Increased intraoperative cardiovascular morbidity in diabetics with autonomic neuropathy

Thirty-eight consenting subjects scheduled for elective ophthalmologic surgery were classified as nondiabetics (n = 21) or diabetics (n = 17) and were tested preoperatively for autonomic dysfunction. The autonomic tests consisted of respiratory sinus arrhythmia and heart rate responses to the Valsalva maneuver to test cardiac vagal function and diastolic blood pressure responses to head-up tilt and cold pressor test to assess sympathetic efferent integrity. At a separate time, anesthesia was established with fentanyl (2 micrograms/kg), sodium thiopental (3-5 mg/kg), and vecuronium (0.1 mg/kg), and maintained with isoflurane, oxygen, and nitrous oxide. An anesthesiologist, blinded to the autonomic test results, recorded perioperative blood pressure and heart rate. The autonomic test results revealed significant autonomic dysfunction among the diabetics. Heart rate and blood pressure declined to a greater degree (P less than 0.05) during induction of anesthesia in diabetics compared with controls and there was less of an increase in these same parameters following tracheal intubation in diabetic patients. Thirty-five percent of diabetics required intraoperative vasopressors compared with only 5% of control patients (P less than 0.05). A major finding was that the diabetics who required intraoperative blood pressure support had significantly greater impairment of autonomic test results compared with those diabetics who did not need vasopressors. Diabetics are at increased risk for cardiovascular lability during anesthesia and preoperative screening of diabetics with simple noninvasive autonomic tests may be useful in identifying those at high risk for perioperative cardiovascular instability.     

Specifics of diabetic nephropathy, viewpoint in diabetology: trends of diabetic nephropathy in diabetes

The evolution of diabetic nephropathy has been studied by Peter Rossing on a cohort of diabetic patients followed at the Steno hospital of Copenhagen during more than 20 years. In the diabetics of type 1, existence of albuminuria at the upper threshold of the normal range, male gender, high blood pressure and poor glycemic control with a very high HbAlc are the main predictive factors of nephropathy evolution. In this population, nephropathy clearly increases the risks of mortality and cardiovascular morbidity. However, the comparison with older studies showed that better control of glycemia, blood pressure and cholesterol, reduction of tobacco consumption and improvement of proteinuria due to antihypertensive treatments, were able to sharply decrease mortality and cardiovascular morbidity with a relative risk reduction of 60%. In type 2 diabetics, besides factors observed in type 1 diabetic patients, the presence of anemia is a predictive criterion of nephropathy progression. In these patients, prevention keys lie not only in the control of glycemia and blood pressure as in type 1 diabetics, but also in that of anemia.     

Diagnostik und Therapie der diabetischen Nephropathie

In Germany, 36% of all new chronic dialysis patients have diabetic nephropathy as the causative renal disease. The majority of these patients are type 2 diabetics. The excessive morbidity and mortality of these patients represent a considerable cost factor for the German health care system. The goal should thus be to recognize diabetic nephropathy very early since intervention during the early stage has the greatest therapeutic effect. Incipient nephropathy can be diagnosed by evidence of microalbuminuria (30–300 mg albumin/g creatinine in spontaneous urine). This test should be performed annually (in type 2 diabetics immediately following diagnosis of the diabetes and in type 1 diabetics commencing after 5 years). Evidence for proteinuria on the standard test strip (albuminuria >300 mg/g creatinine) indicates manifest nephropathy and leads during its course to progressive impairment of renal function. Important influenceable cofactors for progression are arterial hypertension, blood sugar management, smoking, and dyslipidosis. The diabetic patient should be kept at low normal blood pressure levels (<130/80 mmHg without proteinuria and <125/75 mmHg with proteinuria) with ACE inhibitors (proven for type 1 diabetics) or angiotensin receptor blockers (proven for type 2 diabetics). Combination therapies (beneficial with diuretics, beta blockers, and non-dihydropyridine calcium antagonists) are frequently necessary. Early therapeutic intervention can in many cases reverse the stage of microalbuminuria. Special therapeutic measures are judicious for progressive renal insufficiency (osseous metabolism, anemia, acidosis, avoidance of nephrotoxic medications). Timely initiation of renal replacement therapy in diabetics (GFR at approximately <15 ml/min) shortens hospital stay and reduces the 1- and 2-year mortality rates. In addition to hemodialysis and peritoneal dialysis, early kidney transplantation in particular is appropriate and in individual cases in type 1 diabetics combined kidney and pancreas transplantation.     

