Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

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coronary artery disease, cerebral vascular disease, and peripheral vascular disease) can be reduced by careful control of plasma lipids, with current targets in people with diabetes being low density lipoprotein-cholesterol (LDL-C) of <100 mg/ dL (<2.6 mmol/L), high density lipoprotein-cholesterol (HDL-C) of >40 mg/dL (>1.1 mmol/L), and triglycerides <150 mg/dL (<1.7 mmol/L) [1], although it has been suggested that for individuals with diabetes and known coronary artery disease the targets be even more stringent, that is, an LDL-C target of <70 mg/dL (<1.8 mmol/L) [1,2]. Further, if drug-treated patients do not reach targets on maximal tolerated statin therapy, a reduction in LDL cholesterol of 30% to 40% from baseline is an alternative therapeutic goal [1]. This chapter reviews the treatment strategies and available modalities to achieve these goals.

GLYCEMIC CONTROL

Evidence. The evidence of the role of treatment of hyperglycemia and its impact on diabetic microvascular disease is unambiguous. Analyses from epidemiologic studies demonstrate a significant relationship between prevailing level of glycemia and microvascular disease, particularly retinopathy [3]. More importantly, randomized controlled clinical trials have demonstrated a beneficial effect on microvascular disease of lowering glycemia to a level close to normal. The Diabetes Control and Complications Trial (DCCT) showed that improved glycemic control, attained through intensive insulin therapy, can delay the onset and slow the progression of retinopathy, nephropathy, and neuropathy in patients with type 1 diabetes mellitus [4]. The DCCT may be the most important clinical study ever conducted in the field of diabetes, as its results were so dramatic that they effectively ended the debate as to whether glycemic control influences the development of diabetic complications. Importantly, too, in the DCCT, there was no “glycemic threshold”; rather, there was a continuous relationship between glycemic exposure and risk of complications [5,6]. Further, the Epidemiology of Diabetes Interventions and Complications (EDIC) fol- low-up study of the DCCT cohort showed the perhaps somewhat surprising result that the beneficial effects of improved glycemic control are sustained even after there is some slippage in the degree of control attained, and that the adverse effects of hyperglycemia continue even when there is subsequent improvement in glycemic control [7]. Indeed, in the EDIC extension, after a follow-up period of up to 20 years after enrollment on DCCT, there was even a reduction in macrovascular disease events—including death from coronary artery disease [8]. These observations suggest either that there is some sort of “metabolic memory” or that once the processes leading to microvascular complications are initiated, they are self-perpetuating. The lesson is that patients should strive for the best possible control as early as possible in the course of the disease, ideally from the time of diagnosis of their diabetes.

Other trials have confi rmed the relationship between glycemic control and diabetic complications in both type 1 diabetes [9,10] and type 2 diabetes [11–13]. The United Kingdom Prospective Diabetes Study (UKPDS) was the largest of these in type 2 diabetes [12,13]. Epidemiologic analysis of all UKPDS subjects also demonstrated that there was a continuous relationship between glycemic exposure and risk of complications [14]. Moreover, as in the DCCT-EDIC study [8], long-term

follow-up of the UKPDS cohort also demonstrated a “legacy effect” of earlier glycemic control, resulting in sustained benefit on microvascular complications, and the emergence of a statistically significant benefit on macrovascular complications and on death [15]. In contrast, three recent studies (ACCORD, ADVANCE, and VADT) with much shorter duration of follow-up failed to demonstrate a beneficial effect of glycemic control on macrovascular disease [16–18]. In addition, ACCORD, which sought a glycemic target of A1c < 6%, had an increased death rate in the intensive treatment group [16]. As a consequence of these studies and concerns raised about them, the American Diabetes Association, the American College of Cardiology, and the American Heart Association combined to review the data and present a statement about the studies and their implications on clinical practice [19]. That statement specifically noted that “the lack of significant reduction in CVD events with intensive glycemic control in ACCORD, ADVANCE, and VADT should not lead clinicians to abandon the general target of an A1c of <7.0% and thereby discount the benefit of good control on serious and debilitating microvascular complications” [19]. It also noted that “subset analyses of ACCORD, ADVANCE, and VADT suggest the hypothesis that patients with shorter duration of type 2 diabetes and without established atherosclerosis might reap cardiovascular benefit from intensive glycemic control” [19], which is consistent with the beneficial effects of early glycemic control in DCCT-EDIC [8] and UKPDS [15].

