Glomerular filtration rate, cardiorenal end points, and all-cause mortality in type 2 diabetic patients

OBJECTIVE: Chronic kidney disease (CKD) predicts cardiovascular disease (CVD) in the general population. We investigated the effects of stages of renal function using the estimated glomerular filtration rate (eGFR) on all-cause mortality and cardiovascular end points in a prospective cohort of Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Between 1995 and 2000, 4,421 patients without macrovascular disease or end-stage renal disease were recruited. Renal function was assessed by eGFR, as calculated by the abbreviated Modification of Diet in Renal Disease Study Group formula. Clinical end points included all-cause mortality, cardiovascular end point (cardiovascular death, new admissions due to angina, myocardial infarction, stroke, revascularization, or heart failure), and renal end point (reduction in eGFR by >50%, progression of eGFR to stage 5, or dialysis or renal death). RESULTS: After a median follow-up period of 39.4 months (interquartile range 20.3-55), all-cause mortality rate increased from 1.2% (95% CI 0.8-1.7) to 18.3% (9.1-27.5) (P for trend <0.001) as renal function deteriorated from stage 1 (eGFR > or =90 ml/min per 1.73 m(2)) to stage 4 (15-29 ml/min per 1.73 m(2)). The respective rate of new cardiovascular end points also increased from 2.6% (2.0-3.3) to 25.3% (15.0-35.7) (P for trend <0.001). After adjustment for covariates (age, sex, albuminuria, use of renin-angiotensin-aldosterone system [RAAS] inhibitors, lipids, blood pressure, and glycemic control), hazard ratios across different stages of eGFR (> or =90, 60-89, 30-59, and 15-29 ml/min per 1.73 m(2)) for all-cause mortality were 1.00, 1.27, 2.34, and 9.82 (P for trend <0.001), for cardiovascular end points were 1.00, 1.04, 1.05, and 3.23 (P for trend <0.001), and for renal end points were 1.00, 1.36, 3.34, and 27.3 (P for trend <0.001), respectively. CONCLUSIONS: Chinese type 2 diabetic patients with reduced eGFR were at high risk of developing cardiovascular end points and all-cause mortality, independent of albuminuria and metabolic control.     

A prospective cohort study of predictive value of homocysteine in patients with type 2 diabetes and coronary artery disease

BACKGROUND: Little evidence exists on the role of homocysteine as a predictor of mortality in patients with type 2 diabetes. The aim of this study was to investigate whether elevated plasma homocysteine levels are independently associated with all-cause or cardiovascular mortality in patients with type 2 diabetes and coronary artery disease. METHODS: This is a prospective cohort study that included 507 patients with type 2 diabetes and angiographically proven coronary artery disease. Patients were divided into 2 groups according to homocysteine level above or below median value (12.4 micromol/L): the high homocysteine group (255 patients) and the low homocysteine group (252 patients). The primary end-point of the study was all-cause mortality. RESULTS: There were 103 deaths during a 4-year follow-up: 62 deaths in the high homocysteine group and 41 deaths in the low homocysteine group (Kaplan-Meier estimates of mortality 25.6% and 17.4%, respectively (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.03-2.27, P=0.031). Sixty-two of 103 deaths (60.2%) were of cardiovascular origin: 37 deaths (14.5%) occurred in the high homocysteine group and 25 deaths (9.9%) occurred in the low homocysteine group (P=0.115). Cox proportional hazards model showed that plasma homocysteine was not an independent correlate of all-cause (adjusted hazard ratio [HR] 1.10, 95% CI 0.89-1.33; P=0.397 for 5 micromol/L increase in concentration) or cardiovascular (adjusted HR 1.04, 95% CI 0.80-1.36, P=0.753, for 5 micromol/L increase in concentration) mortality. CONCLUSION: In patients with type 2 diabetes and coronary artery disease, elevated level of homocysteine is an associate of increased cardiovascular risk but not an independent predictor of cardiovascular mortality.     

Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy

OBJECTIVE: Cardiac autonomic neuropathy (CAN) has been associated with a poor prognosis in patients with diabetes. Because CAN is common in patients with diabetic nephropathy, we evaluated the predictive value of CAN in type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy and a matched group of 191 patients with long-standing type 1 diabetes and normoalbuminuria were followed for 10.1 years (range 0.0-10.3 years). At baseline, CAN was assessed by heart rate variation (HRV) during deep breathing. HRV was evaluated as a predictor of the primary end point: cardiovascular morbidity and mortality. As secondary end points, all-cause mortality and the influence of HRV on progression of diabetic nephropathy (decline in glomerular filtration rate [GFR]) was evaluated. RESULTS: During the follow-up, 79 patients (40%) with nephropathy reached the combined primary end point vs. 19 patients (10%) with normoalbuminuria (log-rank test, P < 0.0001). The unadjusted hazard ratio (HR) for reaching the primary end point when having an abnormal HRV (< or =10 bpm) measured at baseline compared with a normal HRV was 7.7 (range 1.9-31.5; P = 0.004) in patients with nephropathy. Similarly in the normoalbuminuric patients, the unadjusted HR was 4.4 (1.4-13.6; P = 0.009). In patients with nephropathy, abnormal HRV was significantly associated with fatal and nonfatal cardiovascular disease after adjustment for cardiovascular risk factors. The adjusted HR for reaching the primary end point in a patient with nephropathy and an abnormal HRV was 6.4 (1.5-26.3, P = 0.010), as compared with a normal HRV. The unadjusted HR for dying when having an abnormal HRV compared with a normal HRV was 3.3 (95% CI 1.0-10.7; P = 0.043) in patients with diabetic nephropathy. After adjustment for confounding factors, the impact of HRV on all-cause mortality in patients with nephropathy was no longer significant (P = 0.293). There was no relationship between abnormal HRV and rate of decline in GFR. CONCLUSIONS: HRV is an independent risk factor for cardiovascular morbidity and mortality in type 1 diabetic patients with nephropathy.     

Risk factors for development of incipient and overt diabetic nephropathy in type 1 diabetic patients: a 10-year prospective observational study

OBJECTIVE: To evaluate prospectively putative risk factors for development of microalbuminuria and macroalbuminuria in type 1 diabetes. RESEARCH DESIGN AND METHODS: Prospective observational study of a cohort of type 1 diabetic patients followed in the outpatient clinic at Steno Diabetes Center for < or =10 years (median 9 years). We followed 537 patients aged > or =18 years with type 1 diabetes, with duration of diabetes > or =5 years, with normoalbuminuria (urinary albumin excretion rate < or =30 mg/24 h), and who were not taking antihypertensive medication. Risk factors for development of microalbuminuria and macroalbuminuria were evaluated. RESULTS: The mean progression of urinary albumin excretion rate was 7.6% (SE 0.8) per year. During follow-up, 134 patients (25%) progressed to persistent microalbuminuria or macroalbuminuria (>30 mg/24 h in two of three consecutive urine samples). Cox multiple regression analysis using baseline values of putative predictors of progression showed the following significant predictors of progression from normoalbuminuria to microalbuminuria or macroalbuminuria: baseline log urinary albumin excretion rate 2.63 (relative risk; 95% CI 1.65-4.19), HbA(1c) 1.13% (1.04-1.23), presence of any retinopathy 1.90 (1.26-2.88), and smoking 1.61 (1.11-2.33). Sex, duration of diabetes, arterial blood pressure, serum creatinine, height, and social class were not risk factors. CONCLUSIONS: Our study suggests that several potentially modifiable risk factors predict the development of microalbuminuria and macroalbuminuria in type 1 diabetic patients.     

Serum lipids and the progression of nephropathy in type 1 diabetes

OBJECTIVE: Dyslipidemia contributes to the progression of microvascular disease in diabetes. However, different lipid variables may be important at different stages of nephropathy. This study examines the pattern of dyslipidemia associated with the progression of nephropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 152 patients with type 1 diabetes were recruited in order to represent various phases of nephropathy. Patients were followed for 8-9 years, during which time they received standard care. Renal progression was defined a priori as a doubling in albumin excretion (in patients with normo- or microalbuminuria) or a decline in creatinine clearance (in those with macroalbuminuria). A panel of lipid variables was determined and correlated with indexes of progression. RESULTS: In patients with normoalbuminuria (n = 66), progression was associated with male sex (P < 0.05), borderline albuminuria (P = 0.02), and LDL-free cholesterol (P = 0.02). In patients with microalbuminuria (n = 51), progression was independently associated with triglyceride content of VLDL and intermediate-density lipoprotein (both P < 0.05). In patients with macroalbuminuria (n = 36), a significant decline in the renal function (>3 ml x min(-1) x year(-1)) was independently associated with poor glycemic control, hypertension, and LDL size (P < 0.05). When all patients with progressive nephropathy were analyzed together, only LDL cholesterol was predictive on multivariate analysis (P < 0.05), which masked the importance of triglyceride enrichment in microalbuminuria. CONCLUSIONS: Lipid variables are associated with progression of diabetic kidney disease, but the relationship is not the same at all stages. This finding has implications for the design of renoprotective strategies and the interpretation of clinical trials in type 1 diabetes.     

