The accuracy of cystatin C and commonly used creatinine-based methods for detecting moderate and mild chronic kidney disease in diabetes.

BACKGROUND: The accuracy of measuring serum cystatin C levels for detecting various stages of chronic kidney disease (CKD) in diabetes is still unclear. METHODS: In a cross-sectional study of 251 subjects, a reference glomerular filtration rate (GFR) was measured using (99c)Tc-DTPA plasma clearance (iGFR). Multivariate analysis was used to identify independent clinical and biochemical associations with serum cystatin C and iGFR levels. The diagnostic accuracy of cystatin C and commonly used creatinine-based methods of measuring renal function (serum creatinine, the MDRD four-variable and Cockcroft-Gault formulae) for detecting mild and moderate CKD was also compared. RESULTS: In the entire study population the same five variables, age, urinary albumin excretion rates, haemoglobin, history of macrovascular disease and triglyceride levels were independently associated with both cystatin C and iGFR levels. A serum cystatin C level cut-off > 82.1 nmol/l (1.10 mg/l) had the best test characteristics as a screening tool for detecting moderate CKD (< 60 ml/min per 1.73 m(2)) when compared with creatinine-based methods. At the upper threshold for mild CKD (< 90 ml/min per 1.73 m(2)), cystatin C also had greater diagnostic accuracy than creatinine, but had similar diagnostic accuracy when compared with creatinine-based formulae for predicting renal function. CONCLUSIONS: This study suggests that the clinical and biochemical parameters associated with serum cystatin C levels are closely linked to those associated with GFR and highlights the potential usefulness of screening for moderate or mild CKD in subjects with diabetes by simply measuring serum cystatin C levels.

Estimating glomerular filtration rate in diabetes: a comparison of cystatin-C- and creatinine-based methods.

AIMS/HYPOTHESIS: We compared the predictive performance of a GFR based on serum cystatin C levels with commonly used creatinine-based methods in subjects with diabetes. SUBJECTS, MATERIALS AND METHODS: In a cross-sectional study of 251 consecutive clinic patients, the mean reference (plasma clearance of (99m)Tc-diethylene-triamine-penta-acetic acid) GFR (iGFR) was 88+/-2 ml min(-1) 1.73 m(-2). A regression equation describing the relationship between iGFR and 1/cystatin C levels was derived from a test population (n=125) to allow for the estimation of GFR by cystatin C (eGFR-cystatin C). The predictive performance of eGFR-cystatin C, the Modification of Diet in Renal Disease 4 variable formula (MDRD-4) and Cockcroft-Gault (C-G) formulas were then compared in a validation population (n=126). RESULTS: There was no difference in renal function (ml min(-1) 1.73 m(-2)) as measured by iGFR (89.2+/-3.0), eGFR-cystatin C (86.8+/-2.5), MDRD-4 (87.0+/-2.8) or C-G (92.3+/-3.5). All three estimates of renal function had similar precision and accuracy. CONCLUSIONS/INTERPRETATION: Estimates of GFR based solely on serum cystatin C levels had the same predictive potential when compared with the MDRD-4 and C-G formulas.

Functional erythropoietin deficiency in patients with Type 2 diabetes and anaemia.

AIMS: Anaemia is a common finding in patients with diabetic nephropathy. Impaired production of erythropoietin is thought to be the predominant cause, as a result of renal microvascular disease. This study aims to determine the prevalence of functional erythropoietin deficiency in a cross-sectional survey of patients with Type 2 diabetes. METHODS: Clinical data on 604 patients with Type 2 diabetes were obtained, including a full blood count, iron indices and detailed history of diabetic complications. Erythropoietin levels were correlated with the presence of anaemia, iron deficiency and renal dysfunction. Functional erythropoietin deficiency was defined by erythropoietin levels in the normal range despite the presence of anaemia. RESULTS: Nineteen per cent of patients (n = 112) were anaemic, among whom erythropoietin deficiency (76%) and reduced iron availability (58%) were common findings. Over 90% of patients had erythropoietin deficiency, once those with reduced iron stores or availability were excluded. Most of these patients had moderate renal impairment (60%, n = 67). However, even in the absence of renal impairment, 71% of anaemic patients (n = 32/45) had functional erythropoietin deficiency, although most had other evidence of nephropathy. In addition, two-thirds of patients with reduced iron availability were unable to increase erythropoietin above the normal range. CONCLUSIONS: These findings confirm the failure of the kidney to produce erythropoietin in response to a falling haemoglobin is a key component to anaemia in diabetes. The likelihood of functional erythropoietin deficiency as a cause of anaemia is not dependent on the severity of renal impairment or excluded in diabetic patients with reduced iron stores or availability.

