Soy isoflavones improve cardiovascular disease risk markers in women during the early menopause.

BACKGROUND: Hormone replacement therapy may be beneficial for cardiovascular disease risk (CVR) in post-menopausal women. Soy isoflavones may act as selective estrogen receptor modulators. The aim of this study was to evaluate whether soy isoflavones had an effect on CVR markers. METHODS: The expected 10-year risk of cardiovascular disease and mortality were calculated as a secondary endpoint from a double blind randomised parallel study involving 200 women (mean age 55 years, Caucasian, Hull, UK, 2012) in the early menopause who were randomised to 15 g soy protein with 66 mg isoflavone (SPI) or 15 g soy protein alone (depleted of all isoflavones; SP) given as a snack bar between meals daily for 6 months. Age, diabetes, smoking, blood pressure and lipid profiles were used to calculate CVR using the Framingham CVR engine. RESULTS: SPI treatment resulted in a significant reduction in the metabolic parameters and systolic blood pressure compared to SP (p < 0.01). There were no changes in fasting lipid profile and diastolic blood pressure with either treatment. At 6 months, changes in these parameters with SPI treatment were reflected in a calculated 27% (p < 0.01) reduction in 10 year coronary heart disease risk, a 37% (p < 0.01) reduction in myocardial infarction risk, a 24% (p < 0.04) reduction in cardiovascular disease and 42% (p < 0.02) reduction in cardiovascular disease death risk. CONCLUSIONS: Supplementation with soy protein with isoflavones for 6 months significantly improved CVR markers and calculated CVR at 6 months during early menopause compared to soy protein without isoflavones. ISRCTN REGISTRY: ISRCTN34051237.

Glucagon-like peptide-1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) has been linked to polycystic ovary syndrome (PCOS) and carries an increased risk of liver cirrhosis. Procollagen type 3 amino-terminal peptide (PIIINP) is an independent predictor of liver cirrhosis. OBJECTIVE: To assess whether 6-month treatment with GLP-1 analogue, liraglutide, improves markers of liver fibrosis. DESIGN: A case-control study comparing women with PCOS to age- and weight-matched controls. PCOS was diagnosed according to the Rotterdam criteria. All participants underwent liver function tests and liver ultrasound scan to assess for fatty infiltration. Serum marker for liver fibrosis, PIIINP, was measured at baseline and after 6-month treatment with liraglutide 1·8 mg od. RESULTS: Nineteen women with PCOS and 17 controls were recruited, age 32·8 ± 7·2 vs 33·5 ± 6·7 years and weight 100·9 ± 16·7 vs 99·3 ± 14·7 kg, respectively. At baseline, the PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nm (P = 0·01), HOMA-IR 5·1 ± 2·6 vs 3·5 ± 1·3 (P = 0·03), AST 22·4 ± 5·2 vs 18·8 ± 3·4 u/l (P = 0·04), PIIINP 4·4 ± 0·8 vs 3·5 ± 0·8 ug/ml (P = 0·01) and NAFLD seven (35%) vs none (P = 0·005), respectively. Twenty-five (69%) participants completed the study (13 PCOS, 12 controls). Following treatment, weight was reduced by 3·0 ± 4·2 kg (P = 0·01) and 3·8 ± 3·4 kg (P = 0·001), respectively. Similarly, HOMA-IR, hsCRP, triglycerides and urinary isoprostane significantly reduced in both groups. PIIINP significantly reduced the in PCOS group 4·4 ± 0·8 vs 3·7 ± 0·9 ug/ml (P < 0·01), but not in controls 3·5 ± 0·8 vs 3·2 ± 0·7 ug/ml (P = 0·08). CONCLUSIONS: Treatment with liraglutide, and/or associated weight loss, significantly reduced PIIINP levels in obese women with PCOS. This may be an additional beneficial factor when considering the use of liraglutide in women with PCOS, obesity and NAFLD.