Renin angiotensin aldosterone system blockade and renal disease in patients with type 2 diabetes. An Asian perspective from the RENAAL Study

OBJECTIVE: Asia is predicted to have the largest population of patients with diabetes who are at high risk for renal disease. In the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, approximately 17% of patients were Asians. In this subgroup analysis, we examined the characteristics, response, and adherence to treatment of the Asian population, as well as their baseline predictors of risk of renal end points. RESEARCH DESIGN AND METHODS: A total of 252 Asian patients were enrolled in the RENAAL study, which compared losartan (50 mg titrated to 100 mg) to placebo in addition to conventional antihypertensive medications in type 2 diabetic patients with nephropathy. Mean follow-up was 3.2 years. The effect of losartan therapy on renal and cardiovascular outcomes was examined, and baseline predictors of risk were determined using a Cox proportional hazards model with prespecified baseline covariates. RESULTS: Losartan reduced the risk of the primary composite end point composed of a doubling of serum creatinine, end-stage renal disease, or all-cause mortality in Asian patients by 35% (P = 0.02). No difference between losartan and placebo was observed for the cardiovascular composite outcomes. Losartan reduced the level of proteinuria by 47% (P < 0.001) and rate of decrease in renal function by 31% (0.0074). Discontinuations were lower in the losartan-treated patients. The strongest baseline predictors of risk of renal end points were proteinuria (hazard ratio 1.42, P < 0.0001) and low Hb (0.81, P < 0.0001). CONCLUSIONS: In this subgroup analysis of the RENAAL study, losartan conferred significant renal benefits and was well tolerated in Asian patients with type 2 diabetes and clinical nephropathy. Baseline proteinuria and low Hb were strong predictors of risk of renal outcomes.     

Association of Doppler-derived myocardial performance index with albuminuria in patients with diabetes.

Albuminuria is a predictor of cardiovascular morbidity and mortality in patients with diabetes. In this study, the relationship of albuminuria with left ventricular function by using myocardial performance (Tei) index together with conventional function parameters was aimed to be examined. We studied 123 patients with diabetes but without obvious coronary artery disease and heart failure. The patients were divided into 3 groups: 50 with no albuminuria; 49 with microalbuminuria; and 24 with macroalbuminuria. The Tei index in the patients with diabetes was increased (0.59 +/- 0.12). A significant stepwise increase in the Tei index was seen from no albuminuria to macroalbuminuria (0.51 +/- 0.1, 0.61 +/- 0.1, and 0.7 +/- 0.08, respectively). Tei index was positively correlated with isovolumic relaxation time, isovolumic contraction time, the duration of diabetes, left ventricular mass index, the levels of fibrinogen, creatinine, total cholesterol, and low-density lipoprotein cholesterol. The association of amount of secreted albumin into urine with echocardiographic parameters (Tei index, ejection fraction, peak early and late transmitral filling velocity ratio, peak early transmitral filling velocity decelaration time, isovolumic relaxation time, left ventricle mass index) was evaluated by using regression analysis. It was observed that amount of albumin was significantly associated with only Tei index ( P = .001, B = 0.3).It was found that there was a strong relation between Tei index and albuminuria and also its degree. Therefore, it was concluded that Tei index may be a sensitive marker for diagnosis of ventricular dysfunction in patients with diabetes and prognosis of diabetes.     

Diabetic nephropathy: diagnosis, prevention, and treatment

Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects approximately 40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 microg/min and < or =199 microg/min) and macroalbuminuria (UAE > or =200 microg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.     