Clustering of risk factors in hypertensive insulin-dependent diabetics with high sodium-lithium countertransport.

Diabetic nephropathy is more common in patients with a positive family history of hypertension and with elevated red blood cell sodium-lithium countertransport, a marker of risk for essential hypertension. To evaluate whether there is a relationship between this cation transport system and indicators of risk of renal and cardiovascular complications in diabetic patients before the development of clinical proteinuria, we studied 31 type 1 (insulin-dependent) diabetic patients with arterial hypertension, without clinical proteinuria and 12 normotensive normoalbuminuric diabetic patients. Sodium-lithium countertransport activity was significantly higher in hypertensive patients (0.43 +/- 0.03 mmol/l RBC x hr) than in normotensive patients (0.23 +/- 0.03; P less than 0.001). To better explore the nature of the association between this transport system and arterial hypertension, hypertensive patients were divided in two groups, with high (greater than 0.41 mmol/l RBC x hr) or normal (less than 0.41) sodium-lithium countertransport activity. The two groups of hypertensive diabetics were similar in age, sex, body mass index and blood pressure levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of isoflurane and sevoflurane anesthesia on arteriovenous shunt flow in the lower limb of diabetic patients without autonomic neuropathy

BACKGROUND: Failure of sympathetic nerve control caused by diabetic neuropathy results in vasodilation of arteriovenous shunts. The aim of this study was to test the hypothesis that the function of arteriovenous anastomoses was disordered in mild diabetic patients without apparent neuropathy, and that volatile anesthetics opened arteriovenous shunts more greatly in nondiabetic patients than diabetic patients. METHODS: Autonomic system function was assessed by cardiovascular reflex tests. Arterial-venous oxygen content difference (A-VDeltaO2) and partial oxygen pressure index (Pvo2/Pao2, the ratio of oxygen tension in femoral vein blood to that in femoral artery blood) were measured before and during isoflurane or sevoflurane anesthesia in 16 diabetic and 22 nondiabetic patients. Skin temperatures of the foot and leg were measured in 14 diabetic and 15 nondiabetic patients using thermography before and during anesthesia. RESULTS: Pvo2/Pao2 before anesthesia was significantly higher in diabetic patients. In nondiabetics, venous oxygen content significantly increased and A-VDeltaO2 markedly decreased during anesthesia, but these parameters were unchanged in diabetics. Foot temperatures were higher in diabetics before anesthesia, and increased gradually and significantly in both groups during anesthesia, but with a greater increase in nondiabetic patients. Induction of anesthesia caused a larger decrease in leg temperature in diabetics than in nondiabetics. CONCLUSIONS: Diabetic patients have a higher Pvo2/Pao2 and a small core-to-peripheral temperature gradient before anesthesia, suggesting latent dysfunction of the autonomic nerve system, even in the absence of autonomic neuropathy. Volatile anesthesia opens the arteriovenous shunt in nondiabetics to a greater extent than in diabetic patients.     

