Diabetes in Old Age - part 8 pot

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MANAGING SURGERY 185 14 Metabolic Risk Factors and their Treatment Hosam K. Kamel, John E. Morley St Louis University School of Medicine, and St. Louis VA Medical Center INTRODUCTION Type 2 diabetes is the most prevalent form of diabetes in older adults. This metabolic disorder is character- ized by defects in both insulin secretion and insulin action. In recent years, it has become increasingly recognized that Type 2 diabetes is a part of a cluster of cardiovascular risk factors that constitute what is now referred to as the `metabolic syndrome' (Beck-Nielsen et al 1999). Although most of the individual components of the syndrome were described more than 20 years ago (Zimmet and Albert 1999), it was not until 1988 that Reaven and coworkers focused attention on the cluster and named it `syndrome X' (Reaven 1988). A World Health Organization expert committee proposed that the syndrome be called the `metabolic syndrome' and focused its de®nition mainly on its relationship to cardiovascular disease (CVD) (Alberti and Zimmet 1998). As central visceral obesity was not included in the original description by Reaven, the term `metabolic syndrome' is preferred to `syndrome X'. Each of the factors described in the metabolic syndrome represents an important cardiovascular risk factor on its own. These factors contribute cumula- tively to macrovascular diabetic complications (Zim- met et al 1999). Furthermore, patients with one of these factors (e.g. diabetes or central obesity) often have one or more of the other cardiovascular risk factors described in the metabolic syndrome (Zimmet 1992). Atherosclerosis is the most frequent complication of Type 2 diabetes (Zimmet and Alberti 1997). Cardio- vascular disease accounts for at least 66% of deaths in individuals with Type 2 diabetes (Panzram 1987). In addition, coronary, cerebrovascular and peripheral vascular disease are 2±5 times more common in persons with diabetes (Zimmet and Alberti 1997). These ®ndings, in addition to the frequent association of Type 2 diabetes with other cardiovascular risk factors, indicate that the management of diabetic individuals should not only focus on tight blood glucose control, but should also involve minimizing other cardiovascular risk factors such as obesity, hypertension, hyperinsulinemia and dyslipidaemia (Zimmet 1995). This chapter discusses the metabolic syndrome and the management of metabolic risk factors in individuals with Type 2 diabetes mellitus. THE METABOLIC SYNDROME: AN OVERVIEW A WHO expert committee in 1998 proposed that the metabolic syndrome should be diagnosed in patients who show evidence of glucose intolerance and=or insulin resistance together with two other components of the syndrome (Table 14.1). The expert committee decided to de®ne insulin resistance as insulin sensitivity under hyperinsulinemic euglycemia clamp conditions below the lowest quartile for the population under investigation. This de®nition of insulin resistance matches the degree of insulin sensitivity in patients with Type 2 diabetes mellitus (Beck-Nielsen et al 1999). Epidemiological studies indicate that the metabolic syndrome is prevalent in industrialized countries. When applying the WHO de®nition of the metabolic syndrome to the European Group for the study of Insulin Resistance (EGIR) database (Ferran- ninni et al 1996), the prevalence of the syndrome was estimated at 15.6% among healthy Caucasians in Europe (Beck-Nielson et al 1999). Data from the Danish Twin Register (Kyvik, Green and Beck-Nielsen 1995) indicate a prevalence rate of 12.5% among Danish twins (Beck-Nielsen et al 1999). The actual Diabetes in Old Age. Second Edition. Edited by A. J. Sinclair and P. Finucane. # 2001 John Wiley & Sons Ltd. Diabetes in Old Age, Second Edition, Edited by Alan J. Sinclair & Paul Finucane Copyright#2001 JohnWiley&SonsLtd ISBNs: 0-471-49010-5 (Hardback); 0-470-84232-6 (Electronic) prevalence of the metabolic syndrome in these two populations is likely to be greater, however, since these estimates excluded individuals with overt diabetes mellitus. Studies from the US and Australia also indicate high prevalence of the metabolic syndrome, (Zimmet 1992; Hoffner et al 1990). The occurrence of Type 2 diabetes is probably best represented as the `top of a pyramid' formed of a cluster of cardiovascular risk factors that together constitute the metabolic syndrome (Figure 14.1) (Zimmet and Collier 1999). Paradoxically, studies have clearly demonstrated that some patients may show the other features of the metabolic syndrome up to 10 years before they develop overt hyperglycaemia (Panzram 1987; Haffner et al 1990). This indicates that the risk of developing CVD in some individuals may actually start well before the manifestations of glucose intolerance become apparent, and that early aggressive management of the metabolic risk factors in such individuals may help prevent the development of Type 2 diabetes and CVD (Zimmet and Collier 1999). The EGIR database, the largest database currently available on the metabolic syndrome, demonstrates a statistically signi®cant correlation between the degree of insulin resistance and the other components of the metabolic syndrome; including fasting plasma insulin levels (r  7 0.48; p < 0.01), waist:hip ratio (r  7 0.14, p < 0.01), fasting plasma triglyceride levels (r  7 0.26; p < 0.01), high density lipoprotein (HDL)±cholesterol levels (r  0.14, p < 0.01), and diastolic blood pressure (r  7 0.22, p < 0.01). Mul- tiple regression analysis, however, indicated that insulin resistance is a determinant of only fasting plasma insulin levels but not the