Prognostic effect of insertion/deletion polymorphism of the ace gene on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes

OBJECTIVE: The insertion/deletion (I/D) polymorphism of the ACE gene has been reported to be associated with diabetic microvascular or macrovascular complications. The aim of the present study was to investigate the prognostic effect of I/D polymorphism on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A consecutive cohort of 1,281 Chinese patients with type 2 diabetes were followed for 41.3 +/- 21.6 months. Renal end points were defined as renal death and events (need for dialysis, plasma creatinine >/=500 micromol/l, or doubling of plasma creatinine of baseline value >/=150 micromol/l). Cardiovascular end points were defined as cardiovascular death and events, which included ischemic heart disease, heart failure, cerebrovascular accident, and revascularization requiring hospital admission. The I/D polymorphism of the ACE gene was examined by PCR followed by agarose gel electrophoresis. RESULTS: The frequencies of ACE gene I/D polymorphisms were in Hardy-Weinberg equilibrium. Patients who developed a renal end point (n = 98) had higher frequencies of DD genotype (19.4 vs. 10.8%, P = 0.018) and D allele (41.3 vs. 31.8%, P = 0.006) compared with subjects who did not (n = 1,183). The cumulative rates of renal end points were 10.0, 19.2, and 24.4% in the II (n = 595), DI (n = 539), and DD genotype carriers (n = 147), respectively (log rank P = 0.004). In multiple Cox regression analysis, the occurrence of renal end points remained significantly influenced by I/D polymorphism with a dominant deleterious effect of the DD genotype (DD versus II, adjusted hazard ratio 2.80 [95% CI 1.49-5.29]). There was no prognostic effect of I/D polymorphism on cardiovascular end points. CONCLUSIONS: The DD genotype of the ACE I/D polymorphism was an independent risk factor for renal but not cardiovascular end points in Chinese patients with type 2 diabetes.     

Urinary Liver-Type Fatty Acid-Binding Protein Predicts Progression to Nephropathy in Type 1 Diabetic Patients

OBJECTIVE

Urinary liver-type fatty acid-binding protein (u-LFABP) is a marker of tubulointerstitial inflammation and has been shown to be increased in patients with type 1 diabetes and is further increased in patients who progress to micro- and macroalbuminuria. Our aim was to evaluate u-LFABP as a predictor of progression to micro- and macroalbuminuria in type 1 diabetes.

RESEARCH DESIGN AND METHODS

From an inception cohort of 277 patients, u-LFABP, adjusted for urinary creatinine (enzyme-linked immunosorbent assay), was measured in 24-h urine samples from 165 normoalbuminuric patients 9.6 ± 3.5 (mean ±SD) years after onset of type 1 diabetes. The outcome measured was development of persistent micro- or macroalbuminuria or death.

RESULTS

Patients were followed for a median of 18 (range 1–19) years; 39 progressed to microalbuminuria, 8 of those progressed further to macroalbuminuria, and 24 died. In a Cox regression model, baseline log u-LFABP levels predicted the development of microalbuminuria, adjusted for known risk factors (sex, age, A1C, systolic and diastolic blood pressure, albumin excretion rate, serum creatinine, and smoking) (hazard ratio [HR] 2.3 [95% CI 1.1–4.6]) and log u-LFABP predicted mortality (adjusted HR 3.0 [1.3–7.0]). u-LFABP (above versus below the median) predicted the development of macroalbuminuria (adjusted HR 2.6 [1.2–5.4]). As a continuous variable, u-LFABP tended to predict macroalbuminuria (HR 1.9, P = 0.2), but numbers were small.