Treatment of arterial hypertension in the diabetic

BLOOD PRESSURE CONTROL: More than half of all diabetic patients have high blood pressure. Even more so than in the general population, hypertension compromises the cardiovascular and renal prognosis. Optimal blood pressure control can limit the progression of microangiopathy and macroangiopathy as clearly demonstrated in the HOT and UKPDS studies. For the WHO, the goal is to control pressures < 130/85 mmHg. In this respect, there has been no demonstration of a J-curve relationship between pressure lowering with antihypertension drugs and incidence of cardiovascular events among patients with coronary artery disease included in the HOT study. MULTIPLE DRUG THERAPY: Regular long-term monitoring and, in most cases, multiple-drug regimens, are prerequisites for maintaining pressure figures below 130/85. When elaborating a blood pressure control protocol, it is important to consider the presence of coronary artery disease, suggesting use of beta blockers, or renal disease, which should lead to the use of angiotensin converting enzyme inhibitors. Diuretics play an important role in combination regimens and are indispensable in three-drug protocols or in case of altered renal function. SYSTOLIC HYPERTENSION: Subgroup analyses in the SHEP and SYST-EUR studies demonstrated the importance of treating pure systolic hypertension in diabetics. The protection obtained has the same or even more impact than in the general population. RISK FACTORS: Diabetes control must of course be maintained and coherent management requires taking into consideration all the risk factors, especially smoking and dylipidemia.     

Beneficial impact on cardiovascular risk factors by dual blockade of the renin-angiotensin system in diabetic nephropathy

BACKGROUND: Patients with diabetic nephropathy have a high risk of cardiovascular disease and end-stage renal disease. Dual blockade of the renin-angiotensin system (RAS) with both ACE inhibitors (ACE-I) and angiotensin II receptor blockers may offer therapeutic advantages. METHODS: Based on three double-blind randomized cross-over trials, we analyzed the short-term effects of dual blockade of the RAS on cardiovascular surrogate end points in 51 type 1 diabetic patients with diabetic nephropathy. RESULTS: Compared to ACE-I, dual blockade of the RAS decreased albuminuria 37% from 558 mg/24 hour, and lowered 24-hour blood pressure 7/5 mm Hg from 137/76 mm Hg (P < 0.01). In addition, dual blockade lowered total and LDL-cholesterol 0.3 from 5.4 mmol/L and 3.1 mmol/L, respectively (P < or = 0.01). The antialbuminuric response to dual blockade of the RAS was influenced by the insertion (I)/deletion (D) polymorphism in the ACE gene. CONCLUSION: Dual blockade of the RAS may offer additional cardiovascular and renal protection in type 1 diabetic patients with diabetic nephropathy. Determination of the ACE/ID genotype may help identify patients particularly sensitive to such therapy.     

Morbidity and mortality in diabetic patients following cardiac transplantation.

BACKGROUND: Diabetes remains a relative contraindication to cardiac transplantation. Previous reports have described small numbers of diabetic patients without end-organ damage who have undergone successful cardiac transplantation. METHODS: A retrospective analysis of diabetic patients transplanted and their outcome in a single large center from 1/1/95 to 12/31/99 was performed. Diabetes was defined as "medium risk" by the presence of any of the following parameters: duration of therapy >10 years; use of insulin; serum creatinine >2 mg/dl; urinary protein >300 mg per 24 hours; presence of peripheral vascular disease (ankle:brachial ratio <1.0); and documentation of other diabetic comorbidity (retinopathy, neuropathy, gastroparesis). RESULTS: During this time period, 374 adult cardiac transplants were performed. Seventy-six patients (20%) were diabetic with 33 patients (43%) requiring insulin. Forty-two of the patients had moderate disease. Survival of the diabetic and non-diabetic recipients was comparable (1- and 3-year survival of 86% and 85%. vs 87% and 84%, respectively, p = NS). No difference in survival between "medium-risk" and "low-risk" diabetics was observed. The incidence of acute rejection in the first year, graft vasculopathy and infection, was comparable between diabetic and non-diabetic patients. In both diabetic and non-diabetic patients, there was a similar and small insignificant increase in serum creatinine. CONCLUSIONS: More patients with advanced diabetes are undergoing cardiac transplantation and the early and mid-term survival remains comparable to non-diabetic recipients. Future liberalization of transplantation in diabetics appears likely.     

Effects of Isoflurane and Sevoflurane Anesthesia on Arteriovenous Shunt Flow in the Lower Limb of Diabetic Patients without Autonomic Neuropathy

Background: Failure of sympathetic nerve control caused by diabetic neuropathy results in vasodilation of arteriovenous shunts. The aim of this study was to test the hypothesis that the function of arteriovenous anastomoses was disordered in mild diabetic patients without apparent neuropathy, and that volatile anesthetics opened arteriovenous shunts more greatly in nondiabetic patients than diabetic patients.