Renal hyperfiltration in type 2 diabetes: effect of age-related decline in glomerular filtration rate.

AIMS/HYPOTHESIS: We sought to characterise the effect of the age-related decline of GFR on hyperfiltration in type 2 diabetes and to identify clinical characteristics associated with hyperfiltration. MATERIALS AND METHODS: GFR was measured in 662 type 2 diabetic patients by plasma disappearance of 99 m-technetium-diethylene-triamine-penta-acetic acid. The prevalence of hyperfiltration was calculated using both an age-unadjusted GFR threshold of >130 ml min(-1) 1.73 m(-2) and an age-adjusted threshold incorporating a decline of 1 ml min(-1) year(-1) after the age of 40. The hyperfiltering patients were compared with type 2 diabetic subjects who had a GFR between 90 and 130 ml min(-1) 1.73 m(-2) and were matched for age, sex and disease duration to allow for identification of modifiable factors associated with hyperfiltration. RESULTS: The prevalence of hyperfiltration was 7.4% when age-unadjusted and 16.6% when age-adjusted definitions were used. The age-unadjusted vs -adjusted prevalence rates for hyperfiltration were 50 vs 50%, 12.9 vs 23.4% and 0.3 vs 9.0% for patients aged <40 years, 40 to 65 years and >65 years, respectively. Both the age-unadjusted and -adjusted hyperfiltration groups had lower mean diastolic blood pressure and lower serum creatinine levels than the control groups. Although the age-unadjusted hyperfiltration group had larger kidneys compared to the control group, this difference was no longer significant when the age-adjusted definition was used. There were no differences in HbA(1)c, mean arterial pressure, antihypertensive use, insulin therapy, dyslipidaemia, frequency of macro- or microvascular complications, BMI, urinary sodium, urea and albumin excretion between the groups. CONCLUSIONS/INTERPRETATION: Hyperfiltration was still more common among younger patients with type 2 diabetes even after adjusting for the expected age-related decline in GFR. Hyperfiltration was associated with a lower mean diastolic blood pressure independent of age.

Long-term renoprotection by perindopril or nifedipine in non-hypertensive patients with Type 2 diabetes and microalbuminuria.

AIMS: To assess the efficacy of an angiotensin converting enzyme (ACE) inhibitor (perindopril), a dihydropyridine calcium channel blocker (sustained release nifedipine) and placebo in preventing the progression of albuminuria and decline in glomerular filtration rate (GFR) in patients with Type 2 diabetes and microalbuminaria. METHODS: A prospective, randomized, open, blinded end point study of 77 patients allocated to three treatment groups (23 perindopril, 27 nifedipine, 27 placebo). Drug doses were adjusted to achieve a decrease in diastolic blood pressure (DBP) of 5 mmHg in the first 3 months and additional therapy was given if hypertension developed (supine DBP > 90 mmHg and/or systolic blood pressure (SBP) > 140 mmHg if < or = 40 years; supine DBP > 90 mmHg and/or SBP > 160 mmHg if > 40 years). Median follow-up was 66 months, with 37 patients being followed for at least 6 years. RESULTS: Blood pressure remained within the non-hypertensive range in 83% of perindopril-, 95% of nifedipine- and 30% of placebo-treated patients (P < 0.01). In the first 12 months albumin excretion rate (AER) decreased by 47% only in the perindopril group (P = 0.04). From 12 to 72 months, AER gradients increased by 27% per year only in the placebo group (P < 0.01). After 6 years, macroalbuminuria had developed in 7/15 placebo compared with 2/11 in perindopril and 1/11 nifedipine-treated patients (P = 0.05). GFR did not change in the first 12 months, but thereafter the median GFR gradient (ml/min/1.73 m(2) per year) was -2.4 (P < 0.01) for perindopril-, -1.3 (P = 0.26) for nifedipine- and -4.2 (P = 0.01) for placebo-treated patients. The rate of decline in GFR for the study group as a whole from 12 months to the end of follow-up correlated negatively with mean arterial pressure (MAP) (r = -0.38, P < 0.01). During a 3-month treatment pause in 29 patients AER tended to increase only in the perindopril group (P < 0.07). CONCLUSIONS: Long-term control of blood pressure with perindopril or nifedipine stabilizes AER and attenuates GFR decline in proportion to MAP in non-hypertensive patients with Type 2 diabetes and microalbuminuria.

Elevated iron indices in patients with diabetes.