other factors (Beck-Nielsen et al 1999). It is possible that the effect of insulin resistance on the other components of the syndrome is secondary to the associated hyperinsulinemia. This conclusion is supported by ®ndings from other studies that showed hyperinsulinemia to be a causative factor of both dyslipidaemia and hypertension (Beck-Nielsen and Groop 1994). The EGIR database also provides evidence that only 50% of the variations in insulin resistance could be explained by the other components of the syndrome, which could indicate that other variables (e.g. physical ®tness) may play a role in de- termining the severity of insulin resistance. Poulsen and coworkers (1999) studied the frequency of the metabolic syndrome among twins and showed an overall genetic contribution in the order of 40% to insulin resistance. This ®nding points towards a more important role for environmental factors in the pathogenesis of the metabolic syndrome (Figure 14.2). Studies of the offspring (Martin et al 1992) and ®rst- degree relatives (Vaag, Hemriken and Beck-Nielsen 1992) of patients with Type 2 diabetes mellitus indicate that insulin resistance may appear as early as 30 years prior to the onset of hyperglycaemia. We now know that insulin resistance alone rarely gives rise to hyperglycaemia. Insulin secretion usually rises in com- pensation, thus maintaining a euglycemic state. As long as this compensatory hyperinsulinemia is suf®- cient to overcome insulin resistance and hepatic glucose overproduction, hyperglycaemia does not develop. With time, however, many individuals develop Type 2 diabetes mellitus. Whether the effect of insulin resistance with time leads to impaired beta-cell function and subsequently its ability to maintain adequate insulin secretion, or whether the presence of insulin resistance adds to the predisposition to Type 2 diabetes in individuals who independently inherit or acquire insulin secretary defects, remains uncertain (DeFronzo and Ferrannini 1991). The sequence of events in the development of Type 2 diabetes is shown in Figure 14.3. Table 14.1 World Health Organization de®nition of the metabolic syndrome 1. Insulin resistance: insulin sensitivity below lowest quartile for the population 2. Glucose intolerance: 2-hour oral glucose tolerance test plasma glucose levels >7.8 m M 3. Central obesity: waist=hip ratioÐfemale >0.85, male >0.95 4. Hypertension: blood pressure >160=95 mmHg 5. Hypertriglyceridemia: triglycerides >1.7 m M 6. High-density lipoprotein±cholesterol: female <1.1 mM, male <0.9 m M Figure 14.1 Type 2 diabetes at the top of a pyramid of a cluster of cardiovascular risk factors forming the metabolic syndrome. LDL, low-density lipoprotein; HDL, high-density lipoprotein; PAI-1, platelet activator inhibitor-1 188 DIABETES IN OLD AGE INSULIN RESISTANCE AND HYPERINSULINEMIA Insulin resistance represents the earliest biochemical characteristic associated with the development of Type 2 diabetes mellitus (Lillioja et al 1993). Thus, screening for insulin resistance may represent the earliest phase at which subjects at risk for diabetes may be identi®ed. At the present time, no simple screening method to measure insulin resistance is available. Fasting hyperinsulinemia in non-diabetic subjects has been shown to be closely related to insulin resistance. Insulin assays currently available, however, are not suf®ciently standardized to permit categories of normal and abnormal insulin ranges to be de®ned for this purpose (Robbins et al 1996). In addition, it is estimated that 25% of the population can be shown to be insulin-resistant (Reaven 1988) yet only 6% of the population develop Type 2 diabetes. This indicates that most insulin-resistant individuals do not develop diabetes. Chronic insulin resistance, in addition to being associated with the development of Type 2 diabetes, has also been linked to increased prevalence of dyslipidaemia, hypertension, a procoagulant state, and CVD (DeFronzo and Ferrannini 1991). Fifty percent of the variability in insulin action may be attributed to differences in lifestyle; for example obesity, physical inactivity and cigarette smoking all increase the degree of insulin resistance. The other 50% of the variability is likely to be related to genetic differences. In addition, it is now clear that hyperglycaemia itself may produce insulin resistanceÐa phenomenon known as glucotoxicity (DeFronzo et al 1992). Insulin resistance is common in individuals with Type 2 diabetes mellitus, and this phenomenon is implicated as a major factor in the development of overt hyperglycaemia. In the Insulin Resistance and Atherosclerosis Study (IRAS), Haffner and coworkers (1997) reported that insulin resistance was present in 85% of subjects with diabetes. Insulin resistance may also be found in conditions that are not necessarily associated with glucose intolerance (Table 14.2). (Ferrannini 2000). DeFronzo and Ferrannini (1991) have shown that patients with Type 2 diabetes, obese individuals, and patients with essential hypertension may all have the same degree of insulin resistance relative to individuals with normal insulin sensitivity. Insulin resistance in diabetic individuals, however, is associated with metabolic alterations linked to the metabolic syndrome (Reaven 1988). This association was fully apparent in the EGIR database (Del Prato et Figure 14.2 Pathogenesis of the metabolic syndrome Figure 14.3 Pathogenesis of Type 2 diabetes mellitus METABOLIC RISK FACTORS 189 al 1999). Even in individuals with a body mass index (BMI) 27 kg=m 2 , those with evidence of insulin resistance had higher systolic and diastolic blood pres- sures and higher plasma triglycerides and cholesterol