Methods: Autonomic system function was assessed by cardiovascular reflex tests. Arterial-venous oxygen content difference (A-V[DELTA]O2) and partial oxygen pressure index (Pvo2/Pao2, the ratio of oxygen tension in femoral vein blood to that in femoral artery blood) were measured before and during isoflurane or sevoflurane anesthesia in 16 diabetic and 22 nondiabetic patients. Skin temperatures of the foot and leg were measured in 14 diabetic and 15 nondiabetic patients using thermography before and during anesthesia.

Results: Pvo2/Pao2 before anesthesia was significantly higher in diabetic patients. In nondiabetics, venous oxygen content significantly increased and A-V[DELTA]O2 markedly decreased during anesthesia, but these parameters were unchanged in diabetics. Foot temperatures were higher in diabetics before anesthesia, and increased gradually and significantly in both groups during anesthesia, but with a greater increase in nondiabetic patients. Induction of anesthesia caused a larger decrease in leg temperature in diabetics than in nondiabetics.     

Heart disease in diabetic patients

Cardiac artery disease and heart failure are major causes for morbidity and mortality in diabetes in general and in those with chronic kidney disease (CKD) in particular. Hypertension and dyslipidemia are more common in diabetes and the prevalence of coronary artery disease in diabetics is two-fold to four-fold higher than in nondiabetics. In those with CKD the incidence of cardiovascular complications is nearly two-fold higher than those without CKD. Recent studies suggest that the pathophysiology of cardiac disease is complex process involving both microvascular and macrovascular disease. In addition, myocardial lipotoxicity may be a novel contributing factor particularly in type 2 diabetics. Compelling evidence from cardiovascular outcomes trials indicates that treatment with drugs that block the renin-angiotensin system are cardioprotective in diabetics with microalbuminuria and early stages of kidney disease. Multiple risk factor intervention aimed at optimal blood pressure control (BP <130/<80 mmHG), lowering LDL cholesterol below 100 mg/dl, lowering triglyceride level to 150 mg/dl, A1C <6.5%, treatment with an ACE inhibitor or an angiotensin II receptor blocker, administration of once daily low-dose aspirin and smoking cessation together reduce cardiovascular morbidity and mortality in type 2 diabetics. Novel studies including diabetics with nephropathy aimed at improving outcomes in diabetics by treatment of anemia and optimal control of dyslipidemia are now underway. These and other clinical trials should provide important new insights into improving the quality of life in diabetics and ultimately preventing cardiac disease.     

Cardiovascular effects of rosiglitazone

PROVEN EFFICACY: Since their launch on the French market in 2002, thiazolidinediones ("glitazones") prescribing conditions and therapeutic indications have progressively widened, although remaining strictly defined by the marketing licence. Clinical efficacy on glycemic control (HbA1c and glycemia), as well as beneficial metabolic effects (on lipids, insulinresistance and beta-cellular function) are now well established. Their side effects, generally minor or mild, are also well known. The problem of cardiovascular adverse events, although of a low incidence, should be known and recognized, notably fluid retention (and oedema) and risk of heart failure, more frequent in diabetic than in non diabetic patients. Clinicians must know and take into account the particular risk factors, clinical and diagnosis characteristics, possible pathophysiological mechanisms and their main preventive measures. POTENTIAL BENEFICIAL EFFECTS: On the other hand, numerous experimental and/or preliminary data in type 2 diabetic patients, including favourable effects on the various pathophysiological mechanisms involved in atherosclerosis and effects on cardiovascular risk factors or markers, justifies further large prospective long term clinical studies to assess glitazone effects on cardiovascular morbidity and mortality in type 2 diabetic patients at high cardiovascular risk. Several controlled studies are currently ongoing with rosiglitazone (ADOPT, BARI-2D, DREAM, RECORD, etc.), their results within the next coming Years will answer the questions on the anticipated benefits of rosiglitazone in terms of cardiovascular prevention and/or protection in type 2 diabetic patients.     

