Glycemic control Correction of hyperglycemia can reverse glomerular basement membrane thick ening and mesangial changes. Studies looking at progression to micro- albuminuria and subse quent progression to frank albuminuria (e.g., the Steno 1 and II Studies, the KROC Study) a lso suggest a clinical bene \201 t from improving glycemic control. In the DCCT, tight gly cemic control of type 1 patients was shown to reduce progression to microalbuminuria by 30% and subsequent progression to albuminuria by 54%. 106-Draznin-Chap106.indd 616 3/31/2011 5:28:39 PM TREATMENT 617 Not all trials con \201 rm this \201 nding (e.g., the Microalbuminuria Collaborative Stu dy Group Trial), and not all patients with good control in the above trials gained bene \201 t. Even so, the current treatment aim is to normalize or signi \201 cantly reduce HbA 1c (< 7.2%) while avoiding any weight gain or hypoglycemia associated with the increased us e of both oral agents and insulin needed to do so. Dietary protein restriction High dietary protein can damage the kidney by increasing renal blood \202 ow and intraglomerular pressures in experimental situations. For microalbu- mi nuric type 1 patients, in small studies, reducing dietary animal protein intake appears to reduce both hyper \201 ltration and micralbuminuria, and the bene \201 t in more severe r enal impairment is more evident. In type 2 patients, the UKPDS showed an initial reduction in microalbu- minuria with dietar y modi \201 cation, which may in part be related to protein reduction. A dietary protein c ontent <0.8 g/kg is suggested. Lipid lowering Although diabetic nephropathy is not shown to reduce the progression of micr oalbuminuria to albuminuria or renal failure, these patients have a signi \201 cant dyslip idemia and a high cardiovascular mortality. They require careful lipid monitoring and aggre ssive treatment. The use of aspirin for similar reasons is also advisable. Further reading Ahmad J, Siddiqui MA, Ahmad H (1997). Effective postponement of diabetic ne phropathy in normo- tensive type 2 diabetic patients with microalbuminuria. Diabet Care 20: 1576 \200\2231581. Diabetes Control and Complications Trial Research Group (1993). The effect of intensive tre at- ment of diabetes on the development of microvascular complications of DM. N Engl J Med 329:304 \200\223309. Diabetes Control and Complications Trial Research Group (1995). Effect of intensive therapy on the development and progression of diabetic nephropathy in the DCCT. Kidney Int 42:1703 \200\2231720. EUCLID Study Group (1997). Randomized placebo-controlled trial of lisinopril in normotensiv e patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Lancet 349:1787 \200\2231792. Laffel LMB, McGill JB, Dans DJ, for the North American Microalbuminuria Studsy Group (1995) . The bene \201 cial effect of angiotensin converting enzyme inhibition with captopril on diabetic neph- ropathy in normotensive IDDM patients with microalbuminuria. Am J Med 99:497 \200\223504. Lewis EJ, Hunsicker LG, Bain RP, et al. (1993). The effect of angiotensin converting enzyme inhibi- tion on diabetic nephropathy. N Engl J Med 329:1456 \200\2231462. Microalbuminuria Captopril Study Group (1996). Captopril reduces the risk of nephropathy in IDDM patients with microalbuminuria. Diabetologia 39:587 \200\223593. NICE (2002). Type 2 diabetes \200\224renal disease. Clinical guidelines. http://www.nice.or g.uk NICE (2002). Type 2 diabetes \200\224management of blood pressure and blood lipids. Clinica l guidelines. http://www.nice.org.uk Ravid M, Brosch D, Levi Z, et al. (1998). Use of enalapril to attenuate decline in renal fu nction in normotensive, normalbuminuric patients with type 2 DM. Ann Intern Med 128:982 \200\223988. 106-Draznin-Chap106.indd 617 3/31/2011 5:28:39 PM CHAPTER 106 Diabetic renal disease 618 UK Prospective Diabetes Study Group (1998). Intensive blood glucose control with sulphonylu reas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837 \200\223853. UK Prospective Diabetes Study Group (1998). Tight blood pressure control and risk of macrov as- cular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 317:703 \200 \223713. UK Prospective Diabetes Study Group (1998). Ef \201 cacy of atenolol and captopril in redu cing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BM J 317:713 \200\223720. 