AIMS: Excess iron has been implicated in the pathogenesis of diabetes and its complications. This study documents the assessment of plasma iron indices and the correlation between transferrin saturation with biochemical and clinical parameters in a cross-sectional survey of 820 patients with diabetes in long-term follow-up in a single clinic. METHODS: Plasma iron indices, together with the biochemical and clinical profile of all patients, were recorded over a 2-year period. Predictors of the transferrin saturation were identified using multiple and logistic regression analysis. RESULTS: Eighty per cent of patients had Type 2 diabetes. The prevalence of elevated transferrin saturation (> 35%) was 3-4-fold higher in patients with diabetes, compared with historical prevalence described in the general population. Independent associations with elevated transferrin saturation were male gender, low C-reactive protein, and increased fasting plasma glucose (all P < 0.0001). Patients with Type 1 diabetes were also more likely to have an elevated transferrin saturation [odds ratio 3.9 (95% CI 1.9-8.0), P < 0.001]. Patients with an elevated transferrin saturation were younger, but had a similar duration of diabetes, possibly suggesting an earlier age of onset. There was no correlation between the presence of diabetic complications and the presence of elevated iron indices. CONCLUSIONS: Elevated iron indices are more common in patients with diabetes. Excess iron may have a role in the development of diabetes and subsequently in glycaemic control. This should be balanced by the strong association between iron indices and anaemia in patients with diabetes.

Influence of age on the presentation and outcome of acidotic and hyperosmolar diabetic emergencies.

BACKGROUND: Diabetic emergencies associated with ketoacidosis (DKA) and a hyperosmolar, hyperglycaemic state (HHS) are both acute life-threatening metabolic disturbances. Traditionally, DKA and HHS have been classified as distinct entities but there is evidence to suggest that patients can present with elements of both conditions. AIMS: To examine the presentation profiles, mortality rates and prognostic factors associated with a fatal outcome for diabetic patients admitted with ketoacidosis and/or hyperosmolarity. METHODS: A retrospective analysis of 312 admissions to an Australian tertiary referral hospital between 1986 and 1999. RESULTS: Of the patients surveyed, DKA was the diagnosis for 171 presentations (55%), HHS was the diagnosis for 47 presentations (15%) and combined DKA and HHS (DKA-HHS) was diagnosed for 94 presentations (30%). Age at presentation for DKA patients (33+/-1.2 years) was significantly less (P< 0.01) than DKA-HHS patients (44+/-2.4 years). This, in turn, was significantly less (P < 0.01) than HHS patients (69+/-1.7 years). There were 15 deaths for the 312 presentations, resulting in an overall mortality rate of 4.8%. Combined mortality rates according to age at presentation were: (i) 0/134 for patients aged <35 years, (ii) 1/85 (1.2%) for patients aged 35-55 years and (iii) 14/93 (15.0%) for patients aged >55 years. For the three categories of diabetic emergencies, mortality rates were: (i) 2/171 (1.2%) for DKA, (ii) 5/94 (5.3%) for DKA-HHS and (iii) 8/47 (17%) for HHS. For all presentations associated with ketoacidosis - regardless of the degree of hyperosmolarity - the mortality rate was 7/264 (2.7%), however for all presentations with hyperosmolarity regardless of the degree of acidosis - the mortality rate was 13/141 (9.2%). When the associations between age, category of diabetic emergency, serum osmolarity and various other biochemical parameters with mortality were assessed by logistic regression analysis, age and the degree of hyperosmolarity were found to be the most powerful predictors of a fatal outcome. In particular, patients aged >65 years presenting with a serum osmolarity >375 mOsmol/L were at greatest risk. However, in a multivariate analysis only age emerged as a significant independent predictor of mortality (P < 0.01). CONCLUSIONS: The mixed state of ketoacidosis and hyperosmolarity was observed in 30% of presentations for diabetic hyperglycaemic emergencies. Although age and degree of hyperosmolarity both influenced mortality rates, only age was found to be an independent predictor of mortality. The mortality rate for diabetic emergencies associated with ketoacidosis remained low, in keeping with other studies. By contrast, the mortality rate for diabetic emergencies associated with a hyperosmolar state remained considerably higher. This higher mortality will most likely persist because deaths associated with a hyperosmolar state were in elderly patients with significant comorbidity.

Long-term comparison between perindopril and nifedipine in normotensive patients with type 1 diabetes and microalbuminuria.