Postprandial effects of long-term niacin/laropiprant use on glucose and lipid metabolism and on cardiovascular risk in patients with polycystic ovary syndrome.

AIM: This study investigated the effect of long-term niacin/laropiprant therapy on CV risk and IR in obese women with PCOS. METHODS: In this double-blind randomized placebo-controlled trial, 13 and 12 PCOS women completed a 12 week course of niacin/laropiprant or placebo, respectively. Fasted subjects had an endothelial function test (EndoPat2000) and then consumed a mixed meal with blood sampled postprandially for 6 h before and after intervention. RESULTS: By 12 weeks, niacin/laropiprant lowered low-density lipoprotein cholesterol (LDL-c) (13%) and increased HDL-c (17%). Despite a reduction in fasting triglycerides (21%), the drug had no effect on their postprandial rise (2.69 ± 1.44 vs. 2.49 ± 1.14 mmol/l, p = 0.72). However, following the mixed meal, plasma glucose area under the response curve increased from 13.1 ± 2.9 to 14.0 ± 2.8 mmol/l, p = 0.05, as a consequence of both increased insulin resistance [HOMA-IR: 2.2 (1.2, 4.2) vs. 3.8(1.3, 5.5), p = 0.02] and a reduced acute insulin response to glucose [424 (211, 975) vs. 257(122, 418) pmol/mmol, p = 0.04]. Niacin/laropiprant did not improve RHI (1.97 ± 0.40 vs. 2.05 ± 0.58, p = 0.33) or hsCRP. CONCLUSIONS: In PCOS, niacin/laropiprant had a significant negative impact on postprandial glucose and no improvement in postprandial hypertriglyceridaemia, with at least the former mediated through increased IR and reduced ß-cell function. This data may help explain why the improvement in fasting lipids has not translated into improved CV risk markers in PCOS.

Polycystic ovary syndrome has no independent effect on vascular, inflammatory or thrombotic markers when matched for obesity.

INTRODUCTION: Previous studies investigating cardiovascular (CV) risk in obese women with polycystic ovary syndrome (PCOS) have been potentially confounded by not adequately accounting for body weight. OBJECTIVE: To assess if PCOS increases CV risk independently in young obese women by examining carotid intima-media wall thickness (cIMT) and platelet function. DESIGN: A case-control study comparing women with PCOS (n = 21) to age (32·8 ± 7·2 vs 33·5 ± 6·7 years), and weight (100·9 ± 16·7 vs 99·3 ± 14·7 kg)-matched controls (n = 19). Platelet function was examined by flow cytometry, clot structure and fibrinolysis by turbidimetric assays and endothelial function by ELISA and post ischaemic reactive hyperaemia. RESULTS: The PCOS group had higher testosterone 1·2 ± 0·3 vs 0·9 ± 0·3 nmol/l (P = 0·01), HOMA-IR 2·5 ± 1·7 vs 1·7 ± 1·0 (P = 0·08), impaired glucose regulation 33·3% vs 5·3% (P = 0·02), and urinary isoprostane 16·0 ± 4·4 vs 11·8 ± 7·1 ng/ml (P = 0·04) compared to controls. Mean cIMT 0·5 ± 0·05 vs 0·48 ± 0·06 mm (P = 0·36), and basal platelet surface expression (percentage of positive cells) of P-selectin 0·52 ± 0·3 vs 0·43 ± 0·23 (P = 0·40) and fibrinogen binding 0·97 ± 0·4 vs 0·83 ± 0·3 (P = 0·48) did not significantly differ between the PCOS and control groups respectively. Furthermore, platelets sensitivity to stimulation with adenosine-5'-diphosphate or inhibition with prostacyclin, clot structure and fibrinolytic efficiency ex vivo, endothelial reactive hyperaemic index (RHI), inflammation (hsCRP) and adhesion markers (sE-selectin, sP-selectin, sVCAM-1 and sICAM-1) were not significantly different between the two groups. CONCLUSIONS: PCOS appeared not to independently increase atherothrombotic risk when matched for obesity. It is likely that any excess CV risk in young obese women with PCOS can either be attributed to obesity or is not yet apparent at this early stage of the condition.