Management—Background. The vast majority of cases of diabetes fall into the two main categories: type 1 diabetes and type 2 diabetes. Type 1 diabetes is usually due to an immune-mediated destruction of pancreatic insulin-producing islet β-cells with consequent insulin deficiency and the need to replace insulin [20]. Although usually having an abrupt clinical onset, the disease process unfolds slowly, with progressive loss of β-cells over time. Type 1 diabetes presents as a consequence of significant loss of β-cell mass and/or function and invariably requires therapeutic replacement of insulin.

Type 2 diabetes, the more common type, is usually due to resistance to insulin action in the setting of inadequate compensatory insulin secretory response [21,22]. This is depicted in Figure 18.1. Insulin resistance is actually quite common, as it arises as a consequence of obesity, a sedentary lifestyle, and aging (Fig. 18.2), with resulting hyperglycemia and diabetes, blood pressure elevation, and dyslipidemia. In fact, collectively these abnormalities—which often occur together—have been designated the “metabolic syndrome” (or more properly the “dysmetabolic syndrome”). Type 2 diabetes does not emerge in all persons with insulin resistance, but rather only in those with a genetic defect in insulin secretory capacity such that pancreatic insulin secretion fails to compensate for the insulin resistance (Fig. 18.1). Initially, the insulin secretory abnormality is manifest by a loss of “first phase” insulin secretion after a glucose challenge, resulting in excessive postprandial hyperglycemia. Ultimately, however, in type 2 diabetes, there is a progressive loss of pancreatic islet β-cells, resulting in insulin deficiency and the need to replace insulin [23].

The basis of the abnormalities in carbohydrate, fat, and protein metabolism in diabetes primarily is deficient action of insulin on target tissues, resulting from inadequate insulin secretion and/or diminished tissue responses to insulin at one or more points in the complex pathways of hormone action. Actually, it is a bit more

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Insulin resistance

Figure 18.1. Schematic depiction of the dual defect that is necessary for type 2 diabetes to be manifest: insulin resistance in the setting of impaired β-cell function inadequate to compensate for the insulin resistance.

complex than that, with other hormones playing an important contributory role in glucose homeostasis. Glucagon, a hormone produced by the pancreatic islet α-cells that is normally secreted in response to protein and also to hypoglycemia, stimulates glucose production and release by the liver. In contrast, insulin modulates glucose production and release by the liver, to prevent it from becoming excessive. Thus, hepatic glucose production is regulated by a balance between stimulation by glucagon and inhibition by insulin (Fig. 18.3).

Figure 18.2. Causes and consequences of insulin resistance. Insulin resistance arises from obesity (particularly central obesity), a sedentary lifestyle, aging (perhaps related to progressive loss of muscle mass or sarcopenia), and may have a genetic proclivity to occurrence in some individuals. Potential consequences of insulin resistance include hyperglycemia and type 2 diabetes, blood pressure elevation (potentially leading to hypertension in those with a genetic risk of essential hypertension), and a dyslipidemia characterized by elevated triglycerides, low high density lipoprotein-cholesterol, and small dense low density lipoprotein-cholesterol (an atherogenic lipid pattern).

nervous system

Figure 18.3. Scheme of regulation of blood glucose. Glucose input is from food intake via the gastrointestinal tract, or during the basal state from hepatic glucose production, which is modulated (inhibited) by basal insulin secretion and stimulated by glucagon. The brain and nervous tissue use glucose independent of insulin, while insulin stimulates glucose uptake and utilization by peripheral tissues (here represented by muscle and adipose tissue).

One can conceptually divide the day into two basic time periods—the basal or fasting state (overnight and between meals) and the prandial state (after consuming meals). Hyperglycemia occurs in the basal or fasting state because of increased hepatic glucose production, which is a consequence of both an insulin secretory abnormality (lack of first phase insulin secretion) and hepatic resistance to insulin, the net result being inadequate modulation by insulin of the hepatic glucose production [21,22]. Hepatic glucose production is stimulated by increased glucagon secretion, which coupled with decreased insulin secretion results in a decrease of the insulin/glucagon ratio, important in regulating hepatic glucose production [24]. In contrast, hyperglycemia in the prandial state arises because of (1) increased absorption of glucose from the gastrointestinal tract; (2) continued hepatic glucose production, due to lack of adequate prompt insulin availability to modulate glucose production; and (3) decreased ability to dispose of the consumed glucose load, due to inadequate insulin secretion to compensate for resistance to insulin action in tissues where glucose is disposed—principally muscle and adipose tissue [21,22]. Figure 18.3 depicts the scheme of regulation of blood glucose and provides a number of potential targets for therapeutically regulating blood glucose.