The aim of this study is to compare the efficacy of an angiotensin-converting enzyme inhibitor with a dihydropyridine calcium channel blocker in preventing progression to macroalbuminuria and/or a decline in renal function in normotensive patients with type 1 diabetes and microalbuminuria. Forty-two patients were randomized to treatment with either perindopril, slow-release nifedipine, or placebo. In the first 3 months, drug dosage was titrated to achieve a decrease in diastolic blood pressure of at least 5 mm HG: Thirty-three patients had a minimum of 24 months' data, and 25 patients were followed up beyond 36 months (mean, 67 +/- 4 months). Patients were studied every 3 months and at the end of the treatment period; those who remained normotensive discontinued therapy and were followed up for an additional 3 months. Baseline geometric mean albumin excretion rates (AERs) were as follows: perindopril, 66 microg/min; nifedipine, 59 microg/min; and placebo, 66 microg/min. During the first 3 years, 7 of the perindopril-treated but none of the placebo or nifedipine-treated patients reverted to normoalbuminuria (P < 0.01). Median AERs at 3 years of treatment in each group were 23 microg/min for perindopril, 122 microg/min for nifedipine, and 112 microg/min for placebo patients (P < 0.01). In patients with more than 3 years' follow-up, median AERs decreased by 45% in the first year and then stabilized in the perindopril group, but increased by 17.6% in the nifedipine group and 27.6% in the placebo group (P < 0.03) in the first year, then increased progressively. In these same patients, there was a significant decline in glomerular filtration rate in the nifedipine group (-7.8 +/- 1.8 mL/min/1.73 m(2)/y), but not in the other two groups (perindopril, -1.0 +/- 1.2 mL/min/1.73 m(2)/y; placebo, -1.3 +/- 1.1 mL/min/1.73 m(2)/y; P = 0.004). At the end of the study, cessation of treatment for 3 months was associated with a doubling of AERs in the perindopril-treated group, but no change in the other two groups (P < 0.001). In conclusion, long-term perindopril therapy is more effective than nifedipine or placebo in delaying the progression of diabetic nephropathy and reducing AER to the normoalbuminuric range (<20 microg/min) in normotensive patients with type 1 diabetes and microalbuminuria.

Bone loss at the proximal femur and reduced lean mass following liver transplantation: a longitudinal study.

The longevity of recipients of liver transplant may be compromised by spinal osteoporosis and vertebral fractures. However, femoral neck fractures are associated with a higher morbidity and mortality than spine fractures. As there is little information on bone loss at this clinically important site of fracture, the aim of this study was to determine whether accelerated bone loss occurs at the proximal femur following transplantation. Bone mineral density and body composition were measured at the femoral neck, lumbar spine and total body, using dual x-ray absorptiometry in 22 men and 19 women, age 46 +/- 1.4 y (mean +/- SEM) before and at a mean of 19 mo after surgery (range 3-44). Results were expressed in absolute terms (g/cm2) and as a z score. Before transplantation, z scores for bone mineral density were reduced at the femoral neck (-0.47 +/- 0.21 SD), trochanter (-0.56 +/- 0.19 SD), Ward's triangle (-0.35 +/- 0.14 SD), lumbar spine (-0.76 +/- 0.13 SD), and total body (-0.78 +/- 0.15 SD) (all P < 0.01 to < 0.001). Following transplantation, bone mineral density decreased by 8.0 +/- 1.7% at the femoral neck (P < or = 0.01) and by 2.0 +/- 1.2% at the lumbar spine (P < or = 0.05). Total weight increased by 12.2 +/- 2.3%, lean mass decreased by 5.7 +/- 1.4%, while fat mass increased from 24.1 +/- 2.0% to 35.1 +/- 1.8% (all P < or = 0.001). Patients with end-stage liver disease have reduced bone mineral density. Liver transplantation is associated with a rapid decrease in bone mineral density at the proximal femur, further increasing fracture risk and a reduction in lean (muscle) mass, which may also predispose to falls. Prophylactic therapy to prevent further bone loss should be considered in patients after liver transplantation.

Long-term intraindividual variability of serum lipids in patients with type I and type II diabetes.