CONCLUSIONS

High levels of the tubular inflammation marker u-LFABP predict the initiation and progression to diabetic nephropathy and all-cause mortality, independent of urinary albumin excretion rate and other established risk factors.During the past few decades the prevention and treatment of late complications in diabetes have improved dramatically. The focus on prevention of late diabetes complications has changed and now involves tight glycemic control, reducing blood pressure, and lipid lowering (1), but, despite these efforts, diabetic patients still develop complications.Approximately 30–40% of all patients with diabetes develop diabetic nephropathy (1), and this is the leading cause of end-stage renal disease in the Western world. In addition, diabetic nephropathy is associated with a higher risk of other complications (cardiovascular disease, neuropathy, and retinopathy) and with an increase in all-cause mortality (2).It is known that tubulointerstitial damage plays an important role in diabetic nephropathy (3). Therefore, it would potentially be beneficial if albuminuria, as a marker of glomerular damage, could be supplemented by a marker of tubular damage to provide a more complete status of the kidney injury. This could help us first to more accurately predict the patients at risk of developing diabetic nephropathy and second to provide a better and possibly different treatment for diabetic nephropathy.Liver-type fatty acid-binding protein (LFABP) is an intracellular carrier protein that is expressed in the proximal tubules in the human kidney and the liver (4). It has been demonstrated to be a marker of tubular damage (5).Previously we have, in a cross-sectional setting, shown that urinary (u)-LFABP is increased in diabetic patients, even before they develop signs of glomerular damage, microalbuminuria or macroalbuminuria (6). This indicates that tubular damage is present at an early stage of diabetic kidney damage, even before the development of microalbuminuria. u-LFABP has, to our knowledge, not yet been studied in a prospective cohort study in type 1 diabetic patients.To extend our previous cross-sectional findings we have evaluated the prognostic value of u-LFABP in a prospective study of type 1 diabetic patients who were still in a normoalbuminuric state. We have thereby been able to investigate whether u-LFABP contributes further to the established predictors for development of microalbuminuria or macroalbuminuria and the risk of death.     

Retinopathy predicts cardiovascular mortality in type 2 diabetic men and women

OBJECTIVE: To investigate the association of retinopathy with the risk of all-cause, cardiovascular disease (CVD), and coronary heart disease (CHD) mortality in type 2 diabetic subjects in a population-based 18-year follow-up study with particular emphasis on sex differences. RESEARCH DESIGN AND METHODS: Our study cohort comprised 425 Finnish type 2 diabetic men and 399 type 2 diabetic women who were free of CVD at baseline. The findings were classified based on standardized clinical ophthalmoscopy to categories of no retinopathy, background retinopathy, and proliferative retinopathy. The study end points were all-cause, CVD, and CHD mortality. RESULTS: Adjusted Cox model hazard ratios (95% CIs) of all-cause, CVD, and CHD mortality in men were 1.34 (0.98-1.83), 1.30 (0.86-1.96), and 1.18 (0.74-1.89), respectively, for background retinopathy and 3.05 (1.70-5.45), 3.32 (1.61-6.78), and 2.54 (1.07-6.04), respectively, for proliferative retinopathy and in women 1.61 (1.17-2.22), 1.71 (1.17-2.51), and 1.79 (1.13-2.85), respectively, for background retinopathy and 2.92 (1.41-6.06), 3.17 (1.38-7.30), and 4.98 (2.06-12.06), respectively, for proliferative retinopathy. CONCLUSIONS: Proliferative retinopathy in both sexes and background retinopathy in women predicted all-cause, CVD, and CHD death. These associations were independent of current smoking, hypertension, total cholesterol, HDL cholesterol, glycemic control of diabetes, duration of diabetes, and proteinuria. This suggests the presence of common background pathways for diabetic microvascular and macrovascular disease other than those included in the conventional risk assessment of CVD. The sex difference observed in the association of background retinopathy with macrovascular disease warrants closer examination.     

Prognostic potential of brain natriuretic peptide (BNP) in predialysis chronic kidney disease patients

In the present study, we investigated the potential of N-BNP (N-terminal B-type natriuretic peptide) as a prognostic marker for risk of CV (cardiovascular) events, overall mortality and progression to ESRD (end-stage renal disease) in a cohort of 83 pre-dialysis CKD (chronic kidney disease) patients without clinical evidence of heart failure. During the study, ten patients reached the combined end point of overall mortality and/or CV event. Univariate factors associated with the combined end point were plasma N-BNP (P < 0.0005), creatinine (P < 0.002), systolic blood pressure (P < 0.009) and age (P < 0.015). N-BNP levels were higher in patients with CV events (P < 0.0005). Cox model regression analysis yielded log10 N-BNP (hazard ratio, 9.608; P < 0.007) and pre-existing CV disease (hazard ratio, 4.571; P < 0.029) as independent predictors of overall mortality or CV events. Kaplan-Meier analysis curves for the subgroup with supramedian creatinine levels (225 micromol/l) showed significant separation of the curves stratified for plasma N-BNP levels above and below the group median (291 pmol/l) for all end points. Receiver-operator-characteristic curves for N-BNP (355 pmol/l cut-off) demonstrated a specificity of 65.8% at a sensitivity of 100% for predicting CV events/overall mortality. The measurement of plasma N-BNP may aid in the risk stratification of pre-dialysis CKD patients. The high sensitivity and negative predictive value (100%) may enable the selection of patients who could safely be excluded from further investigations, resulting in better focusing of resources.     

