Carl Erik Mogensen

Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.

BACKGROUND In patients with type 2 diabetes, the effects of intensive glucose control on vascular outcomes remain uncertain. METHODS We randomly assigned 11,140 patients with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve a glycated hemoglobin value of 6.5% or less. Primary end points were composites of major macrovascular events (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular events (new or worsening nephropathy or retinopathy), assessed both jointly and separately. RESULTS After a median of 5 years of follow-up, the mean glycated hemoglobin level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1%, vs. 20.0% with standard control; hazard ratio, 0.90; 95% confidence interval [CI], 0.82 to 0.98; P=0.01), as well as that of major microvascular events (9.4% vs. 10.9%; hazard ratio, 0.86; 95% CI, 0.77 to 0.97; P=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% vs. 5.2%; hazard ratio, 0.79; 95% CI, 0.66 to 0.93; P=0.006), with no significant effect on retinopathy (P=0.50). There were no significant effects of the type of glucose control on major macrovascular events (hazard ratio with intensive control, 0.94; 95% CI, 0.84 to 1.06; P=0.32), death from cardiovascular causes (hazard ratio with intensive control, 0.88; 95% CI, 0.74 to 1.04; P=0.12), or death from any cause (hazard ratio with intensive control, 0.93; 95% CI, 0.83 to 1.06; P=0.28). Severe hypoglycemia, although uncommon, was more common in the intensive-control group (2.7%, vs. 1.5% in the standard-control group; hazard ratio, 1.86; 95% CI, 1.42 to 2.40; P<0.001). CONCLUSIONS A strategy of intensive glucose control, involving gliclazide (modified release) and other drugs as required, that lowered the glycated hemoglobin value to 6.5% yielded a 10% relative reduction in the combined outcome of major macrovascular and microvascular events, primarily as a consequence of a 21% relative reduction in nephropathy. (ClinicalTrials.gov number, NCT00145925.)

Microalbuminuria Predicts Clinical Proteinuria and Early Mortality in Maturity-Onset Diabetes

We studied whether microalbuminuria (30 to 140 micrograms of albumin per milliliter) would predict the later development of increased proteinuria and early mortality in Type II diabetics. During 1973, morning urine specimens of diabetic clinic patients 50 to 75 years of age whose disease had been diagnosed the age of 45 were examined for albumin level by radioimmunoassay. Seventy-six patients with albumin concentrations of 30 to 140 micrograms per milliliter were identified for long-term follow-up. They were compared with normal controls, diabetic patients with lower albumin concentrations (75 patients with concentrations less than 15 micrograms per milliliter and 53 with concentrations of 16 to 29 micrograms per milliliter), and 28 diabetic patients with higher concentrations (greater than 140). Age, duration of diabetes, treatment method, fasting blood glucose level, blood pressure, height, and weight were determined for the four diabetic groups. After nine years the group with albumin concentrations of 30 to 140 micrograms per milliliter was more likely to have clinically detectable proteinuria (greater than 400 micrograms per milliliter) than were the groups with lower concentrations. Mortality was 148 per cent higher in this group than in normal controls--comparable to the increase (116 per cent) in the group with heavy proteinuria (albumin levels greater than 140 micrograms per milliliter). In addition, mortality was increased 76 per cent in the group with albumin levels of 16 to 29 micrograms per milliliter and 37 per cent in the group with levels below 15. We conclude that microalbuminuria in patients with Type II diabetes is predictive of clinical proteinuria and increased mortality.

Predicting Diabetic Nephropathy in Insulin-Dependent Patients

We studied whether microalbuminuria (urinary albumin excretion rates of 15 to 150 micrograms per minute) would predict the development of increased proteinuria in Type I diabetes. We also studied the influence of glomerular filtration rate, renal blood flow, and blood pressure on the later development of proteinuria. Forty-four patients who had had Type I diabetes for at least seven years and who had albumin excretion rates below 150 micrograms per minute were studied from 1969 to 1976, and 43 were restudied in 1983. Of the 14 who initially had albumin excretion rates at or above 15 micrograms per minute, 12 had clinically detectable proteinuria (over 500 mg of protein per 24 hours) or an albumin excretion rate above 150 micrograms per minute at the later examination. Of the 29 who initially had albumin excretion rates below 15 micrograms per minute, none had clinically detectable proteinuria at the later examination, although four had microalbuminuria. Those whose condition progressed to clinically overt proteinuria had elevated glomerular filtration rates and higher blood pressures at the initial examination than did those in whom proteinuria did not develop. Renal blood flow was not elevated in these patients. We conclude that microalbuminuria predicts the development of diabetic nephropathy and that elevated glomerular filtration rates and increased blood pressure may also contribute to this progression.