levels than those with normal insulin sensitivity. This indicates that insulin resistance may be a marker for the future development of diabetes and cardiovascular disease. Over the past decade, many investigators have tested the hypothesis that lifestyle modi®cation or pharmacological interventions may decrease insulin resistance, prevent diabetes and modify other cardiovascular risk factors. The effects of lifestyle modi®cation on insulin resistance are reviewed in other sections of the chapter. Here we focus on available pharmacological interventions. Two drug classes that have been shown to be promising in this regard were the thiazolidinediones and the biguanides. Troglitazone was the ®rst of the thiazolidinediones to become available for clinical use. Other drugs in this category include pioglitazone and rosiglotazone, ci- glitazone, and englitazone. The thiazolidinediones directly improve insulin sensitivity in muscle and liver through the activation of the nuclear transcription factor, peroxisome proliferator-activated receptor gamma (PPARg), enhancing insulin-mediated glucose uptake as well as inhibiting hepatic glucose produc- tion. Signi®cant clinical data are available only for troglitazone. This drug has been shown to inhibit in vitro hyperglycaemia-induced insulin resistance (Kro- der et al 1996), to lower the triglyceride content of pancreatic islets in rats (Shimabukuro et al 1997), and to improve the reduced beta-cell response to glucose found in subjects with impaired glucose tolerance (IGT) (Cavaghan et al 1997). In addition to its ad- vantageous effects on insulin and glucose, troglitazone lowers serum triglycerides and free fatty acids (Iwa- moto et al 1996), has antihypertensive and antioxidant properties (Nolan et al 1994) as well as an anti- proliferative action on smooth muscle cells (Law et al 1996). These effects may have signi®cant bene®ts in the prevention of progression of IGT to diabetes as well as on the risk of developing CVD. In a 12-week, multicenter trial of 51 subjects with IGT who were randomized to 400 mg=day troglitazone or placebo, 80% of the troglitazone-treated subjects reverted to normal glucose tolerance versus 48% of the placebo group. In addition, fasting insulin and C-peptide response to glucose and fasting triglyceride levels were reduced in the troglitazone group (Antonucci et al 1997). In another study, 3 months', treatment with troglitazone resulted in improvement of insulin action in subjects with IGT who have not yet developed diabetes (Cavaghan et al 1997). Troglitazone has been withdrawn from the market in the United States and most of Europe because of serious drug- related hepatic toxicity. Pioglitazone and roseglota- zone have been introduced recently in the US market. Data from the limited clinical trial with these two drugs indicate effects similar to those of troglitazone on insulin resistance, triglycerides, insulin, and glucose without signi®cant hepatic toxicity (Yamasaki et al 1997; Kawamori et al 1998; Shibata et al 1999). In a double-blind, placebo-controlled study, the biguanide metformin was found to reduce insulin secretion rate, while increasing insulin sensitivity and metabolic clearance rate without increasing glucose tolerance in 15 overweight subjects with IGT (Scheen, Letiexhe and Lefebvre 1995). The BIGPRO study is a multicenter primary prevention trial being conducted in France with the aim of examining the effects of metformin in 324 subjects with the insulin resistance syndrome, normal glucose tolerance, and upper-body obesity in a randomized, placebo-controlled trial. At one year, metformin-treated individuals had lost weight and had lower fasting glucose and insulin levels (Fontbonne et al 1996). Metformin is included in the Diabetes Prevention Program (1999) a multicenter study initiated in the United States in June 1996 aimed at testing the effects of lifestyle interventions and=or pharmacotherapy on progression to diabetes in 4000 subjects with IGT (Goldberg 1998). Troglitazone was included initially but discontinued because of associated liver toxicity. Table 14.2 Conditions commonly associated with insulin resistance Type 2 diabetes Thyroid disease (hyper=hypothyroidism) Cushing's syndrome Pheochromocytoma Acromegaly Essential hypertension Liver cirrhosis Rheumatoid arthritis Acanthosis nigricans Surgery Trauma=burns Pregnancy 190 DIABETES IN OLD AGE HYPERGLYCAEMIA There is strong evidence linking the occurrence of diabetic complications to the degree of hyperglycaemia. Klein (1995), in a 10-year follow-up of older patients with Type 2 diabetes, demonstrated that each 1% rise of HBA 1c is associated with an increased risk of retinopathy by 60% and nephropathy by 65%. The mechanism for this apparent glucotoxicity probably involves multiple metabolic pathways. Some of these pathways are modulated by glucose directly, while others are probably indirect consequences of glyco- sylation of proteins and changes in oxidative stress, (Mooradian and Thurman 1999). One of the important accomplishments of the last decade is the completion of two important diabetes clinical trials, namely the Diabetes Control and Com- plications Trial (DCCT) in the United States and Ca- nada, and the United Kingdom Prospective Diabetes Study (UKPDS). The DCCT (1993) demonstrated conclusively that normalization of blood glucose in individuals with Type 1 diabetes mellitus would reduce the risk of microvascular complications as well as neuropathy. The impact of tight glucose control on the frequency of cardiovascular complications could not be addressed by the DCCT trial. Following the release of the DCCT results, the American Diabetes Association (1993) issued