Management—Strategy. Contemporary diabetes management is based on the concept of “targeted glycemic control.” Therapy, based on glycemic goals, utilizes progressive step-wise additions of whatever treatment modality is necessary to achieve glycemic goals [25]. Lifestyle modification—including medical nutritional therapy and promotion of physical activity—is the cornerstone of treatment of diabetes and is needed for all patients, as is basic education on diabetes.

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Type 1 Diabetes. Modern management of type 1 diabetes focuses on replication of normal insulin secretion [26–29]. Also called “flexible diabetes therapy,” this strategy calls for insulin delivery that comprises a basal and a prandial component, frequent home self-monitoring of blood glucose, a flexible dietary plan that accommodates most foods but with specific guidelines on how to alter therapy (such as insulin dose) based on carbohydrate intake. Most importantly, patients require the self-management skills to correct alterations in metabolic control at the time of such occurrences. This could include a change in insulin dose for premeal hyperglycemia, treatment of hypoglycemia, or addition of carbohydrate at bedtime to compensate for exercise earlier in the day. In addition, patients should understand basic principles of diabetes management during illness—“sick day guidelines.” All too often, patients with type 1 diabetes either fail to administer enough insulin during a viral gastroenteritis or fail to measure urinary ketones during illness. As a consequence, life-threatening ketoacidosis may develop.

Flexible diabetes therapy is accomplished, as in the DCCT, with insulin administered either by continuous subcutaneous insulin infusion (CSII) with an insulin pump or by multiple daily insulin injections (MDI); frequent self-monitoring of blood glucose (SMBG); and meticulous attention to balancing insulin dose, food intake, and energy expenditure [26–29]. If, as stated above, one conceptually divides the day into the basal or fasting state and the prandial state, then the insulin program follows logically—a basal insulin (or basal rate in an insulin pump) to work throughout the day, and prandial insulin (or bolus activation of an insulin pump) for each meal. If one fails to achieve near-normal glycemic control (and near-normal A1c), preprandial injections of pramlintide may be added to the treatment program [30,31]. Pramlintide is an analog of the hormone amylin, which is secreted together with insulin from the pancreatic islet β-cell, and allows correction of concomitant amylin deficiency [32]. Studies have demonstrated that the addition of pramlintide to insulin results in better postprandial glycemic control and improved A1c without weight gain [30–32].

Type 2 Diabetes. In type 2 diabetes, when lifestyle modification alone does not result in normalization or near-normalization of metabolic abnormalities, pharmacologic therapy is required. Before 1995 in the United States, only insulin and sulfonylureas were available for the treatment of diabetes. Among patients with type 2 diabetes, more than 50% of patients were treated with oral monotherapy, 40% of patients were treated with insulin therapy, and a small percentage of patients were using sulfonylureas in combination with insulin. Since 1995, there has been an explosion of introductions of new classes of pharmacologic agents [33–37]. Currently available antidiabetic agents are listed in Tables 18.1 and 18.2, with Table 18.2 summarizing insulin preparations, including insulin analogues.

The classes of pharmacologic agents currently available include insulins and insulin analogues [38–40], sulfonylureas [41], glinides [41], biguanides [42–44], glitazones (thiazolidinediones) [45,46], α-glucosidase inhibitors [47], amylin agonists [31,32], incretin mimetics [37,48,49], incretin enhancers (DPP-4 inhibitors) [37], and bile acid sequestrants [50–52]. Combination products have been introduced as well.

Table 18.2. Insulin Preparations Available in the United States

The new insulin analogs [40] include both rapid-acting insulin analogs (insulin lispro, insulin aspart, and insulin glulisine), which are designed to replace regular (soluble) insulin for prandial glycemic control, and relatively peakless longacting insulin analogs (insulin glargine and insulin detemir), which are designed to replace NPH (isophane), lente, and ultralente insulin for basal glycemic control. Indeed, lente and ultralente insulin are no longer sold in the United States.