Biological variation of cardiovascular risk factors in patients with diabetes.

Biological variation refers to the natural fluctuations found when repeated measurements are made in a biological system. Generally, biological variation remains within narrow boundaries in health, but may differ in pathological states, with implications for the diagnosis and monitoring of disease processes. In disease, biological variation may alter such that any subsequent measurement may need to have a greater difference compared with a healthy control to be biologically relevant. Treatments such as insulin or anti-hypertensive therapy have been shown to reduce biological variability closer to normal levels and theoretically this may help prevent complication development or progression in conditions such as diabetes. This article reviews how biological variation can influence our identification and assessment of vascular risk factors in a person with diabetes. The role of biological variation in the diagnosis of diabetes (glucose and HbA1c) is then examined. Finally, the influence that common treatments in diabetes have in modifying biological variation is described.

Implications of new European Union driving regulations on patients with Type 1 diabetes who participated in the Diabetes Control and Complications Trial.

AIMS: Recurrent severe hypoglycaemia in a patient with diabetes is strongly associated with a crash risk while driving. To help ensure road safety, recent changes were made to European Union driving regulations for patients with diabetes. These included the recommendation that more than one episode of severe hypoglycaemia within 12 months would lead to the loss of a driving licence. This study has assessed the impact of this regulation if applied to patients who participated in the Diabetes Control and Complications Trial. METHODS: All patients in the Diabetes Control and Complications Trial were assumed to be drivers. Repeated hypoglycaemic episodes within a year were determined during the mean 6.5 years of the study. RESULTS: Of the 1441 patients in the Diabetes Control and Complications Trial, 439 (30%) had more than one severe hypoglycaemic episode during a 12-month period of their study participation. Amongst the study groups, 312/711 (44%) of intensively treated and 127/730 (17%) of conventionally treated patients would have lost their licence at some point during the trial. The risk of licence loss increased with lower mean HbA1c , longer duration of diabetes and younger age (all P < 0.001). CONCLUSIONS: More than one episode of severe hypoglycaemia within a year was a frequent event in subjects in the Diabetes Control and Complications Trial, especially in intensively treated patients. If applied to current practice, improving road safety through these changes to European Union regulations could have a substantial impact on drivers who have Type 1 diabetes. This emphasizes the need to take into account the potential effects of severe hypoglycaemia in those who rely on a driving licence.

High-polyphenol chocolate reduces endothelial dysfunction and oxidative stress during acute transient hyperglycaemia in Type 2 diabetes: a pilot randomized controlled trial.

AIMS: To investigate the effects of high-polyphenol chocolate upon endothelial function and oxidative stress in Type 2 diabetes mellitus during acute transient hyperglycaemia induced following a 75-g oral glucose challenge. METHODS: Ten subjects with Type 2 diabetes underwent a double-blinded randomized controlled crossover study. A 75-g oral glucose load was used to induce hyperglycaemia, which was administered to participants 60 min after they had ingested either low (control) or high-polyphenol chocolate. Participants undertook testing at weekly intervals, following an initial cocoa-free period. Endothelial function was assessed by both functional [reactive hyperaemia peripheral artery tonometry (EndoPAT-2000) and serum markers (including intercellular adhesion molecule 1, P-selectin and P-selectin glycoprotein ligand 1]. Urinary 15-F2t-isoprostane adjusted for creatinine was used as an oxidative stress marker. Measurements were made at baseline and 2 h post-ingestion of the glucose load. RESULTS: Prior consumption of high-polyphenol chocolate before a glucose load improved endothelial function (1.7 ± 0.1 vs. 2.3 ± 0.1%, P = 0.01), whereas prior consumption of control chocolate resulted in a significant increase in intercellular adhesion molecule 1 (321.1 ± 7.6 vs. 373.6 ± 10.5 ng/ml, P = 0.04) and 15-F2t-isoprostane (116.8 ± 5.7 vs. 207.1 ± 5.7 mg/mol, P = 0.02). Analysis of percentage changes from baseline comparing control and high-polyphenol chocolate showed a significant improvement for high-polyphenol chocolate in both measures of endothelial function (P < 0.05) and for urinary 15-F2t-isoprostane (P = 0.04). CONCLUSION: High-polyphenol chocolate protected against acute hyperglycaemia-induced endothelial dysfunction and oxidative stress in individuals with Type 2 diabetes mellitus.