106-Draznin-Chap106.indd 618 3/31/2011 5:28:39 PM PATHOLOGY 619 Diabetic neuropathy De \201 nition Involvement of cranial, peripheral, and autonomic nerves may be found in pa tients with diabetes and is termed diabetic neuropathy . This usually sug- gests a diffuse, predominantly sensory peripheral neuropathy. The effects on nerve function can be acute or chronic as well as transient or perma- nent. The consequences of neuropathy include the fo llowing: \200 Neuropathic ulcers, usually on the feet \200 Charcot arthropathy \200 A ltered sensation (both pain and i sensitivity to normal sensation) \200 Impotence (with a utonomic neuropathy) b See box 107.1 for classi \201 cation. Box 107.1 Classi \201 cation of diabetic neuropathies \200 Sensory neuropathy Acute \200 Chronic Autonomic neuropathy \200 Mononeuropathy Entrapment neuropathy \200 External pressure palsies \200 Spontaneous mononeuropathy Proximal motor neuropathy (diabetic amyotrophy) Pathology Diabetic neuropathy is one of the microvascular complications of diabe- tes. Path ologically, distal axonal loss occurs with focal demyelination and attempts at nerve regene ration. The vasa nervorum often shows basement membrane thickening, endothelial cell changes, and s ome occlusion of its lumen. This results in slowing of nerve conduction velocities or a com plete loss of nerve function. Both metabolic and vascular changes have been implicated in i ts etiology. 107-Draznin-Chap107.indd 619 3/31/2011 9:36:50 PM CHAPTER 107 Diabetic neuropathy 620 Pathogenesis Hyperglycemia is probably the underlying cause of the histological and functio nal changes. Several possible mechanisms have been suggested: \200 Overloading of the nor mal pathways for glucose metabolism resulting in i use of the polyol pathway, which leads t o i levels of sorbitol and fructose and d levels of myoinositol and glutathione. This may r esult in more free radical damage and lowers nitric oxide levels, thus altering nerve blood \202 ow. Experimental models using aldose reductase inhibitors, which can improve some a spects of diabetic neuropathy, add some weight to this theory. Possible accumulation of AGE (via nonenzymatic glycation) may also have a role to play, as could the hypercoagulable state and altered blood rheology known to occur in all patients w ith diabetes. When used in animal studies, aminoguanidine, which blocks AGE formation, can increase nerve conduction velocities and nerve blood \202 ow in diabetic subjects, streng thening the role of AGE accumulation in this process. In the more acute neuropathies, acute ischemia of the nerves due to vascular abnormalities has been suggested as the cause, but again the underlying reason for this is still unclear. Insulin-induced neuritis may occur when insulin therapy is started and blood glucose level s fall. Other potential etiological factors include changes in local growth factor production and o xidative stress. Further work is needed to clarify the exact role of each of the above mechanisms. In the me antime, studies showing improvements in neuropa- thy associated with good diabetic control strengthen the argument for the role of hyperglycemia and offer us a treatment option while we await other therapies. 107-Draznin-Chap107.indd 620 3/31/2011 9:36:51 PM PERIPHERAL SENSORIMOTOR NEUROPATHY 621 Peripheral sensorimotor neuropathy Although hyperglycemia can alter nerve function and ofte n gives some sensory symptoms at diagnosis, correcting the hyperglycemia can often resolve these. Chronic sensorimotor neuropathy, however, is the most common feature of peripheral n erve involvement seen in patients with diabetes (see Box 107.2 ). The exact prevalence of diabetic neuropathy varies in most studies because of the different de \201 nitions and examination techniques used. For example, sensitive nerve conduction studies can show up to 80% of patients having abnormal results. In more normal practice, however, 20 \200\22330% of unselected patients can be expected to have either symptomatic neuropathy or abnormalities on examination that are clinically sign i \201 cant. At least 50% of these patients are asymptomatic. This \201 gure will increa se with longer duration of diabetes, so although 7 \200\2238% of type 2 patients may have a bnormalities at diagnosis, 50% can be expected to have them 25 years later. Mononeuropathies Peripheral mononeuropathies and cranial mononeuropathies are not uncommon. These may be spontaneous or due to entrapment or external pressure. Of the peripheral mono neuropathies, median nerve involvement Box 107.2 Features of peripheral sensorimotor neuropathy \200 Usually insidious onset wit h numbness or paresthesia, often found on screening rather than as a presenting problem Starts in the toes and on the soles of the feet, then spreads up to mid-shin level, mostly in a symmetrical fashion. Less often, it also involves the \201 ngers and hands. Affects all sensory modalities and results in reduced vibration perception thresholds, pinprick, \201 ne touch, and temperature sensations. d Vibration sensation and absent ankle re \202 exes are often the \201 rst features foun d. Another risk factor for ulceration is the inability to feel a 10 g mono \201 lament. Less often, the skin is tender or sensitive to touch (hyperesthesia), or frank pain can occur. Painful neuropathy affects up to 5% of a general clinic