a position statement indicating that the DCCT ®ndings in individuals with Type 1 diabetes mellitus should be readily applicable to individuals with Type 2 diabetes mellitus since the underlying mechanisms responsible for the complications are similar in the two types of disease. This recommendation at the time lacked supportive evidence, however. Even more confounding is the available evidence at the time from the University Groups Diabetes Program study that was not in favor of intensi®cation of blood glucose control (UGDP 1970). Subsequently, two smaller in- terventional trials in individuals with Type 2 diabetes mellitus yielded con¯icting messages. In the Kuma- moto study, (Ohkubo et al 1995), tightening of blood glucose control with insulin reduced the risks of microvascular disease to the same extent found in the DCCT. On the other hand, in the pilot study of the Veteran Administration (VA) Cooperative Study (Abraira, Colwell and Nuttall 1995) a disturbing trend of increased cardiovascular mortality was noted in individuals with Type 2 diabetes mellitus randomized to the intensive glucose control arm of the study. With this background of con¯icting messages as to the importance of intensive blood glucose control, the UKPDS (1998a±d; Holman et al 1999; see also Mooradian and Chehada 2000) was an important and timely contribution. The key ®ndings from the UKPDS are summarized in Table 14.3. In general these indicate that tight diabetic control is associated with lower microvascular complications. The improvement seen in the frequency of microvascular complications was proportionate to the microvascular bene®ts observed in the DCCT or the Kumamoto study when HBA 1c differences are accounted for. Unlike the effects on microvascular complications, tight glucose control in the UKPDS resulted in only marginal reduction in the incidence of macrovascular complications (16%) that did not achieve statistical signi®cance (UKPDS 1998a). This smaller effect of tight glycemic control on the frequency of cardiovascular complications in individuals with Type 2 diabetes mellitus greatly em- phasizes the importance of managing other cardiovascular risk factors (e.g. hypertension, smoking, dyslipidaemia, and central obesity) in such patients. In another prospective study, however, intensive insulin therapy was shown signi®cantly to decrease mortality in diabetic patients who suffered acute myocardial infarction (Malmberg et al 1999). HYPERTENSION Hypertension has been established as a powerful risk factor to all of the major cardiovascular diseases, Table 14.3 Summary of key ®ndings of the UK Prospective Diabetes Study 1. Strict blood glucose control lowers the incidence of microvascular diabetic complications 2. Insulin, sulfonylureas and metformin had similar effectiveness in lowering HbA 1c level 3. Type 2 diabetes mellitus is a progressive disease over time 4. Intensi®cation of blood glucose control requires pharmacological intervention in addition to lifestyle changes 5. Insulin or sulfonylurea treatment is not associated with increased or decreased incidence of cardiac events 6. Metformin monotherapy is associated with reduced overall mortality and reduced incidence of cardiovascular events in overweight individuals 7. Addition of acarbose results in additional improvement of blood glucose control irrespective of concomitant therapy 8. Lowering blood pressure <150=85 mmHg reduced diabetes- related microvascular and macrovascular complications 9. Using ACE inhibitors compared to beta-blockers had no distinct advantage on clinical outcomes METABOLIC RISK FACTORS 191 including coronary artery disease, stroke, peripheral arterial disease, renal disease and heart failure. Epi- demiological data have shown clearly that hypertension usually occurs in association with other metabolically linked risk factors, and that less than 20% occurs in isolation. Associated risk factors include glucose intolerance, obesity, left ventricular hy- pertrophy, and dyslipidemia (elevated total, low- density lipoprotein (LDL), and small dense LDL cholesterol levels, raised triglycerides, and reduced HDL cholesterol levels). Clusters of three or more of these additional risk factors occur at four-fold times the rate expected by chance. Based on data from the Fra- mingham Study (Kannel 2000), the risk of coronary artery disease increased stepwise with the extent of risk factor clustering. Among persons with hypertension, about 40% of coronary events in men and 68% in women are attributable to the presence of two or more additional risk factors. Only 14% of coronary events in hypertensive men and 5% of those in hypertensive women occurred in the absence of additional risk factors. Clinical trials have demonstrated conclusively that control of blood pressure will result in decreased total and cardiovascular mortality. The Hypertension Optimization Trial (HOT) (Hansson and Zanchetti 1997) studied the potential impact of aggressive antihypertensive therapy with target diastolic blood pres- sures being >90, >85 and >80 mmHg. The HOT trial demonstrated that more effective blood pressure lowering was associated with improvement in cardiovascular outcomes. Hypertension is prevalent in patients with Type 2 diabetes mellitus and its occurrence increases the risk of cardiovascular complications in such individuals (Laakso 1998). In the UKPDS, 1148 individuals with hypertension and Type 2 diabetes mellitus were randomized to tight blood pressure control (blood pressure goal <150=85 mmHg and mean value achieved was 144=82 mmHg) with the use of either an angio- tensin-converting enzyme (ACE) inhibitor (captopril), or a beta-blocker (atenolol) as the main treatment, or