Use of complementary markers in assessing glycaemic control in people with diabetic kidney disease undergoing iron or erythropoietin treatment.

AIMS: HbA(1c) values are unreliable in patients with diabetes who have chronic kidney disease who receive iron and/or erythropoiesis stimulating agents. The study aimed to evaluate the utility of the complementary glycaemic markers glycated albumin, fructosamine and 1,5 anhydroglucitol in this group of patients. METHODS: A prospective study of patients with Type 2 diabetes and chronic kidney disease stage IIIB/IV undergoing intravenous iron or erythropoiesis-stimulating agent therapy. Glycaemic control was monitored using HbA(1c), seven-point daily glucose thrice weekly, continuous glucose monitoring, glycated albumin, fructosamine and 1,5 anhydroglucitol. RESULTS: Fifteen patients [9 men; median age 72 years (interquartile range 68-74), follow-up period (16.4 ± 3.7 weeks)] received parenteral iron; 15 patients [11 men; 70 years (interquartile range 62-75), (17.3 ± 3.3 weeks)] received erythropoiesis-stimulating agent. HbA(1c) fell following treatment with both iron [57 mmol/mol (7.4%) to 53 mmol/mol (7.0%), P < 0.001] and erythropoiesis-stimulating agent [56 mmol/mol (7.3%) to 49 mmol/mol (6.6%), P = 0.01] despite mean blood glucose remaining unchanged (iron: 9.55 to 9.71 mmol/l, P = 0.07; erythropoiesis-stimulating agent: 8.72 to 8.78 mmol/l, P = 0.89). Unlike HbA1c , the glycated albumin, fructosamine and 1,5 anhydroglucitol levels did not change following iron [glycated albumin (16.8 to 16.3%, P = 0.10); fructosamine (259.5 to 256 µmol/l, P = 0.89); 1,5 anhydroglucitol (54.2 to 50.9 µmol/l, P = 0.89)] or erythropoiesis-stimulating agent [glycated albumin (17.9 to 17.5%, P = 0.29), fructosamine (324.3 to 306.0 µmol/l, P = 0.52), 1,5 anhydroglucitol (58.2 to 46.7 µmol/l, P = 0.35)]. Despite this, HbA(1c) was consistently the marker most closely related to mean blood glucose before and after each treatment (R range 0.7-0.88). CONCLUSIONS: These data indicate that HbA(1c) was statistically most closely related to mean blood glucose, but clinical trends in glycaemia in patients undergoing iron or erythropoiesis-stimulating agent therapy are likely best assessed by including one of these additional glycaemic markers.

The effect of atorvastatin and simvastatin on vitamin D, oxidative stress and inflammatory marker concentrations in patients with type 2 diabetes: a crossover study.

The pleiotropic effect of statins may be mediated in part through raising 25 hydroxy vitamin D (25OHD) concentrations. It has also been shown that an increase in oxidative stress and inflammatory markers are a feature of the patients with type 2 diabetes (T2DM). A cross-over study of 26 patients with T2DM taking either simvastatin 40 mg or atorvastatin 10 mg was undertaken. After 3 months on one statin, lipids, C-reactive protein (hsCRP), 25OHD and malondialdehyde (MDA) were measured repeatedly. The same procedure was then followed taking the other statin. Despite similar lipid-lowering, the mean 25OHD was higher on atorvastatin compared with simvastatin and the mean MDA and hsCRP levels lower, irrespective of which statin the patients were taking before crossover. The changes in 25OHD predicted changes in CRP and MDA levels. Thus, compared with simvastatin, atorvastatin shows apparently beneficial pleiotropic effects with respect to 25OHD concentrations as well as markers of oxidative stress and inflammation in patients with T2DM.