The Stages in Diabetic Renal Disease: With Emphasis on the Stage of Incipient Diabetic Nephropathy

Alterations in renal function and structure are found even at the onset of diabetes mellitus. Studies performed over the last decade now allow definition of a series of stages in the development of renal changes in diabetes. Such a classification may be useful both in clinical work and in research activities. Stage 1 is characterized by early hyperfunction and hypertrophy. These changes are found at diagnosis, before insulin treatment. Increased urinary albumin excretion, aggravated during physical exercise, is also a characteristic finding. Changes are at least partly reversible by insulin treatment. Stage 2 develops silently over many years and is characterized by morphologic lesions without signs of clinical disease. However, kidney function tests and morphometry on biopsy specimens reveal changes. The function is characterized by increased GFR. During good diabetes control, abumin excretion is normal; however, physical exercise unmasks changes in albuminuria not demonstrable in the resting situation. During poor diabetes control albumin excretion goes up both at rest and during exercise. A number of patients continue in stage 2 throughout their lives. Stage 3, incipient diabetic nephropathy, is the forerunner of overt diabetic nephropathy. Its main manifestation is abnormally elevated urinary albumin excretion, as measured by radioimmunoassay. A level higher than the values found in normal subjects but lower than in clinical disease is the main characteristic of this stage, which appeared to be between 15 and 300 μg/min in the baseline situation. A slow, gradual increase over the years is a prominent feature in this very decisive phase of renal disease in diabetes when blood pressure is rising. The increased rate in albumin excretion is higher in patients with increased blood pressure. GFR is still supranormal and antihypertensive treatment in this phase is under investigation, using the physical exercise test. Stage 4 is overt diabetic nephropathy, the classic entity characterized by persistent proteinuria (>0.5 g/ 24 h). When the associated high blood pressure is left untreated, renal function (GFR) declines, the mean fall rate being around 1 ml/min/mo. Long-term antihypertensive treatment reduces the fall rate by about 60% 7 and thus postpones uremia considerably. Stage 5 is end-stage renal failure with uremia due to diabetic nephropathy. As many as 25% of the population presently entering the end-stage renal failure programs in the United States are diabetic. Diabetic nephropathy and diabetic vasculopathy constitute a major medical problem in society today.

Microalbuminuria as predictor of increased mortality in elderly people.

OBJECTIVE--Correlation of the urinary albumin excretion rate and the risk of death among elderly subjects. DESIGN--216 Subjects aged 60-74 whose urinary albumin excretion rate had been determined were followed up 62-83 months later. SETTING--Municipality of Fredericia, Denmark. SUBJECTS--223 People who had been selected as control subjects for diabetics found during a systematic screening for diabetes of all people aged 60-74 living in the municipality of Fredericia, Denmark. Of these subjects, 216 had an extensive clinical and biochemical examination within a few weeks of selection. MAIN OUTCOME MEASURE--Death. RESULTS--The median urinary albumin excretion rate was 7.52 micrograms/min. Eight of those with a rate below the median died compared with 23 with a rate equal to or greater than the median (p = 0.0078). The median albumin excretion rate in the 31 who died was 15.00 micrograms/min. Cardiovascular disease was the most common cause of death in both groups. A multivariate regression analysis of survival data was performed using the proportional hazards model. Besides albumin excretion rate, male sex, serum creatinine concentration, and hypertension were found to be of prognostic value. CONCLUSIONS--The association between the albumin excretion rate and mortality that has been described in recent years in patients with diabetes mellitus may be present in elderly people in general, even when other known risk factors are taken into account.

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study.