Survival in patients with type 2 diabetes in a Swedish community: skaraborg hypertension and diabetes project

OBJECTIVE: To explore risk factors for all-cause mortality in patients with type 2 diabetes treated in primary care. RESEARCH DESIGN AND METHODS:A prospective population-based study of 400 patients with type 2 diabetes who consecutively completed an annual checkup in primary care in Skara, Sweden, during 1992-1993. Vital status was ascertained to year 2000. Baseline characteristics as predictors for mortality were analyzed by Cox regression and expressed as relative risks (RRs), with 95% CIs. RESULTS: During a mean follow-up time of 5.9 years, 131 patients died (56 deaths per 1,000 patients per year). In both sexes, all-cause mortality was predicted by HbA(1c) (by 1%; RR 1.14, 95% CI 1.01-1.27), and by LDL-to-HDL cholesterol ratios (1.15, 1.00-1.32). Increased mortality was also seen with prevalent hypertension (1.72, 1.21-2.44), microalbuminuria (1.87, 1.27-2.76), and previous cardiovascular disease (1.70, 1.15-2.50). Subanalyses revealed that increased mortality related to HbA(1c) was restricted to hypertensive patients with type 2 diabetes (1.23, 1.04-1.47). Serum triglycerides (by 1 mmol/l) predicted all-cause mortality in women (1.25, 1.06-1.47). CONCLUSIONS: Poor glucose and lipid control and hypertension predicted all-cause mortality. Survival was also predicted by prevalent microalbuminuria and by previous cardiovascular disease. Confirming results from clinical trials, this population-based study has implications for primary and secondary prevention.     

Reduced mortality associated with the use of ACE inhibitors in patients with type 2 diabetes

OBJECTIVE: ACE inhibitor therapy is widely used in lower-risk patients with type 2 diabetes to reduce mortality, despite limited evidence to support this clinical strategy. The aim of this study was to evaluate the association between ACE inhibitor use and mortality in patients with diabetes and no cardiovascular disease. RESEARCH DESIGN AND SETTINGS: Using the Saskatchewan health databases, 12,272 new users of oral hypoglycemic agents were identified between the years of 1991 and 1996. We excluded 3,202 subjects with previous cardiovascular disease. Of the remaining subjects, 1,187 "new users" of ACE inhibitors were identified (ACE inhibitor cohort). Subjects not receiving ACE inhibitor therapy throughout the follow-up period served as the control cohort (n = 4,989). Subjects were prospectively followed until death or the end of 1999. Multivariate Cox proportional hazards models were used to assess differences in all-cause and cardiovascular-related mortality between cohort groups. RESULTS: Subjects were 60.7 +/- 13.7 years old, 43.6% female, and were followed for an average of 5.3 +/- 2.1 years. Mean duration of ACE inhibitor therapy was 3.6 +/- 1.8 years. We observed significantly fewer deaths in the ACE inhibitor group (102 [8.6%]) compared with the control cohort (853 [17.1%]), with an adjusted hazard ratio (HR) and 95% CI of 0.49 (0.40-0.61) (P < 0.001). Cardiovascular-related mortality was also reduced (40 [3.4%] vs. 261 [5.2%], adjusted HR, 0.63 [0.44-0.90]; P = 0.012). CONCLUSIONS: The use of ACE inhibitors was associated with a significant reduction in all-cause and cardiovascular-related mortality in a broad spectrum of patients with type 2 diabetes and no cardiovascular disease.     