to a less tight control arm aiming at a blood pressure of less than 180=105 mmHg. Tight blood control in individuals with Type 2 diabetes mellitus and hypertension reduced the risk of diabetes-related deaths by 32%, and diabetes-related complications, notably retinopathy and deterioration of visual acuity, by 47%. The risk of stroke was reduced by 44%. There were no statistically signi®cant differences in the outcomes selectively attributable to ACE inhibitor or beta- blocker therapy (UKPDS 1998d). CENTRAL VISCERAL OBESITY Central obesity (obesity localized to central visceral fat depots) is the most prevalent precursor of Type 2 diabetes mellitus (Ohlsson et al 1985). Insulin resistance, which is more prominent in visceral obesity than generalized obesity or that localized to peripheral gluteofemoral depots, is considered to be related to this pattern of obesity (Peiris et al 1986). Free fatty acids have been implicated in the pathogenesis of insulin resistance in muscle through their interface with cri- tical steps in glycolysis. Muscle tissue is the main regulator of systemic insulin sensitivity (Bjorntrop and Rosmond 1999). Compared with subcutaneous fat, visceral fat has increased sensitivity to lipolytic stimuli and has decreased antilipolytic effects to insulin. This means that the potential per unit mass of visceral adipose tissue to mobilize free fatty acid is much larger than that of subcutaneous fat (Bjorntrop 1994). Acute reductions in caloric intake has been shown to improve insulin sensitivity, and weight reduction fur- ther improves insulin action while both decreasing 24- hour insulin secretion and enhancing insulin clearance, thus reducing demand on the beta-cell, particularly in the post-absorptive state (Kelly 1995). In addition, studies have shown that obese individuals with IGT may be prevented from developing diabetes through weight reduction. In a 6-year follow-up study of 109 individuals with IGT and clinically severe obesity who lost more than 50% of their bodyweight after bariatric surgery, only one individual developed diabetes, in comparison to the control group in which 6 out of 27 subjects became diabetic within 5 years (Long, O'Brien and MacDonald 1994). Another study in- volved 35 non-diabetic elderly men who achieved a 9 kg weight loss after a low-fat, hypocaloric diet maintained over a 9-month period (Colman et al 1995). Of 20 subjects with IGT, glucose intolerance was normalized in nine individuals. The improvement in glucose tolerance was related to the reduction in waist circumference and was associated with reduced insulin level and improvement in insulin action. Studies in animals have shown that high-fat diets may cause insulin resistance (Storlien et al 1991), and several prospective studies of subjects with IGT have demonstrated that fat consumption, especially high saturated fat, signi®cantly predicts conversion to Type 2 diabetes after controlling for obesity (Marshall et al 1994; Feskens et al 1995). In 31 individuals with IGT randomized either to a reduced-fat, polyunsaturated fat-enriched diet, or to a high-fat, monounsaturated fat- 192 DIABETES IN OLD AGE enriched diet, fasting glucose levels were slightly lowered by the high monounsaturated-fat diet without signi®cant changes in insulin sensitivity or parameters of insulin secretory response (Sarkkinen et al 1996). There have been no intervention studies in subjects with IGT to evaluate the effect of low saturated-fat diets versus saturated fat-enriched diets on the progression to clinical diabetes. Several studies have reported the advantage of combining weight-reduction and exercise programs on delaying the progression to diabetes in subjects with IGT. The Oslo Diet and Exercise Study (Torjesen et al 1977) demonstrated that a program combining total fat reduction with moderate increase in physical activity in 219 inactive, normoglycemic men and women with features of the insulin-resistance syndrome reduced fasting glucose levels and body mass index and im- proved insulin sensitivity and beta-cell function (as well as lipid pro®le and blood pressure). Insulin sensitivity, estimated using the homeostasis model, im- proved after one year of a low-fat diet alone as well as in the combined diet and exercise group, but not in the exercise-alone group. The Malmo study (Eriksson and Lindgarde 1991) evaluated the effects of a 5-year program of a low-fat, hypocaloric diet combined with increased physical activity in 41 recently diagnosed Type 2 diabetic subjects and in 181 individuals with IGT, in comparison with 79 subjects with IGT and 114 normoglycemic individuals who did not enroll in the program. In addition to demonstrating signi®cant reductions in body mass index and improvements in ®tness (increased maximal oxygen uptake), blood pressure, lipids, and hyperinsulinemia in the intervention group, glucose tolerance was normalized in more than 50% of the subjects with IGT. More than 50% of the diabetic subjects were in remission at the study end. Similar results were obtained in 22 subjects with IGT who completed a 2-year combined diet and exercise program in New Zealand (Borun et al 1994). The Da Qing IGT and Diabetes Study reported from China clearly demonstrated the bene®ts of lifestyle modi®cation (Pan et al 1994). In this study, the effects of a one-year diet or exercise intervention program were assessed in 577 individuals with IGT. Subjects were randomized to control, diet (low-fat and reduced calories in overweight individuals), exercise, or combined diet and exercise groups. Rates of conversion to diabetes were signi®cantly reduced in both lean and overweight members of the diet (47%), exercise (45%), and diet-plus-exercise (44%) groups when compared with subjects in the control group (66%). DYSLIPIDAEMIA Diabetes mellitus and hyperglycaemia are associated with several alterations in lipid metabolism, collectively known as diabetic dyslipidemia (Table 14.4) (Assman and Schulte 1988; Fontbonne et al 1989; Lewis and Steiner 1996) Hypertriglyceridaemia is the key characteristic of diabetic dyslipidaemia. Trigly- cerides have been shown to be an independent risk factor for coronary artery disease (Hokanson and Austin 1996). This may be attributed to their effect on increasing cholesteryl ester heteroexchange between lipoproteins (Durrington 1994). This may result in low HDL cholesterol and in the formation of small dense LDL particles (Durrington 1997). Small dense LDL particles, although highly atherogenic, do not contribute signi®cantly to total cholesterol serum levels and the only clue to their presence is usually a low HDL cholesterol associated with high triglyceride levels. In a prospective study from Germany (Assman and Schulte 1992), increased triglyceride levels increased the risk of coronary artery disease to a greater extent than did increased LDL cholesterol levels. Tri- glycerides are also linked to increased plasma ®- brinogen levels. Increased plasma ®brinogen has been shown to be a risk factor for coronary artery disease (Hamsten et al 1994), and its levels may be lowered by the use of ®brates with the exception of gem®brozil (Branchi et al 1993). In the Paris Prospective Study (Fontbonne et al 1989), the strongest predictor for the incidence of CVD during the follow-up period of 11 years in subjects with IGT was the serum triglyceride level. Patients with triglyceride levels higher than 1.5 m M had a relative risk of 3.3 (p < 0.01). HDL cholesterol was not measured in this study. A follow- up study among 313 diabetic patients in East Finland (Laakso et al 1993) showed that low HDL cholesterol and high triglyceride levels were the only independent risk factors for the development of coronary artery disease 7 years later. Low HDL (<0.9 m M) was associated with a relative risk of 3.9 (p < 0.001), whereas Table 14.4 Features of diabetic dyslipidaemia Increased plasma triglycerides (TG) Decreased high-density lipoprotein (HDL) ± cholesterol Appearance of small dense low density lipoprotein (LDL) ± cholesterol particles Decreased activity of lipoprotein lipase Increased serum levels of very-low-density lipoprotein (VLDL) particles Increased activity of hepatic lipase METABOLIC RISK FACTORS 193 the relative risk of high triglycerides (>2.3 mM)was 2.2 (p  0.001). Nutritional interventions (weight loss and decreased consumption of saturated fat) are recommended as the ®rst step in the management of diabetic dyslipidaemia (Franz et al 1994). However, lifestyle modi®cations alone often do not result in adequate lowering in serum lipid levels and pharmacological interventions are usually needed. In addition, in older persons ther- apeutic diets are often linked to the development of protein energy malnutrition. Two drug groups are often used to manage diabetic dyslipidaemia. These are the statins, which pre- dominantly lower serum cholesterol, and the ®brates, which principally decrease triglycerides. The differ- ential effects of statins and ®brates on cholesterol and triglyceride levels and the impact on cardiovascular outcomes in patients with Type 2 diabetes are being addressed in several clinical trials currently under way. Results from these are expected to be available in the coming few years. The study population of some large lipid clinical trials, however, included patients with diabetes, and results from these studies may help shed some light on some of these issues. The study population of the Scandinavian Simvas- tatin Survival Study (4S) (1994), a secondary-prevention randomized controlled trial utilizing the statin simvastatin, included 202 diabetic subjects. Over the 5.4-year follow-up period, total serum cholesterol levels decreased by 29% and cardiac events decreased by 33%. Another secondary-prevention randomized control trial, the Cholesterol and Recurrent Events (CARE), included 586 diabetic subjects (Goldberg et al 1998). This study investigated the effect of another statin, pravastatin, on cardiovascular outcomes. Over the 5-year follow-up period, serum cholesterol decreased by 20% and cardiovascular events by 20%. Unlike the other two trials, the Helsinki Heart Study (Koskinen et al 1992), investigated the effect of a ®- brate, gem®brozil, on the incidence of primary cardiac events in patients with hyperlipidaemia. Over the 5- year follow-up period, the 135 diabetic subjects in this study showed 34% reduction in the incidence of cardiac events, and a 10% reduction in serum cholesterol levels. The greater impact on cardiovascular events in this study in spite of a minimal effect on serum cholesterol levels (3.4% decrease in CVD incidence for 1% decrease in serum cholesterol), compared with the 4S study (1.1%) and the CARE study (1.2%) indicated that an additional bene®t appears to accrue from triglyceride lowering (Durrington 1997). Thus when both cholesterol and triglycerides are increased in diabetic patients, combining the bene®ts of both statins and ®brates should be considered. The recently introduced statin, atorvastatin, appears to combine the cholesterol- lowering properties of a statin with a greater effect on serum triglycerides compared with other statins (Black 1995). Recently, atorvastatin was found to be more powerful than simvastatin in lowering insulin resistance in 195 elderly diabetics (Paolisoo et al 2000). In this study, the degree of decline in plasma triglyceride concentration was a