The rise and fall of HbA(1c) as a risk marker for diabetes complications.

It is still unclear whether short-term, within-day, variability in glycaemic control is contributory to the development of diabetes micro- or macrovascular complications. However, consistent and compelling data are emerging that longer term fluctuations in glucose, as evidenced by increases in HbA(1c) variability, do indeed add to the mean HbA(1c) value in predicting the risk of microvascular disease. Until now, studies have found this to be the case mainly in type 1 diabetes, but in this issue of Diabetologia (DOI: 10.1007/s00125-012-2572-7 ) an analysis of the Tsukuba Kawai Diabetes Registry in Japan has found that HbA(1c) variability also predicts the risk of nephropathy in type 2 diabetic patients. These observations raise the possibility that reducing rises and falls in HbA(1c) may help avoid hyperglycaemia-related vascular disease without running the same risk of hypoglycaemia that a strategy focusing purely on lower HbA(1c) might incur.

Does severe hypoglycaemia influence microvascular complications in Type 1 diabetes? An analysis of the Diabetes Control and Complications Trial database.

AIMS: Severe hypoglycaemia may have a role in aggravating micro- and macrovascular disease in diabetes. Data from the Diabetes Control and Complication Trial have been reanalysed to ascertain whether the frequency of severe hypoglycaemia exerted an influence on the development and progression of retinopathy or nephropathy in people with Type 1 diabetes. METHODS: Using binary longitudinal multiple logistic regression, HbA(1c) at study baseline, mean HbA(1c) throughout the study and the number of severe hypoglycaemic episodes during the trial were compared to examine the risk of development/progression of retinopathy and nephropathy. RESULTS: Average HbA(1c) during the study and/or HbA(1c) at baseline were independently predictive of retinopathy and nephropathy both in the intensively and the conventionally treated patients (all P ≤ 0.001). However, the number of hypoglycaemic episodes did not add to HbA(1c) in predicting retinopathy [odds ratio (95% CI) 0.99 (0.96-1.01), P = 0.51 in intensively treated patients, 0.94 (0.89-1.00), P = 0.05, conventional] or nephropathy [odds ratio (95% CI) 0.98 (0.95-1.01), P = 0.48 intensive, 1.03 (0.98-1.10), P = 0.17 conventional]. CONCLUSIONS: The frequency of exposure to severe hypoglycaemia did not predict a different risk of developing retinopathy or nephropathy in either treatment group of the Diabetes Control and Complications Trial at any given HbA(1c) .

Short-term glucose variability in healthy volunteers is not associated with raised oxidative stress markers.

It is unknown whether glycaemic variability adds to the risk of microvascular complications of diabetes over and above the mean glucose value for a patient. We examined the effect of purposefully induced short-term glycaemic variability on oxidative stress markers. Eleven healthy subjects underwent three sequential glycaemic states; sustained hyperglycaemia, sustained euglycaemia and variable glycaemia, using glycaemic clamps for 3 h. Twenty-four hours urinary 8-isoprostane-PGF2α was measured before and after each glycaemic state to assess oxidative stress. The median and interquartile range of the urinary 8-iso-PGF2α in ng/24 h were (1373, 513), (996, 298) and (1227, 472) for the euglycaemic, hyperglycaemic and variable states, respectively. There was no significant difference in urinary isoprostanes between the three different states; mean ranks 20.9, 11.9 and 18.2 for the euglycaemic state, hyperglycaemic state and glycaemic variability state, respectively, p = 0.083. In conclusion, we did not see a significant increase in the urinary isoprostanes when glycaemic variability was induced under controlled conditions in healthy individuals.