Metabolic syndrome as a predictor of all-cause and cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study

OBJECTIVE: The aim of this study was to assess in an 11-year survival follow-up of a population-based cohort of type 2 diabetes the predictive role of World Health Organization-defined metabolic syndrome, independent of conventional cardiovascular risk factors. RESEARCH DESIGN AND METHODS: During the follow-up (1991-2001), 1,565 patients were regularly examined with centralized measurements of HbA(1c). The independent role of the metabolic syndrome as a predictor of all-cause and cardiovascular mortality was assessed with multivariate Cox proportional hazards modeling. RESULTS: At baseline, the prevalence of the metabolic syndrome was 75.6% (95% CI 73.6-77.9). Results are based on 685 deaths (520 with the metabolic syndrome and 165 without it) in 10,890.2 person-years of observations. With respect to subjects without the metabolic syndrome, those with the metabolic syndrome had a similar hazard ratio (HR) of cardiovascular mortality after adjustment for age, sex, smoking, total cholesterol level, and coronary heart disease. In contrast, relative to subjects with diabetes only, the HR of subjects with only one component of the syndrome was 2.92 (1.16-7.33), independent of other risk factors. CONCLUSIONS: We found that 1) the prevalence of the metabolic syndrome in a population-based cohort of type 2 diabetes is high (75.6%); 2) the metabolic syndrome is not a predictor of 11-year all-cause and cardiovascular mortality; and 3) more than twofold higher cardiovascular risk, independent of conventional risk factors, is evident in diabetic subjects with only one component of the syndrome compared with those with diabetes only. Categorizing type 2 diabetic subjects as having or not having the metabolic syndrome does not provide further prediction compared with the knowledge of its single components.     

Predictive properties of impaired glucose tolerance for cardiovascular risk are not explained by the development of overt diabetes during follow-up

OBJECTIVE: To evaluate the relationship of impaired glucose tolerance (IGT) at baseline to coronary heart disease (CHD) incidence, and cardiovascular disease (CVD) and total mortality at follow-up, and to analyze whether the relationship is independent of the subsequent development of diabetes during follow-up. RESEARCH DESIGN AND METHODS: A baseline screening survey for diabetes was performed in 1987 using a 2-h 75-g oral glucose tolerance test. A total of 1234 men and 1386 women aged 45-64 years, who were free of diabetes at baseline, were followed up for 10 years. During the follow-up, 153 subjects had an incident CHD event, 224 died, and 100 deaths were due to cardiovascular causes. Multivariate adjusted (adjusted for age, sex, waist-to-hip ratio, systolic blood pressure, cholesterol, HDL cholesterol, and smoking) hazard ratio (HR) was estimated using Cox regression analysis. RESULTS: In subjects who had IGT at baseline and who did not progress to diabetes during the follow-up, the multivariate adjusted HR (95% CI) was 1.49 (0.95-2.34) for CHD incidence, 2.34 (1.42-3.85) for CVD mortality, and 1.65 (1.13-2.40) for all-cause mortality. CONCLUSIONS: Baseline IGT was an independent risk predictor for cardiovascular morbidity and mortality and for total mortality, which was not confounded by the subsequent development of overt diabetes.     

2型糖尿病患者尿白蛋白排泄率与血脂的关系

目的探讨2型糖尿病患者尿白蛋白排泄率与血脂的关系。方法无尿路感染及原发性肾脏疾病病史的2型糖尿病患者68例,按尿白蛋白排泄率分为正常白蛋白尿组、微量白蛋白尿组和大量白蛋白尿组。检测所有患者的空腹血糖、糖化血红蛋白、血清甘油三酯、总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇。结果微量白蛋白尿组和大量白蛋白尿组空腹血糖、糖化血红蛋白、收缩压和舒张压均高于正常白蛋白尿组;大量白蛋白尿组的空腹血糖、糖化血红蛋白、收缩压和舒张压均较微量白蛋白尿组高。微量白蛋白尿组和大量白蛋白尿组血清甘油三酯、总胆固醇和低密度脂蛋白胆固醇水平均高于正常白蛋白尿组;大量白蛋白尿组血清甘油三酯、总胆固醇和低密度脂蛋白胆固醇较微量白蛋白尿组高。3组血清高密度脂蛋白胆固醇水平无统计学意义(P>0.05)。结论2型糖尿病患者尿白蛋白排泄率不仅与糖代谢指标和血压有关,与血脂也存在相关性,提示脂质代谢紊乱在糖尿病肾病的发生、发展中可能起一定的作用。     