signi®cant determinant for the effect of stains on insulin resistance. OTHER METABOLIC RISK FACTORS Since the introduction of the concept of the metabolic syndrome, several other metabolic abnormalities have been de®ned to be related to insulin resistance and increased risk of CVD. The plasminogen activator inhibitor-1 (PAI-1) levels have been shown to be elevated in subjects with insulin resistance (Bastard and Pieroni 1999). In one study, PAI-1 levels were directly associated with the amount of visceral fat in obese men but not women. These levels decreased substantially when subjects lost weight (Kocks et al 1999). High PAI-1 levels may cause reduced endogenous ®brinolytic activity and have been linked to increased risk of CVD (Nordt et al 1999). Data from the Framingham offspring study (Meigs et al 2000) demonstrated an association between insulin resistance and abnormalities in several other hemostatic factors. In this study, elevated fasting insulin levels were associated with increased serum concentration of tissue-type plasminogen activator (tPA) antigen, and von Will- ebrand factor (VWF) antigen in addition to elevated PAI-1 serum levels. In another study (Carmassi et al 1999), intra-arterial infusion of insulin in the forearm resulted in increased local PAI-1 and tPA concentra- tions. These reported alterations in hemostatic factor levels place subjects with insulin resistance in a hypercoagulable state that may enhance their potential for acute thrombosis and places them at increased risk for CVD. Insulin resistance has been linked also to impaired endothelial function. Piatti and coworkers (2000) demonstrated that both glycosylated hemoglo- bin (HbA 1c ) and triglyceride serum levels were found to be independently correlated with endothelin-1 (ET- 1) serum levels in 200 subjects with the insulin resistance syndrome. Elevated circulating ET-1 con- centrations is a well-recognized marker of endothelial dysfunction. 194 DIABETES IN OLD AGE Hyperuriceamia is another factor that has been linked recently to insulin resistance and the metabolic syndrome. In a population of 380 Caucasian subjects, fasting serum uric acid was negatively correlated to the insulin sensitivity index, a measure of insulin resistance (Clausen et al 1998). Data from the First National Health and Nutrition Examination Survey (NHANES I) and the NHANES I Epidemiologic Fol- low-up Study (NHEF) in the US indicate that an increased serum uric acid level is an independent risk factor of cardiovascular mortality (Fang and Alderman 2000). In addition, a study of 7978 hypertensive patients showed that elevated uric acid levels were associated with increased frequency of cardiovascular events. Blood pressure control did not lower serum uric acid levels (Alderman et al 1999). Elevated serum leptin levels is another factor that lately has been shown to be associated with insulin resitance (Liuzzi et al 1999). Hyperleptinemia was shown to be a strong predictor of ®rst-ever acute myocardial infarction in obese individuals (Soderberg et al 1999). CONCLUSION Over the past decade there have been major strides in our understanding of the pathogenesis of Type 2 diabetes mellitus. It is now clear that Type 2 diabetes is one of several cardiovascular risk factors that collectively constitute what is now best referred to as the `metabolic syndrome'. A key feature of this is the presence of insulin resistance. Other important features include abnormalities of glucose, uric acid, lipid metabolism as well as the occurrence of hypertension, central obesity, and a hypercoagulable state. These abnormalities tend to cluster in the same individual, and collectively increase his=her risk for the development of CVD. 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American Diabetes Association (1993) Implications of the Diabetes Control and Complications Trial. Diabetes, 42, 1555± 1558. Antonucci T, Wicomb R, Mclain R et al (1997) Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care, 20, 188±193. Assman G, Schulte H (1988) The prospective cardiovascular Munster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and or diabetes mellitus and the relationship to coronary heart disease. American Heart Journal, 116, 1713±1724. Assmann G, Schulte H (1992) Relation of HDL-cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (The PROCAM experience). American Journal of Cardiology, 70, 733±773. Bastard JP, Pieroni L (1999) Plasma plasminogen activator inhibitor- 1, insulin resistance and android obesity. Biochemistry and Pharmacotherapy, 53, 455±461. Beck-Nielsen H and the European Group for the study of Insulin Resistance (EGIR) (1999) General characteristics of the insulin resistance syndrome. Drugs, 1, 7±10. Beck-Nielsen H, Groop L (1994) Metabolic and genetic character- ization of prediabetic states: sequence of events leading to non- insulin dependent diabetes mellitus. Journal of Clinical Inves- tigations, 94, 1714±1721. Bjorntrop P (1994) Fatty acids, hyperinsulinemia, and insulin resistance: which comes ®rst? Current Opinion in Lipidology, 5, 166±174. Bjorntrop P, Rosmond R (1999) Visceral obesity and diabetes. Drugs, 58 (Suppl. 