population. This pain may be sharp, stabbing, or burning in nature and at times very severe. There may also be some wasting of the intrinsic muscles of the foot with clawing of the toes. 107-Draznin-Chap107.indd 621 3/31/2011 9:36:51 PM CHAPTER 107 Diabetic neuropathy 622 and carpal tunnel syndrome may be found in up to 10% of patients and require nerve conducti on studies and then surgical decompression. Entrapment of the lateral cutaneous nerve of the thigh is also seen more commonly in those with diabetes, producing pain over the lateral aspect of the thigh. Common peroneal nerve i nvolvement causing foot drop and tarsal tunnel syndrome are also recognized but less common . Cranial mononeuropathies usually occur suddenly and have a good prognosis. Palsies of crani al nerves III and VI are the most common ones seen, although these are not a common problem in patients with diabetes. In the third nerve palsy, sparing of the pupillary responses is usual. Spontaneous recovery is slow over several months and no treatment apart from symptomatic he lp such as an eye patch is needed. Unlike entrapment neuropathies, where decompression may help, no effective treatment is currently available in most of these cases with spontaneous mononeuropathies. Proximal motor neuropathy (diabetic amyotrophy) This is an uncommon but disturbing conditio n that mostly affects men in their 50s with type 2 diabetes. It presents with severe pain a nd paresthesia in the upper legs and is felt as a deep, aching pain that may be burning in nature and can keep patients awake at night, prevent them from eating, and result in marked cachexia. This neuropathy, with proximal muscle weakness and wasting of the quadriceps in particular, can be very debilitating. The lumbar sacral plexus lower motor neurons are affected, and i mprovement is usually spontane- ous over 3 \200\2234 months. Before making this diagnosis, however, consider other causes, such as malignancies and lumbar disc disease. Oral antidiabetic agents may play a part in the etiology of this problem. Conversion to ins ulin therapy is advised, although the anorexia experi- enced when the pain is severe can ma ke this dif \201 cult. Although recovery happens over a few months, only 50% recover fully . No other treatment is currently known to improve on this rate. Examination \200 Mandatory at diagnosis and at least yearly in all asymptomatic patients \200 Test vibration, \201 ne touch (with a 10 g mono \201 lament), and re \202 exes a s a minimum. Use of a neurothesiometer or biosthesiometer gives a more quantitative measure of vibration than a 128 Hz tuning fork. Inability to feel the vibrating head at >25 V in t he toes is associated with a signi \201 cant risk of neuropathic ulceration and should be considered a sign of at-risk feet. Differential diagnoses \200 Uremia \200 Vitamin B 12 de \201 ciency \200 Infections (e.g., HIV and leprosy) \200 Toxins (e.g., alcohol, lead, mercury) \200 Malignancy 107-Draznin-Chap107.indd 622 3/31/2011 9:36:51 PM PERIPHERAL SENSORIMOTOR NEUROPATHY 623 Treatment For all patients All patients should be reviewed by a podiatrist and, if indicate d, an ortho- tist to give them education on foot care and suitable footwear. If followed by regular chiropody review, this can help prevent some problems from developing. Asymptomatic patients No drugs are currently available. In the past, aldose reductase inhib itors, such as tolrestat, were advocated by some for this indication, but a recent Cochrane review suggests no bene \201 t over placebo. Painful neuropathy Initially, try capsaicin 0.075% topically to the affected area, being ca reful to avoid normal skin because this chili pepper extract, which depletes sen- sory nerv e terminals of substance P, can be uncomfortable when applied to normal skin. It can take s everal weeks to be effective and may induce tingling and thus worsening of symptoms initial ly. In some patients, simple analgesics have been shown to help. In more severe cases, tricycli c antidepressants (TCAs) are the \201 rst-line treatment of choice, with imipramine 20 \200\223100 mg at night being less sedative than amitriptyline 25 \200\22375 mg. Although agents such as carbamazepine , phenytoin , and paroxetine have less anticholinergi c effects, they are also not as effective and are therefore used as second-line treatment. G abapentin and pregabalin are well tolerated and more effective and thus are usually used before other anticonvulsants and antidepressants. If the pain is severe and like an electric shock, anticonvulsants such as carbamazepine and phenytoin may be effective. A more recent addition to the therapy for painful neuropathy is duloxetine , a combined ser otonin and noradrenaline reuptake inhibitor. Comparative trials against other agents are cu rrently not available, but it is effective compared to placebo in