Few data are available to clarify whether changes in albuminuria over time translate to changes in cardiovascular risk. The aim of the present study was to examine whether changes in albuminuria during 4.8 years of antihypertensive treatment were related to changes in risk in 8206 patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Urinary albumin/creatinine ratio (UACR) was measured at baseline and annually. Time-varying albuminuria was closely related to risk for the primary composite end point (ie, when UACR decreased during treatment, risk was reduced accordingly). When the population was divided according to median baseline value (1.21 mg/mmol) and median year 1 UACR (0.67 mg/mmol), risk increased stepwise and significantly for the primary composite end point from those with low baseline/low year 1 (5.5%), to low baseline/high year 1 (8.6%), to high baseline/low year 1 (9.4%), and to high baseline/high year 1 (13.5%) values. Similar significant, stepwise increases in risk were seen for the components of the primary composite end point (cardiovascular mortality, stroke, and myocardial infarction). The observation that changes in UACR during antihypertensive treatment over time translated to changes in risk for cardiovascular morbidity and mortality was not explained by in-treatment level of blood pressure. We propose that monitoring of albuminuria should be an integrated part of the management of hypertension. If albuminuria is not decreased by the patient’s current antihypertensive and other treatment, further intervention directed toward blood pressure control and other modifiable risks should be considered.

Albuminuria and Cardiovascular Risk in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study