The effect of extensive flooding in Hull on the glycaemic control of patients with diabetes.

AIMS: To examine the impact of extensive flooding in a UK city in 2007 on the glycaemic control of patients with diabetes mellitus. METHODS: This was a longitudinal study in patients with diabetes mellitus 12 months before and after the floods in Hull and East Yorkshire, UK. All patients registered with diabetes mellitus were sent questionnaires about their experiences during and after the floods. Glycaemic control for patients directly affected by the floods was compared against those unaffected. RESULTS: Of 1743 respondents, 296 patients had been affected by the floods (110 insulin treated, 186 lifestyle and oral agents) and 1447 unaffected (482 insulin treated, 965 lifestyle and oral agents). There was a rise in mean HbA(1c) of affected individuals comparing 12 months before the floods with 12 months after [mean (95% confidence interval), 7.6% (7.5-7.7) vs. 7.9% (7.7-8.0), P = 0.002], but not those unaffected [7.5% (7.4-7.6) vs. 7.5% (7.4-7.6), P = 0.46]. The difference was mainly in insulin-treated patients [8.6% (8.3, 8.9) affected vs. 8.2% (8.1, 8.3) unaffected, (P = 0.002)]. CONCLUSIONS: Glycaemic control deteriorated in diabetes patients following the floods but was almost exclusively confined to patients taking insulin and was worst at 6-9 months following the event. Insulin-treated patients may need specific targeting in the event of a natural disaster.

Insulin resistance variability in women with anovulatory and ovulatory polycystic ovary syndrome, and normal controls.

Women with polycystic ovary syndrome (PCOS) were found to have a higher biological variability in insulin resistance (IR) compared to controls, but it is unknown whether this variability in IR differs between PCOS who are anovulatory compared to those who have an ovulatory cycle. The primary aim of this study was to compare and contrast the variability of IR in women with ovulatory and anovulatory PCOS, in comparison to normal subjects. 53 Caucasian women with PCOS and 22 normal ovulating women were recruited. Fasting blood was collected each day on 10 consecutive occasions at 3-4 day intervals for analysis of insulin, glucose, progesterone, and testosterone. Analysis of progesterone levels showed 22 of 53 women with PCOS to have had an ovulatory cycle. Insulin resistance was calculated by HOMA method. Women with anovulatory PCOS had higher mean and variability of IR compared to those having an ovulatory cycle, and both were significantly higher than controls (mean ± SEM; HOMA-IR 4.14 ± 0.14 vs. 3.65 ± 0.15 vs. 2.21 ± 0.16, respectively) after adjustment or BMI. The mean BMI for individual PCOS patients correlated with mean HOMA-IR (p=0.009). Insulin resistance in women with anovulatory PCOS is both higher and more variable than in ovulatory PCOS. Since anovulatory PCOS therefore mimics the IR features of type 2 diabetes more closely, anovulation may be particularly associated with a higher cardiovascular risk compared to PCOS patients who ovulate.

For debate. Glucose variability and diabetes complication risk: we need to know the answer.

There is still a debate as to whether or not glucose variability contributes to diabetes complication risk. There is much in vitro laboratory evidence that glycaemic instability gives rise to increased production of reactive oxygen species and has a detrimental effect on endothelial dysfunction. While some in vivo studies have also shown similar findings in patients with or without diabetes, others have been unable to confirm any association. Furthermore, clinical studies which have sought to translate this possible risk into an increased likelihood of developing micro- or macrovascular complications have so far not demonstrated an effect. However, few of these trials were specifically designed to establish any influence of glucose fluctuations. This issue is now one of the largest remaining unanswered questions in diabetes. While this article focuses on the data which do not support a role for glucose variability in the development of complications, it also highlights the need for further studies to be performed which will definitively resolve the matter.

High-cocoa polyphenol-rich chocolate improves HDL cholesterol in Type 2 diabetes patients.