The objective of this study was to estimate the long-term intraindividual variability of lipid levels in adult type I and type II diabetic patients. Total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and hemoglobin A1c were measured every 3-6 months in 135 patients attending the Austin Hospital diabetes clinic. Analysis was performed on 60 diabetic patients (33 type I and 27 type II) who had not been treated with lipid lowering drugs and who met the inclusion criteria of at least five measurements [mean +/- standard error of the mean (SEM), 9.5 +/- 0.4; range, 5-17] collected over a minimum of 4 years (5.1 +/- 0.1; 4-6.5 years). Total variability, expressed as coefficient of variation, was 8.8 +/- 0.4% for total cholesterol, 23.9 +/- 1.5% for triglycerides, 10.2 +/- 0.5% for HDL cholesterol, and 12.0 +/- 0.5% for LDL cholesterol. Biological variability, derived from total and analytical variability, was higher than previous estimates in nondiabetic subjects for total cholesterol and HDL cholesterol but similar for triglycerides and LDL cholesterol. No relationship was observed between total lipid variability and diabetes type, age, baseline or mean lipid levels, duration of follow-up, or the number of samples per patient. Men demonstrated greater variability than women for total cholesterol (men 9.5 +/- 0.5%, n = 34, women 7.9 +/- 0.5%, n = 26, p < 0.01) and triglycerides (men 26.5 +/- 2.2%, women 20.4 +/- 1.4%, p = 0.03). Total lipid variability was also unrelated to baseline or mean hemoglobin A1c or to the change in hemoglobin A1c during the study as a whole. However, the change in hemoglobin A1c was associated with the change in total cholesterol (r = 0.30, p < 0.03) and the change in LDL cholesterol (r = 0.27, p < 0.05). In conclusion, long-term intraindividual lipid variability in adult diabetic subjects is higher for total and HDL cholesterol than previously published values in nondiabetic subjects. Variability of triglycerides is at least double that of total cholesterol, HDL cholesterol and LDL cholesterol. Biological variability, not measurement error, accounts for the greatest proportion of total variability for all lipid parameters. Confidence levels calculated from these data have implications for the initiation of lipid lowering therapy and in monitoring the effects of intervention.

Early nephropathy predicts vision-threatening retinal disease in patients with type I diabetes mellitus.

In type I (insulin-dependent) diabetes mellitus, nephropathy may be identified in its early stages by the development of persistent microalbuminuria. This longitudinal study sought to examine the development of vision-threatening retinal disease (VTRD) (proliferative retinopathy and clinically significant macular edema) in such patients with early and evolving diabetic kidney disease. Eighty patients with type I diabetes and at least 8 yr of longitudinal data were identified. Glycated hemoglobin and albumin excretion rate (AER) were measured every 3 mo. Ophthalmologic examination was performed at least yearly. Thirteen patients were identified as having evolving nephropathy by a progressive increase in AER and the presence of microalbuminuria during the study period. Sixty-seven patients remained persistently normoalbuminuric. VTRD developed in eight of 13 (62%) patients with evolving nephropathy compared with five of 69 (7%) patients who were persistently normoalbuminuric (P < 0.001) in the absence of any difference in long-term glycemic control or duration of diabetes between the two groups. Clinically significant macular edema (P < 0.05) and proliferative retinopathy (P < 0.01) were both more common in patients with evolving nephropathy. In such patients, AER was 150 x/divided by 1.7 micrograms/min at the time of laser photocoagulation for VTRD. These data suggest that patients with type I diabetes and evolving nephropathy may be at higher risk of developing VTRD than patients who remain persistently normoalbuminuric despite similar long-term glycemic control and duration of diabetes.

Why is proteinuria such an important risk factor for progression in clinical trials?

There are strong reasons to justify the concept that proteinuria is a major risk factor for progression in clinical trials. The evidence is strongest where therapeutic intervention has been focused on established renal disease, when changes in albumin excretion rate (AER) and glomerular filtration rate (GFR) occur within a short time span. Proteinuria is also important in emerging renal disease, such as incipient diabetic nephropathy (DN), since natural history studies show that small increases in AER predict clinical nephropathy and, ultimately, a decline in GFR. However, the absence of concurrent changes in GFR in incipient DN complicates the evaluation of clinical trials in this condition. It is also not certain that the degree of coupling of changes in AER and GFR is the same during intervention as during natural history studies. The importance of proteinuria as a risk factor for progression has been strengthened by recent evidence showing that proteinuria itself causes renal damage. Traditional concepts of the damaging effects of proteinuria have focused on the glomeruli, where mesangial expansion induced by transcapillary passage of proteins has been considered to lead to a decrease in glomerular filtration surface and a decline in GFR. New evidence suggests that interaction of albumin with proximal renal tubules may not only lead to renal damage but may also be causally related to increases in AER.

Do genetic factors explain associations between muscle strength, lean mass, and bone density? A twin study.

Are the associations between muscle strength, lean mass, and bone mineral density (BMD) genetically determined? Based on within-pair differences in 56 monozygotic (MZ) and 56 dizygotic (DZ) female twin pairs, mean age 45 yr (range 24-67), BMD was associated with lean mass, independent of fat mass and height (P < 0.05). A 10% increment in femoral neck (FN) BMD was associated with a 15% increment in lean mass (approximately 6 kg). BMD was associated with muscle strength (measured in 35 pairs) before, but not after, adjusting for lean mass. Based on age-adjusted cross-sectional analyses, same-trait correlations (+/- SE) in MZ pairs were double those in DZ pairs: FN BMD (0.62 +/- 0.08, 0.33 +/- 0.12) and lean mass (0.87 +/- 0.03, 0.30 +/- 0.11; all P < 0.001), consistent with a genetic hypothesis. The cross-trait correlation (r) between lean mass and FN BMD in the same individual was 0.43 +/- 0.06. The cross-trait cross-twin correlation between lean mass in one twin and FN BMD in the other was 0.31 +/- 0.07 in MZ pairs, approximately 75% of the cross-trait correlation (r) and 0.19 +/- 0.09 in DZ paris (P < 0.001). After adjusting for height and fat mass, the MZ and DZ cross-trait cross-twin correlations were no different (0.16 +/- 0.08 and 0.13 +/- 0.09, respectively). Therefore, genetic factors account for 60-80% of the individual variances of both FN BMD and lean mass, and > 50% of their covariance. The association between greater muscle mass and greater BMD is likely to be determined by genes regulating size.