over half of people who h ave tried it. For hyperesthesia, occlusive dressings such as Opsite may prove help- ful. For more severe pain, oral agents are needed. More recent studies with agents such as the protein kinase C inhibitors show more encouragi ng results, and treatment with these agents may soon be available. General treatments While speci \201 c treatments are available for each form of neuropathy , there is some evidence for more general therapies. Poor diabetic control appears to be associated with worsening neu- ropathy. Improving glyce mic control is advocated in any patient, especially if neuropathy is present. Results from the use of evening primrose oil in rats and in preliminary human studies sugge st that this may improve some aspects of diabetic neurop- athy. The mechanism by which this works is not certain, but it does increase 107-Draznin-Chap107.indd 623 3/31/2011 9:36:51 PM CHAPTER 107 Diabetic neuropathy 624 production of cyclooxygenase-mediated prostanoids such as prostacyclin, which could act as a vasodilator and thus improve nerve blood supply. Other more speci \201 c vasodilators have also been examined, with blockers and ACE inhibi tors showing particularly useful results in experi- mental settings. An alternative approach is not to try to improve the underlying problem but to alter the bo dy \200\231s response to it. Nerve growth factor (NGF) and IGF-I have been examined for the ir ability to cause nerve regeneration and growth; NGF in particular may be promising in th is role. Other such agents are also under investigation, such as the protein kinase C B inhibitors. Study results of these are encouraging. Autonomic neuropathy The most common effect of autonomic neuropathy is erectile dysfunction , which affects 40% of males with diabetes. Only a small number develop severe GI and bladd er dysfunction. The recent interest in sildena \201 l has highlighted this effect. Abnormal autonomic func tion tests can be expected in 20 \200\22340% of a general diabetic clinic population. The increased problems during surgery from cardiac involvement should also be remembered. Clinical features \200 Impotence \200 Postural hypotension, giving dizziness and syncop e in up to 12% \200 Resting tachycardia or \201 xed heart rate/loss of sinus arrhythmia in up to 20% Gustatory sweating \200\224sweating after tasting food \200 Dysphagia with delayed gastri c emptying, nausea/vomiting \200 Constipation or diarrhea \200 Urinary retention or ove r \202 ow incontinence \200 Anhidrosis \200\224absent sweating on the feet is especially problematic as it increases the risk of ulceration Abnormal pupillary re \202 exes Assessment At least annually check the following: \200 Lying and standing BP (measure sys tolic BP 2 minutes after standing; normal is <10 mmHg drop, >30 mmHg is abnormal) Pupillary responses to light Other less commonly performed tests to consider if the diagnos is is uncer- tain or in high-risk patients include the following: \200 Loss of sinus arrh ythmia: Measure inspiratory and expiratory heart rates after 5 seconds of each (<10 beats/min difference is abnormal, >15 is normal). 107-Draznin-Chap107.indd 624 3/31/2011 9:36:51 PM AUTONOMIC NEUROPATHY 625 Loss of heart rate response to Valsalva maneuver: Look at the ratio of the shortest R \200 \223R interval during forced expiration against a closed glottis compared to the longest R \200\223R interval after it (<1.2 is abnormal). BP response to sustained hand-grip: Diastolic BP prior to the test is compared to diastolic BP after 5 minutes of sustaining a grip equivalent to 30% of maximal grip. A diastolic BP rise >16 mmHg is normal, <10 mmHg is abnormal. A rolled-up BP cuff to achieve the required hand-grip may be used. For gastric symptoms consider a radioisotope test meal to look for delayed gastric emptying. Treatment This is based on the speci \201 c symptom and is usually symptomatic only. In al l patients, improvement in diabetic control is advocated in case any of it is reversible, a lthough this is not usually very helpful or effective. Postural hypotension \200 May be exacerbated by drugs such as diuretics, vasodilators, an d TCAs \200 Mechanical measures such as sleeping with the head elevated and wearing support stockings may help. Ensure an adequate salt intake. \200 Fludrocortisone 100 mcg once daily initially and i a s required up to 400 mcg may be helpful, but watch for hypertension or edema. Desmopressin and octreotide have also been used. Impotence ( b see Erectile dysfunction, p. 306) Libido is not normally affected and pain is also unusual, so look for hypogo- nadism and Peyronie \200\231s disease if these condition s are present. Autonomic neuropathy is the likely cause, but many drugs, especially thiazid es and B-blockers, can also cause it, as can alcohol, tobacco, cannabis, and stress. These agents