AIM: To examine the effects of chocolate on lipid profiles, weight and glycaemic control in individuals with Type 2 diabetes. METHODS: Twelve individuals with Type 2 diabetes on stable medication were enrolled in a randomized, placebo-controlled double-blind crossover study. Subjects were randomized to 45 g chocolate with or without a high polyphenol content for 8 weeks and then crossed over after a 4-week washout period. Changes in weight, glycaemic control, lipid profile and high-sensitivity C-reactive protein were measured at the beginning and at the end of each intervention. RESULTS: HDL cholesterol increased significantly with high polyphenol chocolate (1.16 ± 0.08 vs. 1.26 ± 0.08 mmol/l, P = 0.05) with a decrease in the total cholesterol: HDL ratio (4.4 ± 0.4 vs. 4.1 ± 0.4 mmol/l, P = 0.04). No changes were seen with the low polyphenol chocolate in any parameters. Over the course of 16 weeks of daily chocolate consumption neither weight nor glycaemic control altered from baseline. CONCLUSION: High polyphenol chocolate is effective in improving the atherosclerotic cholesterol profile in patients with diabetes by increasing HDL cholesterol and improving the cholesterol:HDL ratio without affecting weight, inflammatory markers, insulin resistance or glycaemic control.

Low density lipoprotein-cholesterol variability in patients with type 2 diabetes taking atorvastatin compared to simvastatin: justification for direct measurement?

AIM: The benefit of direct, as opposed to calculated, low density lipoprotein -cholesterol (LDL-C) measurement remains unclear. This study compared the biological variability of direct LDL in patients with type 2 diabetes (T2DM) on equivalent doses of the short half-life statin, simvastatin or the longer half-life statin, atorvastatin. METHODS: A cross-over study of biological variation of lipids in 26 patients with T2DM taking either simvastatin 40 mg (n = 10) or atorvastatin 10 mg. After 3 months on one statin, fasting lipids were measured on 10 occasions over a 5-week period. The same procedure was then followed on the other statin. The variability of LDL-C was established using a Beckman direct assay. RESULTS: As a group, mean LDL was no different between statins (mean +/- s.d.) (1.69 +/- 0.60 mmol/l simvastatin vs. 1.67 +/- 0.60 mmol/l atorvastatin, p = 0.19). However, in all patients, the intraindividual biological variability of LDL while taking simvastatin was markedly higher than with atorvastatin (average s.d. = 0.17 mmol /l simvastatin vs. 0.01 mmol/l, p < 0.0001). Friedewald calculated LDL variability was no different between statins (average s.d. = 0.34 mmol /l simvastatin vs. 0.21 mmol/l atorvastatin, p = 0.19). CONCLUSIONS: In contrast to calculated values, direct measurement revealed LDL to be much more stable (the s.d. being an order of magnitude) in T2DM patients taking atorvastatin rather than simvastatin. This means LDL targets can be consistently met with less lipid monitoring using atorvastatin rather than simvastatin. Direct LDL measurement may therefore have a particular role in monitoring patients on statin treatment.

Effect of metformin, orlistat and pioglitazone treatment on mean insulin resistance and its biological variability in polycystic ovary syndrome.

CONTEXT: Mean insulin resistance (IR) is greater and it is also more variable in overweight women with polycystic ovarian syndrome (PCOS) compared to weight matched controls. Whilst treatment will reduce the mean IR, it is not known if the IR variability is also reduced. OBJECTIVE: To compare the change in IR and its variability before and after treatment with insulin sensitization through metformin and pioglitazone, compared to that induced by weight loss with orlistat. DESIGN: Randomized, open labelled parallel study. SETTING: Endocrinology outpatient clinic at a referral centre. PATIENTS: Thirty obese PCOS patients [BMI 36.0 +/- 1.2 kg/m(2) (mean +/- SEM)] participated in the study. INTERVENTION: The change in biological variability (BV) was assessed by measuring IR (homeostasis model assessment method) at 4-day intervals on 10 consecutive occasions before and 12 weeks after randomization to metformin, pioglitazone or orlistat. OUTCOME MEASURED: The primary end point of the study was a change in BV of IR. RESULTS: Treatment with pioglitazone, orlistat and metformin reduced the overall IR by 41.0 +/- 4.1%, 19.7 +/- 6.4% and 16.1 +/- 6.8% (P = 0.005, P = 0.013, P = 0.17, respectively) and IR variability by 28.5 +/- 18.0%, 41.8 +/- 11.6% and 23.7 +/- 17.0 (P = 0.20, P = 0.015 and P = 0.28, respectively). Free androgen index reduced significantly with all treatments. CONCLUSION: Only orlistat reduced both IR and its variability significantly, though all three drugs were effective in reducing hyperandrogenism within the 12-week period of the study.