The newer insulin secretagogues [41] include both long-acting sulfonylureas (glimiperide, glipizide-GITS) designed for once or twice daily use, and the very short acting glinides (repaglinide, natiglinide) designed for prandial use. There are two classes of insulin sensitizers—the biguanides (metformin) [42–44], which act principally by restraining hepatic glucose production, and the glitazones

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Table 18.4. Principal Limiting Factors in the Use of Currently Available Classes of Agents for Treatment of Diabetes Mellitus

class are summarized in Table 18.4. The availability of agents with differing and complementary mechanisms of action allows them to be used in various combinations, thus increasing the likelihood that satisfactory glycemic control can be achieved in any given patient. Some debate exists over what sequence agents should be added, although most authorities start with metformin, as recommended in current guidelines [53]. The concept of “targeted glycemic control” calls for progressive step-wise additions in order to achieve near-normal glycemic goals.

BLOOD PRESSURE CONTROL

Evidence. Many randomized controlled clinical trials have addressed the influence of blood pressure control in diabetes. The Hypertension in Diabetes Study (HDS) was embedded in the UKPDS by using a factorial design [54,55]. There were substantial risk reductions for “any diabetes-related endpoint,” diabetes-related death, heart failure, stroke, and microvascular disease (deterioration of retinopathy or of visual acuity). An “epidemiological” assessment of HDS demonstrated that the lower the systolic blood pressure, the lower the risk, and suggested a systolic blood pressure target of ≤130 mmHg [56].

The Hypertension Optimal Treatment (HOT) Study was a randomized trial involving 18,790 hypertensive patients (including 1501 patients with diabetes at baseline) with diastolic blood pressure of 100 to 115 mmHg [57]. They were randomly assigned to three different target diastolic blood pressure groups: ≤90, ≤85, and ≤80 mmHg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In the patients with diabetes in HOT, with the lowest target blood pressure (≤80 mmHg), there was a decline in

the rate of major cardiovascular events, cardiovascular mortality, and total mortality. In the group randomized to ≤80 mmHg, the risk of major cardiovascular events was halved in comparison with that of the target group ≤90 mmHg. These results suggest a diastolic blood pressure target of ≤80 mmHg in people with diabetes [57]. As a consequence of the above studies, current treatment recommendations for hypertension in patients with diabetes are to target a blood pressure of ≤130/80 mmHg [58–61]. Yet, the recently reported Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT) study in patients with coronary artery disease (CAD) but normal blood pressure found beneficial results of treatment in patients with a baseline blood pressure that averaged 129/78 mmHg [62]. Benefit was particularly seen in terms of atherosclerosis progression as measured by intravascular ultrasound [62]. This prompted an editorialist to suggest that the optimal target level of systolic blood pressure “is clearly lower than 140 mmHg and perhaps in the 120 mmHg range” [63].

The Systolic Hypertension in the Elderly Program (SHEP) and Systolic Hypertension in Europe (Syst-Eur) trials demonstrated that diabetic patients with isolated systolic hypertension benefited from treatment [64,65]. The Heart Outcomes Prevention Evaluation (HOPE) study demonstrated beneficial effects of intervention with an angiotensin-converting enzyme (ACE) inhibitor in diabetic patients with cardiovascular risk [66]. The Losartan Intervention for Endpoint reduction in hypertension study (LIFE) also showed a reduction in cardiovascular morbidity and mortality with an angiotensin receptor blocker (ARB) [67]. ARBs were also shown to be of benefit in diabetic patients with nephropathy, both early and late [68–70]. Yet, several other studies have found little or no difference amongst the various antihypertensive classes or agents [71–73], suggesting that it is blood pressure per se that is the critical issue [74]. However, most of these studies did not focus on diabetes per se. As a consequence, it is reasonable to continue to recommend that either an ACE inhibitor or an ARB be used in patients with diabetes.

Current Recommendations. There are consistent and substantial beneficial effects of improved blood pressure control in diabetic patients, impacting on various diabetic complications. In patients with diabetes, current blood pressure recommendations of the American Diabetes Association appear in its Position Statement on Treatment of Hypertension in Diabetes [58], which is based on a Technical Review on the same subject [59]. Similar recommendations are contained in the “Seventh Report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure” [60] and in the Guidelines developed by the European Society of Hypertension and European Society of Cardiology [61].

The primary goal of therapy for (nonpregnant) adults (>18 years of age) with diabetes is to decrease blood pressure to, and maintain it, at <130 mmHg systolic and <80 mmHg diastolic. In children, blood pressure should be decreased to the corresponding age-adjusted 90th percentile values. It should be noted, however, that in the general population, the risks for end-organ damage appear to be lowest when the systolic blood pressure is <120 mmHg and the diastolic blood pressure is <70 mmHg. For patients with an isolated systolic hypertension of >180 mmHg,