medical attention if dehydration, persistent vomiting, or uncontrolled hyperglycemia develop. Using these strategies, early DKA can be prevented or detected and treated appropriately on an outpatient basis.


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InternalMed_Harrison. HYPERGLYCEMIC HYPEROSMOLAR STATE Clinical Features The prototypical patient with HHS is an elderly individual with type 2 DM, with a several-week history of polyuria, weight loss, and diminished oral intake that culminates in mental confusion, lethargy, or coma. The physical examination reflects profound dehydration and hyperosmolality and reveals hypotension, tachycardia, and altered mental status. Notably absent are symptoms of nausea, vomiting, and abdominal pain and the Kussmaul respirations characteristic of DKA. HHS is often precipitated by a serious, concurrent illness such as myocardial infarction or stroke. Sepsis, pneumonia, and other serious infections are frequent precipitants and should be sought. In addition, a debilitating condition (prior stroke or dementia) or social situation that compromises water intake usually contributes to the development of the disorder.


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InternalMed_Harrison. Pathophysiology Relative insulin deficiency and inadequate fluid intake are the underlying causes of HHS. Insulin deficiency increases hepatic glucose production (through glycogenolysis and gluconeogenesis) and impairs glucose utilization in skeletal muscle (see above discussion of DKA). Hyperglycemia induces an osmotic diuresis that leads to intravascular volume depletion, which is exacerbated by inadequate fluid replacement. The absence of ketosis in HHS is not understood. Presumably, the insulin deficiency is only relative and less severe than in DKA. Lower levels of counterregulatory hormones and free fatty acids have been found in HHS than in DKA in some studies. It is also possible that the liver is less capable of ketone body synthesis or that the insulin/glucagon ratio does not favor ketogenesis.


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InternalMed_Harrison. Laboratory Abnormalities and Diagnosis The laboratory features in HHS are summarized in Table 418-6. Most notable are the marked hyperglycemia (plasma glucose may be >55.5 mmol/L [1000 mg/dL]), hyperosmolality (>350 mosmol/L), and prerenal azotemia. The measured serum sodium may be normal or slightly low despite the marked hyperglycemia. The corrected serum sodium is usually increased (add 1.6 meq to measured sodium for each 5.6-mmol/L [100-mg/dL] rise in the serum glucose). In contrast to DKA, acidosis and ketonemia are absent or mild. A small anion-gap metabolic acidosis may be present secondary to increased lactic acid. Moderate ketonuria, if present, is secondary to starvation.


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InternalMed_Harrison. Volume depletion and hyperglycemia are prominent features of both HHS and DKA. Consequently, therapy of these disorders shares several elements (Table 418-8). In both disorders, careful monitoring of the patient’s fluid status, laboratory values, and insulin infusion rate is crucial. Underlying or precipitating problems should be aggressively sought and treated. In HHS, fluid losses and dehydration are usually more pronounced than in DKA due to the longer duration of the illness. The patient with HHS is usually older, more likely to have mental status changes, and more likely to have a life-threatening precipitating event with accompanying comorbidities. Even with proper treatment, HHS has a substantially higher mortality rate than DKA (up to 15% in some clinical series).


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InternalMed_Harrison. Fluid replacement should initially stabilize the hemodynamic status of the patient (1–3 L of 0.9% normal saline over the first 2–3 h). Because the fluid deficit in HHS is accumulated over a period of days to weeks, the rapidity of reversal of the hyperosmolar state must balance the need for free water repletion with the risk that too rapid a reversal may worsen neurologic function. If the serum sodium is >150 mmol/L (150 meq/L), 0.45% saline should be used. After hemodynamic stability is achieved, the IV fluid administration is directed at reversing the free water deficit using hypotonic fluids (0.45% saline initially, then 5% dextrose in water [D5W]). The calculated free water deficit (which averages 9–10 L) should be reversed over the next 1–2 days (infusion rates of 200–300 mL/h of hypotonic solution). Potassium repletion is usually necessary and should be dictated by repeated measurements of the serum potassium. In patients taking diuretics, the potassium deficit can be quite


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InternalMed_Harrison. hypotonic solution). Potassium repletion is usually necessary and should be dictated by repeated measurements of the serum potassium. In patients taking diuretics, the potassium deficit can be quite large and may be accompanied by magnesium deficiency. Hypophosphatemia may occur during therapy and can be improved by using KPO4 and beginning nutrition.