Context Microalbuminuria is a known risk factor for cardiovascular disease. Contribution In this large prospective study of hypertensive patients with left ventricular hypertrophy, increasing microalbuminuria was associated with increasing risks for cardiovascular disease. Risks continuously increased without evidence of a threshold or plateau level. Implications Microalbuminuria assessment in hypertensive patients may improve cardiovascular risk stratification. Cautions The study was based on data collected during a randomized, controlled trial of antihypertensive therapy. Albuminuria was measured as the albumincreatinine ratio in a single spot urine collection. Other than for the study drug received, the authors did not adjust for treatments received during the trial. The Editors Microalbuminuria was first associated with essential hypertension in nondiabetic individuals by Parving and colleagues (1), and subsequent studies (2, 3) confirmed the association. Albuminuria is an independent risk factor for cardiovascular disease and increased all-cause mortality in relatively unselected (4, 5) or general (6-8) populations, postmenopausal women (9), older people (10, 11), diabetic patients (12, 13), hypertensive patients with or without concomitant diabetes (8, 14, 15), and people with known high risk for cardiovascular disease (16). Left ventricular hypertrophy is an independent predictor of adverse prognosis (17-19) and is related to albumin excretion independent of age, blood pressure, diabetes, race, serum creatinine level, or smoking; these associations suggest parallel cardiac damage and increased renal albumin excretion rate (20). Other studies suggest that albuminuria at levels well below traditional partition values is a risk factor for coronary vascular disease in patients with and without diabetes (16, 21), indicating that the relation between albuminuria and cardiovascular risk from other populations cannot be directly applied to nondiabetic hypertensive patients. More precise information about the relation between albuminuria and cardiovascular risk would not only help clinicians better estimate the patients absolute risk but also strengthen the decision to initiate antihypertensive treatment, since current guidelines consider not only blood pressure but also target organ damage (for example, albuminuria) (22). We conducted a prospective study to determine the albuminuria level at which cardiovascular morbidity and mortality are increased in a large group of hypertensive patients with left ventricular hypertrophy. In a predefined protocol, we hypothesized that no unique albuminuria threshold predicts increased cardiovascular risk but rather that increasing albuminuria is associated with a graded increase in risk. We anticipated that in hypertensive patients with left ventricular hypertrophy, any threshold identified would be much lower than the threshold traditionally defined in diabetic populations. Methods Patients Participants in our study were outpatients between 55 and 80 years of age. They were recruited from a mix of general and hospital practices and had previously untreated or treated stage II or III hypertension with electrocardiographically confirmed left ventricular hypertrophy (measured according to the product of QRS duration multiplied by Cornell voltage or according to SokolowLyon voltage). The patients were randomly assigned to receive double-blind therapy with losartan or atenolol in the Losartan Intervention For Endpoint reduction (LIFE) study (23, 24). Study Design The hypotheses of the current study were prespecified as part of the LIFE protocol. Inclusion criteria were a mean trough sitting systolic blood pressure of 160 to 200 mm Hg or a diastolic blood pressure of 95 to 115 mm Hg after 1 and 2 weeks of single-blind placebo treatment and no other antihypertensive medication at the time of randomization. Exclusion criteria were myocardial infarction or stroke within 6 months, current congestive heart failure or previously known left ventricular ejection fraction less than 0.40, and renal insufficiency (serum creatinine level >160 mmol/L [>1.8 mg/dL]). We excluded patients who had a condition that the treating physician believed required treatment with losartan or another angiotensin II-receptor blocker, atenolol or another -blocker, hydrochlorothiazide, or angiotensin-converting enzyme inhibitors. Patients gave informed consent under protocols approved by the ethics committees of the participating institutions. End Points and Adjudication This study of the 8206 LIFE participants who had baseline albuminuria determinations (>90% of the entire sample) is based on analysis of a primary composite end point (n = 971): the first occurrence of cardiovascular death, fatal or nonfatal stroke, and fatal or nonfatal myocardial infarction. Additional end points were all-cause mortality (n = 703) and the first occurrence of each component of the composite end point, regardless of whether it was preceded by another component of the primary end point: 383 cardiovascular deaths, 479 strokes, and 344 myocardial infarctions. In the nondiabetic subgroup there were 755 composite end points, including 292 cardiovascular deaths, 379 fatal and nonfatal strokes, 261 fatal and nonfatal myocardial infarctions, and 554 all-cause deaths. Investigators reported all end points; source data were verified by independent monitors and were adjudicated by an independent committee on the basis of definitions provided in a predefined end point manual (24). Patients and the investigators reported the prevalences of coronary, cerebral, or peripheral vascular disease and smoking habits. Diabetes was defined according to investigator report and plasma glucose level. The Framingham risk score (25) was estimated from baseline blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, smoking status, glucose level, and level of left ventricular hypertrophy on electrocardiography (ECG). Renal Evaluation On the same day, a spot urine sample was collected as the first morning voiding and the serum creatinine level was measured. Urine albumin concentration was determined by standard methods (26) using a turbidometric method (Hitachi 717 analyzer, Hoffmann-La Roche Ltd., Basel, Switzerland) (27) on a single urine specimen. Both serum and urine levels of creatinine were analyzed by using the Jaff reaction without deproteinizing and then quantified by a photometric method using the same analyzer. The ratio of urine albumin (in mg/L) to creatinine concentration (UACR) (in mmol/L) provided a composite measure (in mg/mmol) of renal glomerular capillary permeability that adjusted for urine dilution (28). To derive U.S. measures of UACR (mg/g), UACR in mg/mmoL is multiplied by 8.84. Statistical Analysis We used SPSS software, version 11.0.1 (SPSS, Inc., Chicago, Illinois), for statistical analyses. The study sample as a whole and the nondiabetic patients were divided into UACR deciles; diabetic patients were divided into UACR quintiles. We used Cox proportional-hazards models to compare hazard ratios among groups and to evaluate the contributions of differences in the degree of left ventricular hypertrophy (both Cornell voltage duration product and SokolowLyon voltage as continuous variables), the Framingham risk score (25), and treatment allocation (losartan or atenolol) as covariates. To express the increase in risk per increase in UACR as a continuous variable, we log-transformed UACR. We used a Cox model in the test for trend and used the decile group as a continuous variable. Hazard ratios from the decile groups were then used to estimate the best-fitting curve (SPSS curve estimation function). Two-tailed P values less than 0.05 were considered statistically significant. Role of the Funding Source The funding source had no role in the design, analysis, and reporting of the study or in the decision to submit the manuscript for publication. Results Patient Characteristics Descriptive data for the LIFE study sample (23) and relations of microalbuminuria and macroalbuminuria to cardiovascular risk factors have been reported elsewhere (20). Of the 9193 patients participating in the LIFE study, 8206 had the baseline UACR measurements necessary for inclusion in the present study. The mean age (SD) was 66 7 years; 54% of patients were women, and 92% were white. Thirteen percent had diabetes, 13.5% had coronary heart disease, and 7.7% had had a stroke. The mean arterial blood pressure (SD) was 174 14/98 9 mm Hg, the mean serum creatinine level (SD) was 87 20 mmol/L, and the median UACR was 1.28 mg/mmol. Additional baseline characteristics of patients with albuminuria are described elsewhere (20). To stratify risk in hypertensive patients with albuminuria and left ventricular hypertrophy, patients were divided into UACR deciles, with 814 to 821 patients in each group. Patients were followed for a median of 4.8 years and a total of 39 122 patient-years. End point rates were 24.8 per 1000 patient-years of follow-up for the composite endpoint, 9.4 for cardiovascular mortality, 17.6 for all-cause mortality, 11.9 for stroke, and 8.5 for myocardial infarction. Age; sex; race; body mass index; blood pressure; level of left ventricular hypertrophy on ECG; Framingham risk score; prevalence of known diabetes, coronary heart disease, or peripheral vascular disease; and smoking habits did not differ between the patients who provided a urine sample and the 987 patients who did not. The prevalence of history of cerebral vascular disease (13.2% vs. 10.5%; P = 0.029) and mean serum creatinine level (90.0 vs. 86.7 mmol/L; P = 0.001) were higher in patients who did not provide a urine sample than in those who did. When we considered differences in left ventricular mass on ECG, Framingham risk score, and study treatment, patients without a urine sample had a 52% higher all-cause mortality rate (95% CI, 23% to 87%); the rates of t