should be assessed by direct questioning. Examination should include the following: \200 Genitalia and secondary sexual characteris tics \200 Peripheral pulses, as vascular insuf \201 ciency may play a part \200 Lower limb re \202 exes and vibration thresholds to con \201 rm that neuropathy is present Biochemical screening should at least include the following: \200 Prolactin \200 Testos terone \200 Gonadotrophins (LH/FSH) Exacerbating factors such as alcohol and antihyperten sive drugs should be modi \201 ed. The main therapies are as follows: \200 Oral therapie s include sildena \201 l (start at 25 \200\22350 mg, increase to 100 mg if needed and take n 1 hour prior to sexual intercourse), vardena \201 l (start at 10 mg, i to 20 mg if neede d and taken 25 \200\22360 minutes prior to sexual intercourse), and tadala \201 l (start a t 10 mg i to 20 mg if needed and taken 30 minutes to 12 hours prior to sexual intercourse). 107-Draznin-Chap107.indd 625 3/31/2011 9:36:51 PM CHAPTER 107 Diabetic neuropathy 626 Intraurethral alprostadil (start at 125 mcg, increase to 250 or 500 mcg if needed) Intracavernosal alprostadil (trial dose is 2.5 mcg, treatment is 5 \200\22340 mcg) \200 V acuum devices None of these therapies is ideal. Sildena \201 l, although an oral therapy, is effective in only 60% of those with diabetes and is contraindicated in those with severe heart disease and those on nitrates, which rules out many individuals. Gastroparesis Delayed gastric emptying can cause recurrent hypoglycemic episodes. Promotili c agents can also help. Treatment options are as follows: \200 Metoclopramide (5 \200\223 10 mg pre-meals/3 \227 day) \200 Domperidone (10 \200\22320 mg pre-meals) \200 Erythro mycin acts as a motilin agonist to increase gastric emptying but may make patients feel nauseated so it is of limited use. Surgery \200\224gastric drainage procedures should not be undertaken lightly. Large bowel involvement Constipation is treated with standard bulking and softening laxatives. The epis odic diarrhea is more troublesome. Treatment for this may include \200 Loperamide (2 mg 4 \227 day) or codeine phosphate (30 mg 4 \227 day) \200 Antibiotics in case of bacteria l overgrowth, such as erythromycin 250 mg 4 \227 day for 7 days, or tetracycline 250 mg 2 \227 day for 7 days Neuropathic bladder Sacral nerve involvement can cause bladder abnormalities with reduced s ensations of bladder fullness and i residual volume after micturition. Regular toileting in itially may help, but intermittent self-catheterization or a long-term catheter may be requ ired. Anhidrosis Dry feet can cause cracks in the skin and act as a site for infection. Use of em ollient creams may help prevent this. Further reading Boulton AJM, Gries FA, Jervell LA (1998). Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med 15(6):508 \200\223514. NICE (2004). Type 1 diabetes. Diagnosis and management of type 1 diabetes in adults Clinica l guideline. http:// www.nice.org.uk NICE (2004). Type 2 diabetes. Prevention and management of foot problems Clinical guideline . http://www.nice.org.uk 107-Draznin-Chap107.indd 626 3/31/2011 9:36:51 PM EPIDEMIOLOGY 627 Macrovascular disease People with diabetes have a signi \201 cantly greater risk of coronary heart disease, cere brovascular disease, and peripheral vascular disease than that of the nondiabetic populatio n. Most people with diabetes will die from one of these conditions (75% of patients with type 2). It has been suggested that a diagnosis of type 2 diabetes equates to a cardiovascular r isk equivalent to aging 15 years. Epidemiology The exact prevalence and incidence of macrovascular disease and its out- comes vary depending on the age, sex, and ethnic mix of patients being assessed. In general, car diovascular disease accounts for 75% of deaths in type 2 patients and 35% in type 1 patient s. Although the atheroma seen is histologically the same as that in a nondi- abetic population , it tends to be more diffuse and progresses more rapidly. It also occurs at an earlier age and affects both sexes equally. Women, therefore, seem to lose their natural premenopausal advantage. Overall, peripheral vascular disease occurs in up to 10% of patients and they have up to 15 -fold greater risk of needing a nontraumatic amputation than that of the nondiabetic popula tion. Thromboembolic cerebrovascular events occur in up to 8%, which is a 2- to 4-fold i risk com pared to that of the nondiabetic population, and accounts for 15% of deaths in type 2 patie nts. The risk of having a myocardial infarction is also i 2 \200\2234 times. Women seem particul arly at risk of cardiovascular disease compared to the nondi- abetic population. Patients with type 1 diabetes have half the rate of coronary heart dis- ease, 1/3 the rate of cerebrovascular disease, and 2/3 the rate of peripheral vascular disease compared