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InternalMed_Harrison. As in DKA, rehydration and volume expansion lower the plasma glucose initially, but insulin is also required. A reasonable regimen for HHS begins with an IV insulin bolus of 0.1 unit/kg followed by IV insulin at a constant infusion rate of 0.1 unit/kg per hour. If the serum glucose does not fall, increase the insulin infusion rate by twofold. As in DKA, glucose should be added to IV fluid when the plasma glucose falls to 13.9 mmol/L (250 mg/dL), and the insulin infusion rate should be decreased to 0.05–0.1 unit/kg per hour. The insulin infusion should be continued until the patient has resumed eating and can be transferred to a SC insulin regimen. The patient should be discharged from the hospital on insulin, although some patients can later switch to oral glucose-lowering agents.


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InternalMed_Harrison. Virtually all medical and surgical subspecialties are involved in the care of hospitalized patients with diabetes. Hyperglycemia, whether in a patient with known diabetes or in someone without known diabetes, appears to be a predictor of poor outcome in hospitalized patients. General anesthesia, surgery, infection, or concurrent illness raises the levels of counterregulatory hormones (cortisol, growth hormone, catecholamines, and glucagon) and cytokines that may lead to transient insulin resistance and hyperglycemia. These factors increase insulin requirements by increasing glucose production and impairing glucose utilization and thus may worsen glycemic control. The concurrent illness or surgical procedure may lead to variable insulin absorption and also prevent the patient with DM from eating normally and, thus, may promote hypoglycemia. Glycemic control should be assessed on admission using the HbA1c. Electrolytes, renal function, and intravascular volume status should be assessed


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InternalMed_Harrison. eating normally and, thus, may promote hypoglycemia. Glycemic control should be assessed on admission using the HbA1c. Electrolytes, renal function, and intravascular volume status should be assessed as well. The high prevalence of CVD in individuals with DM (especially in type 2 DM) may necessitate preoperative cardiovascular evaluation (Chap. 419).


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InternalMed_Harrison. The goals of diabetes management during hospitalization are nearnormoglycemia, avoidance of hypoglycemia, and transition back to the outpatient diabetes treatment regimen. Upon hospital admission, frequent glycemic monitoring should begin, as should planning for diabetes management after discharge. Glycemic control appears to improve the clinical outcomes in a variety of settings, but optimal glycemic goals for the hospitalized patient are incompletely defined.


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InternalMed_Harrison. In a number of cross-sectional studies of patients with diabetes, a greater degree of hyperglycemia was associated with worse cardiac, neurologic, and infectious outcomes. In some studies, patients who do not have preexisting diabetes but who develop modest blood glucose elevations during their hospitalization appear to benefit from achieving near-normoglycemia using insulin treatment. However, a large randomized clinical trial (Normoglycemia in Intensive Care Evaluation Survival Using Glucose Algorithm Regulation [NICESUGAR]) of individuals in the ICU (most of whom were receiving mechanical ventilation) found an increased mortality rate and a greater number of episodes of severe hypoglycemia with very strict glycemic control (target blood glucose of 4.5–6 mmol/L or 81–108 mg/dL) compared to individuals with a more moderate glycemic goal (mean blood glucose of 8 mmol/L or 144 mg/dL). Currently, most data suggest that very strict blood glucose control in acutely ill patients likely


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InternalMed_Harrison. to individuals with a more moderate glycemic goal (mean blood glucose of 8 mmol/L or 144 mg/dL). Currently, most data suggest that very strict blood glucose control in acutely ill patients likely worsens outcomes and increases the frequency of hypoglycemia. The ADA suggests the following glycemic goals for hospitalized patients: (1) in critically ill patients: glucose of 7.8–10.0 mmol/L or 140–180 mg/dL; (2) in non–critically ill patients: premeal glucose <7.8 mmol/L (140 mg/dL) and at other times blood glucose <10 mmol/L (180 mg/dL).