Treatment principles for the metabolic syndrome

GENERAL PRINCIPLES: The general progression throughout the world in type 2 diabetes has lead medical Authorities to develop mass screening but also prevention measures, notably for "high-risk" subjects such as those exhibiting a metabolic syndrome. Studies on the topic have shown that preventing type 2 diabetes was possible via lifestyle changes, possibly in association with pharmacological therapy (metformine, acarbose, thiazolidinediones, orlistat). The other therapeutic stakes in the context of the metabolic syndrome also concern the management of all identified cardiovascular risk factors. REGARDING HYPERTENSION: there are currently no specific recommendations available in the framework of metabolic syndrome, with regard to lowering blood pressure and how to obtain it. However there is evidence that patients may benefit from the strict control of blood pressure (< or =130/85 mm Hg). REGARDING DYSLIPIDEMIA: LDL cholesterol remains the main target, with a goal depending on individual cardiovascular risk (<1 or 1.30 g/l in the case of metabolic syndrome). Statins are of major interest in this context. However, it is also established that normalisation of triglycerides and HDL cholesterol contributes to the improvement of cardiovascular Issues. The respective indications for fibrates or fibrate/statin associations still need to be defined in primary as in secondary prevention.     

Histamine release and cardiovascular reactions to implantation of bone cement during total hip replacement]

Cardiovascular reactions to acrylic bone cement in patients with total hip replacement are a common complication. Hypotension and arrhythmias are the most frequently observed symptoms. Elderly patients with fractures of the femoral neck constitute a special risk group. In some patients these reactions can be fatal. The mechanisms suggested to explain these reactions are embolism of air, polymer or fat, reaction to the heat, and toxic or vasodilating effects of the acrylic monomer. In a pilot study and in a case report a significant rise of the plasma histamine was described following cementation of the femur. We therefore performed an investigation to find whether application of bone cement to the femur caused histamine release in elective hip surgery, and, independently of this, also investigated whether premedication with H1- + H2-antagonists had any effect on the cardiovascular reactions due to bone cement implantation into the femoral shaft in elderly patients with hip fracture. METHODS. Part I. In all, 40 patients, scheduled for elective surgical hip replacement were anesthetized by general or epidural anesthesia. Patients were continuously monitored by ECG. Blood pressure was recorded noninvasively at 2-min intervals during the study. Blood samples for the determination of the plasma histamine were taken immediately before implantation of the bone cement into the femur, and 2, 5, and 10 min after. Part II. A further group of 20 patients aged greater than or equal to 70 years with fractures of the femoral neck and in whom total hip replacement was planned were included in the study. In this group, 10 patients were randomly assigned to receive 4 mg clemastine + 400 mg cimetidine i.v. about 15 min before implantation of the bone cement. All patients were operated on under general anesthesia. ECG was monitored continuously and blood pressure was monitored at 2-min intervals during the study. Changes of the blood pressure and heart rate and therapeutic interventions following the implantation of the bone cement were documented. RESULTS. Part I. In 11 of the 40 patients (27.5%) plasma histamine increased by greater than 0.5 ng/ml (9 patients greater than 1 ng/ml). In comparable groups (patients with a control systolic blood pressure less than or equal to 130 mmHg) the histamine responders showed a significantly greater reduction in systolic blood pressure (-5.7 +/- 14.7 vs -17.7 +/- 8.6 mmHg). Part II. In the control group we observed a significantly greater fall in systolic blood pressure than in premedicated patients (41.5 +/- 25.4 vs 11.0 +/- 13.4 mmHg). In the control group 7 of the 10 patients required therapeutic interventions, while in the premedicated group only one therapeutic intervention was necessary (P less than 0.05). DISCUSSION. We have demonstrated that the implantation of acrylic bone cement into the femur may increase plasma histamine by greater than 1 ng/ml. In elderly patients with preexisting cardiac diseases or/and hypovolemia even moderate histamine release can cause serious, sometimes potentially fatal, cardiovascular complications. In this special risk group with hip fractures we found a significant reduction in the frequency of cardiovascular reactions to bone cement implantation in patients premedicated with H1 + H2 antagonists. Because we also observed significant falls in systolic blood pressure in premedicated patients, we assume that the pathogenesis of cardiovascular reactions to bone cement implantation is multifactorial. It may be that potentially lethal complications only occur if two or more of the predisposing factors (hypovolemia, myocardial insufficiency, arrhythmia, embolism, histamine release) are present simultaneously. Pre- and intraoperative measures therefore have to be instituted to eliminate all possible risk factors.     