Treatment of cholesterol abnormalities

Cardiovascular disease and its subset coronary heart disease are leading causes of morbidity and mortality in the United States and worldwide. In general, higher levels of low-density lipoprotein cholesterol are associated with an increased risk of coronary heart disease, myocardial infarction, and stroke. Reducing dietary fat can improve total cholesterol levels, but consequent reductions in cardiovascular outcomes are not well documented. The Mediterranean diet is the only dietary intervention associated with a reduction in all-cause mortality. Treatment with cholesterol-lowering medications decreases the rate of cardiovascular events, but a reduction in all-cause mortality with these agents has been found only in patients with pre-existing coronary heart disease. Drug treatment in patients with a history of heart disease and average-to-high cholesterol levels can decrease the risk for stroke. In patients with peripheral vascular disease, treatment of elevated cholesterol levels may slow disease progression.     

Normotensive women with type 2 diabetes and microalbuminuria are at high risk for macrovascular disease

OBJECTIVE: The excess risk of macrovascular disease and death associated with diabetes seems higher in women than in men. The pathogenesis for this risk difference has not been fully elucidated. We investigated whether female sex was associated with macrovascular disease and death, independently of known risk factors related to type 2 diabetes, nephropathy, or retinopathy in normotensive patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS: We conducted a prospective, prolonged follow-up study of a subgroup of 67 diabetic patients (46 men and 21 women) without established cardiovascular disease who participated in a larger clinical trial. Data were collected on current and past health, medication use, blood pressure, renal function, and HbA(1c) during the follow-up period of 4.7 +/- 0.8 (means +/- SE) years. The end point was a composite of death, cardiovascular disease, cerebrovascular events, and peripheral artery disease. RESULTS: Of the women, eight (38.1%) met the end point compared with six (13.4%) of the men (P = 0.02 for difference in event-free survival). The hazard ratio of women relative to men was 3.19 (95% CI 1.11-9.21), which further increased after adjusting for age, systolic blood pressure, BMI, smoking, total-to-HDL cholesterol ratio, urinary albumin excretion, and retinopathy. CONCLUSIONS: In our study population of normotensive patients with type 2 diabetes and microalbuminuria, female sex was associated with increased risk of fatal and nonfatal cardiovascular disease, independent of the classical cardiovascular risk factors, the severity of nephropathy or presence of retinopathy, or health care utilization.     

The effects of diabetes on the risks of major cardiovascular diseases and death in the Asia-Pacific region

OBJECTIVE: To provide reliable age- and region-specific estimates of the associations between diabetes and major cardiovascular diseases and death in populations from the Asia-Pacific region. RESEARCH DESIGN AND METHODS: Twenty-four cohort studies from Asia, Australia, and New Zealand (median follow-up, 5.4 years) provided individual participant data from 161,214 people (58% from Asia) of whom 4,873 had a history of diabetes at baseline. The associations of diabetes with the risks of coronary heart disease, stroke, and cause-specific mortality during follow-up were estimated using time-dependent Cox models, stratified by study cohort and sex and adjusted for age at risk. RESULTS: In all, 9,277 deaths occurred (3,635 from cardiovascular disease). The hazard ratio (95% CI) associated with diabetes was 1.97 (1.72-2.25) for fatal cardiovascular disease; there were similar hazard ratios for fatal coronary heart disease, fatal stroke, and composites of fatal and nonfatal outcomes. For all cardiovascular outcomes, hazard ratios were similar in Asian and non-Asian populations and in men and women, but were greater in younger than older individuals. For noncardiovascular death, the hazard ratio was 1.56 (1.38-1.77), with separately significant increases in the risks of death from renal disease, cancer, respiratory infections, and other infective causes. The hazard ratio for all-causes mortality was 1.68 (1.55-1.84), with similar ratios in Asian and non-Asian populations, but with significantly higher ratios in younger than older individuals. CONCLUSIONS: The relative effect of diabetes on the risks of cardiovascular disease and death in Asian populations is much the same as that in the largely Caucasian populations of Australia and New Zealand. Hazard ratios were severalfold greater in younger people than older people. The rapidly growing prevalence of diabetes in Asia heralds a large increase in the incidence of diabetes-related death in the coming decades.