to rat es for type 2 patients, but their incidence rate for all of these conditions is greater tha n that of the nondiabetic population. Males and females are equally affected, with the incidence rates for ischemic heart disease being about 6 times that of both cerebrovascular and peripheral vascular disease. Secondary prevention \200 Stop smoking \200 Aspirin \200 B-blockers \200 Lipid-lowe ring drugs 108-Draznin-Chap108.indd 627 4/1/2011 6:43:08 PM CHAPTER 108 Macrovascular disease 628 Pathogenesis Atherosclerosis has a well-known set of risk factors, such as smoking and fami ly history, all of which still apply in a diabetic population. Some factors, however, are m ore common in those with diabetes and may also confer a greater risk to the diabetic popula tion. These include the following: \200 Glycemic control. In patients with type 1 diabete s, worsening levels of hyperglycemia, as suggested by higher average HbA1c levels, are said to relate to the degree of disease present. In those with type 2 diabetes, this associatio n is less clear-cut, although the UKPDS does suggest that this is the case, as better glyce mic control was associated with a trend for fewer myocardial infarctions. Hypertension is more common in both type 1 and type 2 patients and results in vascular endo thelial injury, thus predisposing to atheroma formation. The UKPDS suggests that BP control may be a more important individual risk factor than glycemic control. Hyperlipidemia is common \200\224e.g., hyperinsulinemia in insulin-resistant type 2 patients causes reduced HDL cholesterol, elevated triglycerides (and VLDL), and smal ler, denser, and, therefore, more atherogenic LDL cholesterol. Obesity is an independent risk factor, being more common in type 2 patients. Central obesity in particular is more atherogenic. Insulin resistance or elevated circulating insulin/proinsulin-like molecule levels are known to increase the risk of atherosclerosis in both diabetic and nondiabetic p opulations. This may be linked to impaired endothelial function. Altered coagulability. Circulating \201 brinogen, platelet activator inhibitor (PAI)-1, a nd von Willebrand factor levels are i and platelets are less deformable. This alteration ma y be more prothrombotic, but the exact signi \201 cance remains uncertain. The UKPDS has shown the major risk factors for coronary heart disease in type 2 patients to be elevated LDL cholesterol, d HDL cholesterol, hyper- tension, hyperglycemia, and smoking . Exactly why these risk factors are commonly seen or linked in the same patient, particula rly type 2 diabetic patients, is uncertain. Several hypotheses have been put forward, but none as yet explains them all adequately. How ever, each suggests an element of genetic sus- ceptibility mixed with environmental effects . A genetic predisposition to insulin resistance, for example, may combine with poor intrau terine nutri- tion to produce a low \200\223birth weight infant with a susceptibility to va scular disease and diabetes later in life. But other factors must be involved, as not all those who later develop diabetes and vascular disease were small at birth. 108-Draznin-Chap108.indd 628 4/1/2011 6:43:08 PM LIPID ABNORMALITIES FOUND IN PATIENTS WITH DIABETES 629 Lipid abnormalities found in patients with diabetes Hyperlipidemia in a patient with diabet es, at any level of cholesterol, is associ- ated with a greater risk of macrovascular disea se than that for a nondiabetic population. Patients with diabetes may have altered activity of insulin- dependent enzymes such as lipoprotein lipase that results in delayed systemic clearance of certain lipids. This, combined with altered hepatic production of apoprotein-B -containing lipoproteins, gives a more atherogenic pro \201 le. Usual \201 ndings are i triglyceride-containing lipoproteins, chylomicrons, and VLDL. Alt hough more common in insulin-resistant type 2 patients, this can also be seen in type 1 pat ients, as can a low HDL cholesterol level (HDL 2 especially). Other atherogenic changes include a tendency to develop small, dense LDL cholesterol partic les and a greater tendency toward oxidative dam- age, which renders patients even more athe rogenic. Lipoprotein (Lpa) levels are also often raised. Even so, other common primary causes of hyperlipidemia, such as familial hypercholesterolem ia or familial combined hyperlipidemia, should not be missed. Screening for secondary cause s of hyperlipidemia such as hypothyroidism or drug-induced causes (alcohol, thiazides, and B-blockers in particular) is also strongly advised. Management In all patients, the \201 rst treatment is dietary modi \201 cation. In a pat ient who is actually following a good diabetic diet, however, there is often not much room for improvement. Other standard advice should also be given: Stop smoking \200\224this reduces risk