Effects of insulin on body composition in patients with insulin-dependent and non-insulin-dependent diabetes.

Insulin is used to control blood glucose but may have an adverse effect on the amount and distribution of fat mass and other cardiovascular risk factors. To test this hypothesis the effect of insulin therapy on blood glucose, body composition, and lipid levels was measured during 6 months in 9 patients with newly diagnosed insulin-dependent (Type 1) diabetes mellitus (IDDM) and 15 patients with non-insulin dependent (Type 2) diabetes (NIDDM) and secondary failure of therapy with oral hypoglycaemic agents. Both groups received similar daily doses of insulin (approximately 0.6 units kg-1 day-1). Glycaemic control improved during 6 months treatment in both groups, although the reduction in HbA1c was greater in IDDM (5.2 +/- 0.7%) than in NIDDM (2.0 +/- 0.4%, p < 0.001). All parameters of the lipid profile improved in IDDM but not in NIDDM. Body weight, lean mass, and fat mass, measured by dual energy x-ray absorptiometry, increased at 1 month in IDDM but not in NIDDM. By 6 months, body weight had increased more in IDDM than NIDDM (9.1 +/- 1.2 vs 3.77 +/- 0.5 kg, p < 0.01). The increase in weight was predominantly lean mass in IDDM (60.4 +/- 9.3%) and fat mass in NIDDM (59.9 +/- 8.4%). The increase in lean mass was greater in IDDM than NIDDM (5.6 +/- 1.1 vs 1.4 +/- 0.3 kg, p < 0.001). Fat mass increased by similar increments in IDDM and NIDDM (3.4 +/- 0.8 vs 2.4 +/- 0.5 kg, p = ns) and was predominantly an increase in trunk fat (IDDM: 2.3 +/- 0.6 kg, NIDDM: 2.0 +/- 0.4 kg, p = ns). The central/peripheral fat mass ratio prior to treatment was lower in IDDM than NIDDM (0.64 +/- 0.05 vs 1.09 +/- 0.09, p < 0.01) and then increased in IDDM by 0.32 +/- 0.15 (p = 0.07) and in NIDDM by 0.22 +/- 0.06 (p < 0.001). In conclusion, insulin therapy is associated with weight gain in both IDDM and NIDDM. In the former, weight gain reflects increases in lean mass whereas in NIDDM it reflects an increase in trunk fat mass. It remains to be determined whether this trend to central obesity partly offsets other benefits of insulin therapy in NIDDM.

Present and future of osteoporosis therapy.

In the 50-year "modern" history of osteoporosis, there have been about 17 antifracture studies with sufficient attention to design to allow inference regarding efficacy. Antivertebral fracture efficacy has been reported with etidronate, estrogen patch, calcitonin, and 1,25-dihydroxyvitamin D. Two studies using fluoride were positive, and two were negative. Hip fractures have been neglected. One study showed efficacy of hip protectors, one showed efficacy of vitamin D and calcium in nursing home dwellers. The source of most hip fractures is the community. One community based antihip fracture efficacy study using annual injections of vitamin D was positive. There have been no antivertebral or antihip fracture studies in men, or in corticosteroid-related osteoporosis in men or women. Lack of independently repeated demonstration of efficacy, small fracture numbers, and data pooling in some of these (the best) studies leave great uncertainty. Estrogen and bisphosphonates appear to be the best options at this time. New data suggest that calcium supplementation is likely to reduce the rate of bone loss and perhaps reduce fracture rates. The challenge is to maintain and restore the constituents of bone mineral density (BMD), that is: to promote periosteal and endosteal bone formation; reduce endosteal bone resorption and cortical porosity; and increase trabecular thickness, number, and connectivity. There are many opportunities, for instance, intermittent parathyroid hormone (PTH) increases bone strength and, with estrogen, may increase connectivity. The anabolic effects of PTH may be partly mediated by IGF-1. IGF-1 increases periosteal, endosteal, and trabecular bone formation, cortical and trabecular width, and trabecular and endocortical connectivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Complementary effects of pravastatin and nicotinic acid in the treatment of combined hyperlipidaemia in diabetic and non-diabetic patients.