The mean and the biological variation of insulin resistance does not differ between polycystic ovary syndrome and type 2 diabetes.

BACKGROUND: There is an assumption that the mean and biological variation of insulin resistance (IR) is less in polycystic ovary syndrome (PCOS), and intuitively higher in type 2 diabetes (T2DM). To test this hypothesis we compared the mean and biological variation in IR in PCOS to that of T2DM and to age- and weight-matched controls. METHODS: Twelve PCOS, 11 matched healthy women; 12 postmenopausal diet-controlled T2DM and 11 matched healthy postmenopausal women were recruited. Blood samples were collected at 4-d intervals on 10 consecutive occasions. The biological variability of IR was derived on duplicate samples. RESULTS: Mean and biological variability of HOMA-IR for PCOS did not differ from T2DM. Both measures were higher than the matched controls. There was no difference in insulin or IR measures between the body mass index matched pre- and postmenopausal women. Percentage beta cell function were 208.8%, 62.3%, 106.5% and 111.9%, respectively, in PCOS, postmenopausal women with T2DM, healthy premenopausal and healthy postmenopausal women. CONCLUSIONS: The progression from PCOS to the development of T2DM is unlikely to be due to a further increase in IR (or variability), but rather the progressive failure of pancreatic beta cells with a decrease in insulin production. The clinical trial registration number for this study is ISRCTN65353256.

Intensive glucose therapy and clinical implications of recent data: a consensus statement from the Global Task Force on Glycaemic Control.

BACKGROUND: There is compelling evidence showing that achieving good glycaemic control reduces the risk of microvascular complications in people with type 1 and type 2 diabetes. Likewise, there is clear evidence to show that achieving good glycaemic control reduces the risk of macrovascular complications in type 1 diabetes. The UKPDS 10-year follow up suggests that good glycaemic control also reduces the risk of macrovascular complications in type 2 diabetes. Despite this, recent results from ACCORD, ADVANCE and VADT present conflicting results and data from the ACCORD trial appear to suggest that very low HbA(1c) targets (<6.0%) may, in fact, be dangerous in certain patient populations. AIM: To review recent results from ACCORD, ADVANCE and VADT and provide clear guidance on the clinical significance of the new data and their implications for the practising physician treating patients with type 2 diabetes. METHODS: A Pubmed search was used to identify major randomised clinical trials examining the association between glycaemic control and diabetes-associated complications. The data was reviewed and discussed by the GTF through a consensus meeting. The recommendations for clinical practice in this statement are the conclusions of these analyses and discussions. RESULTS: Evidence from ACCORD, ADVANCE, VADT and UKPDS suggests that certain patient populations, such as those with moderate diabetes duration and/or no pre-existing CVD, may benefit from intensive blood glucose control. These trials highlight the benefit of a multifactorial treatment approach to diabetes. However, ACCORD results indicate that aggressive HbA(1c) targets (<6.0%) may not be beneficial in patients with existing CVD and a longer duration of diabetes. CONCLUSIONS: Glycaemic control remains a very important component of treatment for type 2 diabetes and contrasting results from the ACCORD, ADVANCE and VADT should not discourage physicians from controlling blood glucose levels.