of death by about 50% over a 15-year period. Reduce weight if overweight or obese. \200 Increase physical activity. While the reductio ns in mortality, reinfarction, and stroke in the major lipid-lowering trials such as the 4S study (Scandinavian Simvastatin Survival Study), CARE (Cholesterol and Recurrent Events Tr ial), LIPID (Long-term Intervention with Pravastatin in Ischemic Disease), and WOSCOPS (Wes t of Scotland Coronary Prevention Study) are all very impressive, the dia- betic subgroups show as good if not better reductions, although the num- bers in each were relatively small ( b see Table 108.1). In the 4S study, for example, the simvastatin-treated diabetic subgroup (4.5% of those in t he study) had a 23% rate of major coronary events com- pared to 45% in the diabetic placebo group; the nondiabetic simvastatin group had a rate of 19% and the placebo nondiabetic gro up, 27%. On the basis of these results, it is suggested that if 100 patients with diabetes who have angina or are post \200\223myocardial infarction are treated with simvastatin for 6 years, 24 of the 46 expected coronary deaths and nonfatal myocardial infarctions can be prevented. More recent lipid-lowering trials including larger numbers of people with diabetes such as CARDS (Collaborative Atorvastatin Diabetes Study) 108-Draznin-Chap108.indd 629 4/1/2011 6:43:08 PM 1 0 8 D r a z n i n C h a 6 3 0 p 1 0 8 . i n d Table 108.1 Lipid reduction studies C H A P T E R d 6 3 4S WOSCOPS CARE LIPID 0 Type of study 2 prevention of CHD 1 prevention of CHD 2 prevention of CHD 2 prevention of CHD 1 0 8 Duration of study (years) 6 5 5 6 M a c r o v a s c u l a r Number studied 4444 6595 4159 9014 Mean total cholesterol (mmol/L) (range) 6.8 (5.5 \200\2238.0) 7.0(>6.5) 5.4 (<6.2) (4.0 \200\2237.0) Age range (years) 35 \200\22370 45 \200\22364 21 \200\22375 31 \200\22375 % Men 81 100 86 83 % With diabetes 4.5 1 17 8.6 d i s e a s e Treatment Simvastatin 20 \200\22340 mg daily Pravastatin 40 mg daily Pravastatin 40 mg daily Pravastatin 40 mg daily Event reduction for 34% for nondiabetics 55% for diabetics 31% overall 23% for nondiabetics 25% for diabetics 23% overall 1, primary; 2, secondary; 4S, Scandinavian Simvastatin Survival Study; CARE, Cholesterol an d Recurrent Event; LIPID, Long-term Intervention with Pravastatin in Ischemic Disease; WOSC OPS, West of Scotland Coronary Prevention Study; 4 / 1 / 2 0 1 1 6 : 4 3 : 0 8 P M LIPID ABNORMALITIES FOUND IN PATIENTS WITH DIABETES 631 and ASPEN (Atorvastatin Study for the Prevention of Endpoints in Non- insulin dependent dia betes) again show signi \201 cant bene \201 t, but the Anglo- Scandinavian Cardiac Outcom es Trial lipid-lowering arm (ASCOT-LLA) was not quite so encouraging. Once lifestyle measures have been implemented, drug therapy should be considered. In the pa st, the Shef \201 eld tables, New Zealand tables, Joint British Societies Coronary Risk Pr ediction Chart, and the Framingham Risk Score calculations ( b see Tables 113.1, pp. 664 \200\223665, and 113.2, pp. 666 \200\223667) were used to determine risk in primary prevent ion, but now any person with diabetes is thought of as being at such a high risk that sec- ondary prevention targets of a total cholesterol <150 mg/dL, an LDL <80 mg/dL, and an HDL > 38 mg/dL are now advocated. A \201 t patient with diabetes has a similar risk to that of a nondiabetic of the same ag e and sex who has also had a coronary event. Other targets are advocated by many, especiall y for those patients post \200\223coronary artery bypass grafting or post-angioplasty. Trig lycerides should be brought to <140 mg/dL, as above this level atherogenic lipoprotein chan ges are said to occur. In those with mixed hyperlipidemia, a \201 brate or statin licensed for this indication s hould be considered. A \201 brate will reduce triglycerides by 30 \200\22340% and LDL cho lesterol by 20%, while a statin would reduce triglyc- erides slightly less (10 \200\22315%) and LDL cholesterol slightly more (25 \200\22335%). Fibrates also alter LDL cholesterol to its less atherogenic form. The choice of agent must be tailored to the individual patient. For hypercholesterolemia alone, a statin is \201 rst choice, as in the nondi- abetic pati ent, and in severely resistant patients combination therapy with statins, ezetimibe, \201 brates, and, less often, resins may be required. Combination statin and ezetimibe may redu ce LDL more effectively than increasing the statin dose alone. Treatment aims for lipids \200 Total cholesterol <4.0 mmol/L \200 LDL cholesterol <2.0 mmol/L \200 Aim to have triglycerides <1.5 mmol/L Box 108.1 Investigations of lipid abnormalities Take a full history and carefully examine the patient. In all patients, then check the foll owing: \200 Dip test urine for protein \200 Serum urea, electrolytes, and creatinine (a nd creatinine clearance if