BACKGROUND: Given that treatment with a single drug is frequently unsuccessful in patients with combined hyperlipidaemia, there is a rationale for the study of regimens using drugs that have complementary therapeutic profiles. We therefore set out to compare the efficacy of a combined pravastatin and nicotinic acid regimen with higher dose monotherapy using either drug in patients with non-insulin-dependent diabetes and in non-diabetic patients with combined hyperlipidaemia. METHODS: Forty-four patients with total-cholesterol levels of 6.5 mmol/l or higher and triglyceride levels of 2.5 mmol/l or above were randomly assigned to receive either pravastatin alone (40mg/day) or nicotinic acid alone (1500mg/day) for 12 weeks. At the end of this period, the participants received a combination of pravastatin (20mg/day) and nicotinic acid (1000mg/day) for a further 12 weeks. The lipid parameters measured included levels of total cholesterol, triglycerides, low-density-lipoprotein (LDL) cholesterol and high-density-lipoprotein (HDL) cholesterol. RESULTS: Thirty-three patients (22 without and 11 with diabetes) completed the protocol. Monotherapy with pravastatin was more effective than that with nicotinic acid in reducing levels of total cholesterol (-24.9 versus -9.8%, P<0.001) and LDL cholesterol (-32.1 versus -16.9%, P < 0.01), similar in reducing levels of triglyceride (-28.0 versus -31.8%, NS) and tended to be less effective in elevating levels of HDL cholesterol (+16.4 versus +30.8%, P = 0.06). Combination therapy was more effective than pravastatin monotherapy in reducing levels of triglyceride (-39.3 versus -28.0%, P < 0.05) and elevating those of HDL cholesterol (+35.6 versus +16.4%, P < 0.001) and was equally effective in reducing total-cholesterol (-22.3 versus -24.9%, NS) and LDL-cholesterol (-27.1 versus -32.1%, NS) levels. Combination therapy was more effective than nicotinic acid monotherapy in reducing levels of total cholesterol (-23.8 versus -9.8%, P < 0.001), triglyceride (-39.4 versus -31.8%, P < 0.05) and LDL cholesterol (-35.7 versus -16.9%, P < 0.05) and equally effective in elevating HDL-cholesterol levels (+33.6 versus +30.8%, NS). Diabetic and non-diabetic participants responded similarly to combination therapy. Eleven patients (25%) were withdrawn from the study: nine as a result of nicotinic acid intolerance (flushing and nausea) and one through pravastatin intolerance (nausea); one patient died of a myocardial infarction. Combination therapy elevated glycosylated haemoglobin A1c levels in non-diabetic patients (5.5 to 5.8%, P < 0.001); in diabetic patients, however, the observed rise (7.4 to 7.9%) was not statistically significant. Fasting plasma glucose levels, liver function tests and levels of creatine kinase or uric acid were unaffected by either monotherapy or by combination therapy, with the exception of an elevation of the glucose level in diabetic patients receiving nicotinic acid monotherapy. CONCLUSION: Pravastatin and nicotinic acid in lower-dose combination are more effective than pravastatin alone in reducing levels of triglyceride and elevating those of HDL cholesterol and are more effective than nicotinic acid alone in reducing total-cholesterol triglyceride and LDL-cholesterol levels. Combination therapy is equally effective in type-II diabetic and non-diabetic people. The complementary effects of the combination therapy on lipid levels suggest that this regimen should be considered as a therapeutic option in patients with combined hyperlipidaemia who tolerate the side effects of nicotinic acid.

Reduced femoral neck bone density in the daughters of women with hip fractures: the role of low peak bone density in the pathogenesis of osteoporosis.

Low bone density in women with hip fractures ("senile" osteoporosis) may be due to excessive bone loss or low peak bone density. If excessive bone loss is responsible, then no reduction in bone density is expected in their daughters. If low peak bone density is responsible, then bone density should also be reduced in their daughters because genetic and family environmental factors influence the variability in bone density. Bone density was measured using dual-photon absorptiometry and expressed as a standardized deviation or Z score relative to 697 controls, adjusting for age, height, weight, and menopausal status. In 74 women with hip fractures, the Z score (mean +/- SEM) was -0.52 +/- 0.14 (P < 0.001) at the femoral neck, -1.04 +/- 0.17 (P < 0.001) at the femoral shaft, and -0.43 +/- 0.10 (P < 0.001) at the lumbar spine. In their 41 daughters, the Z score was -0.40 +/- 0.17 (P < 0.05) at the femoral neck, -0.41 +/- 0.19 (P < 0.001) at the femoral shaft, and 0.23 +/- 0.13 (NS) at the lumbar spine. We conclude that daughters of women with hip fractures are likely to be at increased risk for hip fractures themselves because they have reduced femoral neck bone density. Femoral neck fractures may not be entirely attributable to trauma; reduced bone density is likely to contribute and may be caused by the attainment of a lower peak femoral neck bone density.