1), 13±18. Black DM (1995) Atorvastatin: a step ahead for HMG-COA reductase inhibitors. In: Woodford FP, Davignon J, Snidman A (eds). Atherosclerosis X. Amsterdam: Elsevier Science, 307± 310. Borun DM, Waldron MA, Mann JI et al (1994) Impaired glucose tolerance and NIDDM: does a lifestyle intervention program have an effect? Diabetes Care, 17, 1311±1319. Branchi A, Rovellini A, Sommariva D et al (1993) Effects of three ®brate derivatives and of two HMG-CoA reductase inhibitors on plasma ®brinogen level in patients with primary hypercholesterolaemia. Thrombosis and Haemostasis, 70, 241±243. Carmassi F, Morale M, Ferrini L et al (1999) Local insulin infusion stimulates expression of plasminogen activator inhibitor-1 and tissue-type plasminogen activator in normal subjects. American Journal of Medicine, 107, 344±350. Cavaghan MK, Ehrmann DA, Byme NM et al (1997) Treatment with the antidiabetic agent troglitazone improves P cell responses to glucose in subjects with impaired glucose tolerance. Journal of Clinical Investigations, 100, 530±537. Clausen JO, Borch-Johnsen K, Ibsen H, Pedersen O (1998) Analysis of the relationship between fasting serum uric acid and the insulin sensitivity index in a population-based sample of 380 young healthy Caucasians. European Journal of Endocrinology, 138, 63±69. Colman E, Katzel LI, Rogus E et al (1995) Weight loss reduces abdominal fat and improves insulin action in middle-aged and METABOLIC RISK FACTORS 195 [...]... short-acting insulin can disrupt the patient's lifestyle Ultra-short-acting insulin analogues were developed with the hope of overcoming these limitations Lispro insulin is identical to human regular insulin with a minor transposition of a lysine and proline in the beta chain This transposition results in acceleration of the dissociation rate of the insulin hexamers Lispro insulin acts quickly within... (Heinemann et al 1999) Amylin Analogues Amylin was identi®ed in 1 987 (Cooper et al 1 987 ), and is a 37-amino-acid hormone secreted in conjunction with insulin by the pancreatic beta-cells in response to a glucose load or other insulin secretagogues (Ogawa et al 1990; Inoue et al 1991) In Type 1 diabetes, the reduction in amylin concentration parallels the decline in insulin secretion (Koda et al 1992)... nonobese Caucasian ®rst-degree relatives of patients with non-insulindependent diabetes mellitus Journal of Clinical Investigations, 89 , 782 ± 788 Yamasaki Y, Kawamori R, Wasada T et al (1997) Proglitazone (AD 483 3) ameliorates insulin resistance in patients with NIDDM AD- 483 3 Glucose Clamp Study Group, Japan Tohoku Journal of Experimental Medicine, 183 , 173± 183 Zimmet PZ (1992) Challenges in diabetes epidemiologyÐfrom... probably secondary to increased insulin secretion Diabetes in Old Age Second Edition Edited by A J Sinclair and P Finucane # 2001 John Wiley & Sons Ltd 200 DIABETES IN OLD AGE Table 15.1 Comparative pro®le of available oral agents for treatment of Type 2 diabetes Sulfonylureas Meglitinides Biguanide (metformin) Thiazolidinediones Alpha-glucosidase inhibitors Mode of Action Stimulate insulin release from... complications in patients with Type 2 diabetes Lancet, 352, 83 7 85 3 UKPDS (UK Prospective Diabetes Study) Group (1998b) Effect of intensive blood-glucose control with metformin on complications in overweight patients with Type 2 diabetes Lancet, 352, 85 4 86 5 UKPDS (UK Prospective Diabetes Study) Group (1998c) Tight blood pressure control and risk of macrovascular and micro- 1 98 DIABETES IN OLD AGE vascular... differ between Lispro insulin and human regular insulin-treated groups (Anderson et al 1997) Another short-acting insulin analogue `Insulin Aspart' (B 28 Asp) has a proline at position B 28 replaced with a negatively charged aspartic acid (Simpson and Spencer 1999) In addition to its rapid onset of action, insulin Aspart also has a favorable effect on postprandial hyperglycemia in both Type 1 and Type... effect of insulin Aspart, even under strict experimental conditions, is 10±20%, which is comparable to that of regular human insulin (Hume et al 19 98) Currently, insulin Aspart is still in the late phase of clinical trials The clinical utility of these short-acting insulin analogues and their advantages over the regular insulin in the elderly population has yet to be established Recently, a protamine derivative... terms of improving post-prandial hyperglycemia (Hirschberg et al 1999; Kalbag et al 1999) Finally, the real advantage of these relatively costly agents over a small dose of short-acting sulfonylurea is still not clear (Mooradian 19 98) INSULIN AND INSULIN ANALOGUES Insulin therapy in diabetes is discussed in detail in Chapter 13 This section deals mainly with the role of some of the newer insulin preparations... ef®cacy of metformin against insulin resistance parameters Drugs, 58 (Suppl 1), 21 Zimmet PZ, Cox VR, Dowse GK et al (1994) Is hyperinsulinemia a central characteristic of a chronic cardiovascular risk factor syndrome? Mixed ®ndings in Asian Indians, Creole and Chinese Mauritians Diabetic Medicine, 11, 388 ±396 Diabetes in Old Age, Second Edition, Edited by Alan J Sinclair & Paul Finucane Copyright... these agents Of concern is the wide range of variability in drug elimination kinetics In addition, a pre-prandial dosing regimen may be an obstacle to achieving long-term compliance in some individuals Nateglinide is a new meglitinide which is soon to be marketed and has a faster and shorter duration of insulin secretory activity than repaglinide Thus, nateglinide pharmacokinetics are more favorable in . activator inhibitor-1 188 DIABETES IN OLD AGE INSULIN RESISTANCE AND HYPERINSULINEMIA Insulin resistance represents the earliest biochemical characteristic associated with the development of Type 2 diabetes. insulin sensitivity, and weight reduction fur- ther improves insulin action while both decreasing 2 4- hour insulin secretion and enhancing insulin clearance, thus reducing demand on the beta-cell,. factor syndrome? Mixed ®ndings in Asian Indians, Creole and Chinese Mauritians. Diabetic Medicine, 11, 388 ±396. 1 98 DIABETES IN OLD AGE 15 Drug Therapy: Current and Emerging Agents Joe M. Chehade,

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