creatinine is raised) Fasting lipids \200 ECG (for left ventricular hypertrophy and signs of ischemia) Also con sider the following: \200 The need for a chest X-ray for signs of heart failure or cardio megaly \200 An echocardiogram \200 Cortisol + dexamethasone suppression test \200 Cat echolamines \200 Renin/aldosterone 108-Draznin-Chap108.indd 631 4/1/2011 6:43:09 PM CHAPTER 108 Macrovascular disease 632 Hypertension Epidemiology Hypertension is twice as common in the diabetic population as in the nondiabetic population, and standard ethnic differences in the prevalence of hypertensi on still hold true. Hypertension worsens the severity and increases the risk of developing both microvascular and macrovascular disease. With a cutoff of >160/90 mmHg, hypertension o ccurs in \200 10 \200\22330% of patients with type 1 diabetes \200 20 \200\22330% of mi croalbuminuric type 1 patients \200 80 \200\22390% of macroalbuminuric type 1 patients \200 30 \200\22350% of Caucasians with type 2 diabetes With suggested targets of 130/80, h ypertension is even more common. Pathogenesis Type 1 diabetes Hypertension is strongly associated with diabetic nephropathy and micro- albuminuria and occurs at an earlier stage than that seen in many other causes o f renal disease. This may in part be linked to a genetic predisposition toward i activity in red blood cell sodium \200\223lithium countertransport activity, which leads to i peripheral vascular resi stance. Insulin may also have a suppressive effect on renin release, producing hyporeninemi c hypoaldosteronism. Type 2 diabetes Hypertension is associated with insulin resistance and hyperinsulinemia; ag ain, this may be genetically mediated. Hyperinsulinemia can directly cause hypertension thr ough i sympathetic nervous system activity, i proximal tubule sodium resorption, and stimul ating vascular smooth muscle cell proliferation. Hyperglycemia also has an antinatiuretic effect, which, along with hyper- insulinemia leadi ng to hypokalemia, results in both glucose and sodium reabsorption being increased. All of these factors increase the potential for hypertension. Management Treatment aim The current recommendation is for all patients with diabetes to ha ve a blood pressure <140/80 mmHg. The hypertension study in the UKPDS highlights the bene \201 ts for type 2 patients of this treatment level on mor- tality, diabetes-related end po ints, and microvascular end points. In this study, a 10/5 mmHg difference in BP was associa ted with a 34% risk reduc- tion in macrovascular end points, a 37% risk reduction in microv ascular end points, and a 44% risk reduction in stroke. The Hypertension Optimum Treatment (HOT) study again suggests a target of <140/80 mmHg, alt hough in those who already have signi \201 cant end-organ damage a lower target (<130/80) is advocated by some. 108-Draznin-Chap108.indd 632 4/1/2011 6:43:09 PM HYPERTENSION 633 The Anglo-Scandinavian Cardiac Outcomes Trial \200\223Blood Pressure Lowering Arm (ALLHAT \200\223BPLA) reinforced the bene \201 cial role of calcium channel blockers and ACE inhib itors in combination. Predisposing conditions Other conditions that can cause both hypertension and hyperglyc- em ia should be considered, e.g., Cushing \200\231s syndrome, acromegaly, and pheochromocytoma . End-organ damage Look for evidence of end-organ damage (eyes, heart, kidneys, and periph- e ral vascular tree in particular). Assessment of cardiac risk factors Look for associated risk factors for coronary heart dise ase. Treatment General Once this initial assessment is complete, modify other risk factors such as glycemic control, smoking, and dyslipidemia. Then look at the following: \200 Weight r eduction if obese \200 Reduced salt intake (<6 g/day) \200 Reduced alcohol intake (<21 units/week in males, <14 in females) \200 Exercise (20 \200\22340 minutes of moderate exe rtion 3 \200\2235 \227/week) Pharmacological After modifying risk factors, drug therapy should be started for the hyper- tension. Most agents currently available will drop systolic BP by no more than 20 mmHg. In the UKPDS BP study, 1/3 of those achieving the tight BP targets now aimed for required thr ee or more drugs to do so. Recently, the National Institute for Health and Clinical Excellence (NICE) guidelines for B P treatment were updated and now advocate an \200\234A/CD \200\235 approach: starting with an ACE inhibitor (or an angiotensin II receptor blocker/antagonist if the ACE inhibitor is not tolerated) and then adding in either a calcium channel blocker or a thiazide-type diur etic with an A-blocker, a B-blocker, or further diuretic therapy if this fails to reduce BP adequately. In the presence of microalbuminuria or frank proteinuria, an ACE inhibi- tor s hould always be considered \201 rst line, or an angiotensin II receptor antagonist if ACE inhibitors are not tolerated.