The diabetic disadvantage: historical outcomes measures in diabetic patients undergoing cardiac surgery -- the pre-intravenous insulin era

Seven percent of the United States population is diabetic. However, diabetics are two to five times more likely to develop cardiovascular disease and therefore populate 30% of open heart procedures in this country. In addition, it has been well documented that diabetic cardiac surgery patients are further disadvantaged with worse outcomes following those procedures. This has been termed the "Diabetic Disadvantage." To benchmark these specific disadvantages, we evaluated the short- and long-term outcomes for diabetics and nondiabetics undergoing coronary artery bypass graft (CABG), CABG/valve, and aortic or mitral valve replacement surgery before the broader acceptance and use of intravenous insulin infusions in this patient population in 2001. All such patient records (n = 1,369,961) from the Society of Thoracic Surgeons national database operated on between 1990 and 2000 were assessed for short-term outcomes. Ten-year survival was evaluated among 36,835 patients from the Northern New England Cardiovascular Disease Study Group longitudinal registry. The diabetic population was found to have higher rates of 30-day mortality, deep sternal wound infection, stroke, and longer length of stay than the nondiabetic population. In addition, diabetic patients had approximately two-fold worse 10-year survival. All differences were statistically significant (P < 0.001). In summary, The Diabetic Disadvantage in the pre-intravenous insulin era is characterized by worse short- and long-term outcomes for diabetic patients undergoing cardiac surgery in the United States and Canada.     

High doses of epoetin do not lower mortality and cardiovascular risk among elderly hemodialysis patients with diabetes

A randomized trial had suggested that high doses of erythropoiesis-stimulating agents (ESAs) might increase the risk of cardiovascular outcomes in predialysis diabetic patients. To evaluate this risk in diabetic patients receiving dialysis, we used data from 35,593 elderly Medicare patients on hemodialysis in the US Renal Data System of whom 19,034 were diabetic. A pooled logistic model was used to estimate the monthly probability of mortality and a composite cardiovascular end point. Inverse probability weighting was used to adjust for measured time-dependent confounding by indication, estimated separately for diabetic and non-diabetic cohorts. The adjusted 9-month mortality risk, significantly different between an ESA dose of 45,000 and 15,000?U/week, was 13% among diabetics and 5% among non-diabetics. In diabetic patients, the hazard ratio (HR) for more than 40,000?U/week was 1.32 for all-cause mortality and 1.26 for a composite end point of death and cardiovascular events compared with patients receiving 20,000 to 30,000?U/week. The corresponding HRs in non-diabetic patients were 1.06 and 1.10, respectively. A smaller effect of dose was found in non-diabetic patients. Thus, higher ESA doses, which are often necessary to achieve high hemoglobin levels, are not beneficial, and possibly harmful, to diabetic patients receiving dialysis. Our findings support a Food and Drug Administration advisory recommending that the lowest possible ESA dose be used to treat hemodialysis patients.     

Carotid artery disease: the influence of diabetes mellitus

Patients with diabetes mellitus are more prone to stroke than non-diabetic patients. Using Duplex ultrasound imaging of the carotid bifurcation, we have found it possible to classify atherosclerotic plaques into four groups which appear to reflect the plaque pathology. Using this classification we have found that diabetics and non-diabetics have similar ultrasound plaque type distributions in symptomatic patients. Further subdivision of the diabetic patients on the basis of their mode of diabetic control has shown that insulin treated diabetics tend to show little evidence of intraplaque haemorrhage and ulceration. These features suggest that factors other than atherosclerosis at the carotid bifurcation may be responsible for the increased stroke risk in diabetic patients. Diabetic microangiopathy and reduced vessel compliance due to medial calcification have been suggested as possible factors. Insulin treatment of diabetics may protect against the development of occlusive atherosclerosis.     