Albuminuria and Kidney Function Independently Predict Cardiovascular and Renal Outcomes in Diabetes

There are limited data regarding whether albuminuria and reduced estimated GFR (eGFR) are separate and independent risk factors for cardiovascular and renal events among individuals with type 2 diabetes. The Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study examined the effects of routine BP lowering on adverse outcomes in type 2 diabetes. We investigated the effects of urinary albumin-to-creatinine ratio (UACR) and eGFR on the risk for cardiovascular and renal events in 10,640 patients with available data. During an average 4.3-yr follow-up, 938 (8.8%) patients experienced a cardiovascular event and 107 (1.0%) experienced a renal event. The multivariable-adjusted hazard ratio for cardiovascular events was 2.48 (95% confidence interval 1.74 to 3.52) for every 10-fold increase in baseline UACR and 2.20 (95% confidence interval 1.09 to 4.43) for every halving of baseline eGFR, after adjustment for regression dilution. There was no evidence of interaction between the effects of higher UACR and lower eGFR. Patients with both UACR >300 mg/g and eGFR <60 ml/min per 1.73 m(2) at baseline had a 3.2-fold higher risk for cardiovascular events and a 22.2-fold higher risk for renal events, compared with patients with neither of these risk factors. In conclusion, high albuminuria and low eGFR are independent risk factors for cardiovascular and renal events among patients with type 2 diabetes.

Prevention of Diabetic Renal Disease with Special Reference to Microalbuminuria

In the past year six sets of recommendations on the prevention of diabetic nephropathy, with special reference to microalbuminuria, have been published [1–6]. The background to this activity was the large and increasing number of diabetic patients in whom end-stage renal failure (ESRD) develops and who therefore require dialysis or renal transplantation. Throughout the world about half a million patients are registered as being on renal replacement therapy, and diabetic nephropathy is the cause in nearly one-fifth of them [7]. These data are extrapolated from countries which have registries but in many areas, especially in the densely populated countries of the Far East, accurate information on numbers of patients with ESRD is not yet available. Moreover, the half-million figure probably underestimates the number of diabetic patients with ESRD because selection criteria for renal replacement therapies vary from country to country. Both insulin dependent (IDDM) and non-insulin-diependent (NIDDM) diabetic patients contribute to the increase in ESRD. Prevention of diabetic renal disease, or at least the postponement or slowing down of the disease process, has emerged as a key issue. Our strategy is to develop programmes for all patients with diabetes, focused on early detection of renal disease followed by intervention.

Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the scientific advisory board of the nationals Kidney Foundation from an Ad Hoc Committee of the council on diabetes mel of the national kidney foundation

All individuals with diabetes mellitus should be screened yearly with a spot urine albumin:creatinine ratio to identify those who are at increased risk for the development of complications of diabetes mellitus, including nephropathy, retinopathy, and cardiovascular disease. Once these high-risk individuals are appropriately identified, it is recommended that therapy with an angiotensin-converting enzyme (ACE) inhibitor be initiated. In addition, cardiovascular risk factors should be investigated, and when appropriate, therapeutic interventions should be initiated according to existing recommendations.