Progressive decline in renal function in diabetic patients with and without albuminuria.

This study describes patterns of progression of albuminuria and renal function in a subgroup of 40 patients from a total cohort of 211 diabetic patients (118 type I, 93 type II) followed over a period of 8-14 years. Forty patients (18 with type I diabetes, 22 with type II diabetes) showed progressive increases in albumin excretion rate (AER) and/or decreases in creatinine clearance (CC) during the study period. Of these, AER alone increased in 15 patients, AER increased and CC decreased in 13 patients, and CC alone decreased in 12 patients, with a similar distribution of type I and type II diabetic patients in each group. Of the 28 patients who showed an increase in albuminuria, AER increased at an annual rate of 30-40%, resulting in a 4- to 8-fold increase in AER to > 20 micrograms/min during the study. Of the 25 patients who showed a decrease in renal function, CC decreased at an annual rate of 4-5 ml/min, resulting in an approximate halving of CC to < 90 ml/min during the study. The rate of fall in CC was not related to the presence or absence of concomitant increases in albuminuria. However, a significant preponderance of women in the group showed a decline in CC alone. The decline in CC was associated with an increase in plasma creatinine as well as a progressive decrease in urinary creatinine excretion, but the underlying mechanisms remain unexplained. These data support the concept that a subgroup of diabetic patients may show a decline in renal function in the absence of significant increases in AER.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term glycemic control and the rate of progression of early diabetic kidney disease.

In this prospective study of 11.9 years duration (range 9 to 14), we examined the progression of albuminuria prior to and after the onset of microalbuminuria [albumin excretion rate (AER): 20 to 200 micrograms/minute]. Glycated hemoglobin (HbA1), AER and blood pressure were measured every six months. Twenty-two (13 type I, 9 type II) patients were identified in whom AER increased progressively (progressors). These patients were compared with 22 others matched for age, duration and type of diabetes in whom AER did not change significantly during the study period (non-progressors). In the progressors, the rate of increase in AER correlated with mean HbA1 for the study period in patients with type I (r = 0.68, P < 0.01) and type II diabetes (r = 0.71, P < 0.05). Furthermore, AER began increasing well before the conventional 20 micrograms/minute threshold of microalbuminuria had been reached and within the first five years of diagnosis of type I diabetes. We conclude that in predisposed diabetic patients, long-term glycemic control is correlated with the rate of development of early renal abnormalities. Repeated measurements of AER from the time of diagnosis may be useful in the early detection of patients who will develop microalbuminuria and ultimately overt diabetic nephropathy.

Relationship of progressively increasing albuminuria to apoprotein(a) and blood pressure in type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetic patients.

This study has explored the temporal relationship between apoprotein(a), blood pressure and albuminuria over a mean interval of 11 years in a cohort of 107 diabetic patients of whom 26 (14 Type 2 (non-insulin-dependent), 12 Type 1 (insulin-dependent) had progressively increasing albuminuria ('progressors'). In Type 2 diabetic patients, no significant differences were noted for HbA1, blood pressure, creatinine clearance or serum lipids between progressors and non-progressors. In Type 1 diabetic patients, final systolic and diastolic blood pressures were higher in progressors compared with non-progressors and progressors showed impairment of renal function in association with a rise in blood pressure at the macroalbuminuric stage. Initial apoprotein(a) levels were similar in progressors and non-progressors of either diabetes type. Apoprotein(a) levels increased exponentially with time in 12 of 14 Type 2 progressors but only in 5 of 12 Type 1 progressors (p < 0.01). In Type 2 diabetic patients, the annual increase in apoprotein(a) levels was 9.1 +/- 2.4%, which was significantly greater than in non-progressors, 2.0 +/- 1.2% (p < 0.01) and also exceeded the rates of increase of apoprotein(a) in progressors with Type 1 diabetes, 4.0 +/- 1.4%, (p < 0.05). Apoprotein(a) levels correlated significantly with albuminuria in 8 of 14 Type 2 progressors but only in 3 of 12 Type 1 progressors (p < 0.05). The rate of increase of apoprotein(a) levels was not related to mean HbA1, creatinine or creatinine clearance levels, or to albuminuria.(ABSTRACT TRUNCATED AT 250 WORDS)