Impaired fibrinolytic activity in type II diabetes: correlation with urinary albumin excretion and progression of renal disease

Progression of renal disease and cardiovascular complications in type II diabetes mellitus have been shown to correlate with control of blood glucose, lipids, blood pressure, and smoking. These factors, however, do not appear to totally explain these diabetic complications. Renal disease and cardiovascular complications in type II diabetes are associated with vascular abnormalities and fibrosis, both of which may occur with impaired fibrinolysis. A cross-sectional study was therefore performed in 107 type II diabetic patients recruited from the Denver Metropolitan Area to examine the effect of impaired fibrinolysis, as assessed by the ratio of plasminogen activator inhibitor (PAI-1) to tissue-type plasminogen activator (t-PA). With urinary albumin excretion (UAE) as a risk factor for both renal disease progression and cardiovascular complications, the patients were analyzed with respect to UAE less than and greater than 1 gm/day. The age, blood glucose, hemoglobin A1C, duration of diabetes, lipids, body mass index, and smoking were no different between the groups. As expected, the group with greater UAE had worse renal function, the serum creatinine (1.98 +/- 0.24 vs 1.21 +/- 0.05 mg/dl, P < 0.001) and creatinine clearance (55.5 +/- 6.0 vs 76.8 +/- 2.7 ml/min, P < 0.001) were significantly different. The type II diabetic patients with greater UAE exhibited significantly higher PAI-1/t-PA (2.43 +/- 0.26 vs 1.85 +/- 0.07, P < 0.03). The past history of cardiac complications was also higher (87.5 vs 72.3%, P < 0.07) in the diabetic patients with more impaired fibrinolysis and greater UAE. Thus a prospective, randomized clinical trial in type II diabetes with PAI-1 inhibitors is needed.     

Management of diabetes mellitus

The management of diabetes mellitus involves patient education and dietary modifications, both of which play a key role in determining the success of therapy. Other therapeutic measures include oral hypoglycaemic agents and insulin. In type II diabetic patients not responding to diet alone the second-generation sulphonylureas are preferred. Biguanides are indicated in the very obese type II diabetic, provided there are no contraindications. Where insulin therapy is indicated (e.g. type 1 diabetes mellitus), the trend is to use a human preparation because it evokes a very weak antibody response. Optimal diabetes control, as gauged by home blood glucose monitoring and glycosylated haemoglobin levels or, in the case of type II diabetics, fasting blood glucose levels, prevents the acute symptoms of diabetes mellitus as well as coma and in addition appears to minimise the risk of vascular complications.     

Treating hypertension in the patient with overt diabetic nephropathy

Arterial blood pressure is a major determinant of renal and cardiovascular outcomes in diabetic nephropathy. There is a proportional relationship between the systolic blood pressure and renal and mortality outcomes. Decreasing the diastolic pressure does not significantly decrease these outcomes. Irrespective of the magnitude of pretreatment systolic hypertension in the patient with type 2 diabetic nephropathy, the systolic pressure achieved with antihypertensive therapy is the important determinant of renal and cardiovascular risk. Achieving a lower systolic pressure down to 120 mm Hg is associated with substantial risk reduction. Although the data are limited, systolic blood pressure less than 120 mm Hg may be associated with increased all-cause mortality in this patient population, increasing the possibility of a J-curve response. A marked decrease in diastolic pressure, which is a danger when undertaking aggressive therapy with the goal of decreasing the systolic pressure to 130 mm Hg, can be associated with an increased risk of cardiac events. The renoprotective and proteinuria-decreasing effects of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers recommend these agents as the standard of care in type 2 diabetic nephropathy. In addition to angiotensin-converting enzyme inhibitor and angiotensin-receptor blocker therapy, controlling the systolic blood pressure in this difficult to control patient population may require the use of 3 or more antihypertensive agents.