Michel P. Hermans

Correct Homeostasis Model Assessment (HOMA) Evaluation Uses the Computer Program

tight glycemic control, in the treatment of patients with macroalbuminuria from diabetic nephropathy. In the first case, a 58-year-old woman with type 1 diabetes that was diagnosed when she was 17 years old was found to have 1,260 mg/day of protein in the urine. Her history was pertinent for diabetic retinopathy neuropathy, and for recurrent congestive heart failure. Medications included digoxin, furosemide, Cozaar, and aspirin, as well as NPH and regular insulin twice daily. The HbAlcwas 7.7% (4.1-6.1). The treatment regimen was changed to the insulin pump, and therapy with pentoxifylline (400 mg t.i.d.) was begun. Because of gastrointestinal side effects from the pentoxifylline, the dosage was reduced to 400 mg twice per day, which was tolerated. Three months later, the 24-h urine protein was 284 mg/day, and 6 months after that, 237 mg/day. The HbAlc fluctuated between 7.2 and 7.5% during that time. All other medications were continued as before. In the second case, a 74-year-old man with type 1 diabetes that was diagnosed when he was 42 years old had been noted at age 70 years to have 312 mg/day of protein in the urine. Therapy with 10 mg/day lisinopril was begun. After 18 months, a 24-h urine sample revealed 3,643 mg/day of protein. Therapy with pentoxifylline (400 mg t.i.d.) was begun. Also at that time, the insulin regimen was changed from three injections per day to use of the insulin pump. After 6 months, a 24-h urine sample revealed 1,836 mg of protein. When tested 6 months later, the urinary protein was 1,056 mg/day and after an additional 6 months, it was 490 mg/day Lisinopril therapy was continued during this time. HbAlc levels fluctuated between 7.2 and 8.3% (4.1-6.1) during this time, compared with values between 9.0 and 9.3% before introduction of the insulin pump. In the third case, an 84-year old female who had type 2 diabetes with diabetic retinopathy and peripheral neuropathy was found to have 3,967 mg/day of urinary protein. Her history was pertinent for hypertension and congestive heart failure, for which she was treated with captopril (25 mg t.i.d.) and furosemide (40 mg b.i.d.). Her diabetes was managed with Humulin N and Humulin R in the morning, Humulin R at supper, and Humulin N at bedtime. Pentoxifylline was begun for the proteinuria at a dosage of 400 mg t.i.d. After 4 months, the 24-h urinary protein had been reduced to 733 mg/day, and 1 year later, the urinary protein was 787 mg/day. During this time, HbAlc ranged between 5.8 and 6.5% (4.1-6.1). These cases illustrate that pentoxifylline, in conjunction with intensive therapy for diabetes, may be particularly useful in reducing significant proteinuria. All three patients maintained stable serum creatinine levels in the range of 1.0-1.5 mg/dl. Tight glycemic control was maintained in all patients, and in the second case, there was a significant improvement in HbAlc after insulin pump therapy was introduced. Two patients were taking concomitant ACEls, and the third was on an angiotensin-receptor blocker (ARB). ARBs have been shown in .an animal model to attenuate diabetic nephropathy (7). Further studies to elucidate the mechanism of improved macroalbuminuria by pentoxifylline in conjunction with tight glycemic control in the treatment of diabetic nephropathy should be considered. This treatment appears to be beneficial in forestalling the typically relentless downhill course of diabetic nephropathy.

Comparison of insulin sensitivity tests across a range of glucose tolerance from normal to diabetes

Aims/hypothesis. Adequate comparison of the relative performance of insulin sensitivity tests is not yet available. We compared the discrimination of four insulin sensitivity tests, commonly used in vivo, across a range of glucose tolerance. Methods. Normal (n = 7), impaired glucose tolerant (n = 8) and Type II (non-insulin-dependent) diabetic subjects (n = 9) had in random order two tests from the following: frequently sampled insulin-modified intravenous glucose tolerance test (FSIVGTT-MinMod); homeostasis model assessment (HOMA) and 2-h continuous infusion of glucose with model assessment (CIGMA) with immunoreactive or specific insulin; short insulin tolerance tests (ITT). The discriminatory power of tests was assessed by the ratio of the within-subject standard deviation to the underlying between-subject standard deviation (discriminant ratio –DR). The degree to which tests measured the same variable was assessed by comparing rank correlation with the maximum expected correlation given the imprecision of the tests. The unbiased lines of equivalence taking into account the precision of tests were constructed. Results. Reciprocal fasting plasma insulin (FPI–1), HOMA %S and 2-h CIGMA %S, had similar DRs with ITT being less informative. The FSIVGTT-MinMod analysis was able to assess 13 out of 24 subjects and had a performance similar to ITT. Using specific rather than immunoreactive insulin for HOMA-CIGMA did not improve the DR. Reciprocal fasting plasma insulin FPI–1, HOMA %S, 2-h CIGMA %S and SI FSIVGTT intercorrelated more than 90 % of the expected rank correlation given the imprecision of the tests, but ITT gave only limited correlation. Conclusion/interpretation. The HOMA-CIGMA test with immunoreactive insulin provides similar information in distinguishing insulin sensitivity between subjects with normal glucose tolerance, those with impaired glucose tolerance and those with Type II diabetes as does FSIVGTT, whereas ITT is less informative. [Diabetologia (1999) 42: 678–687]

The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients

Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue. This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3i highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.

Residual macrovascular risk in 2013: what have we learned?

Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.

Association Between Plasma Triglycerides and High-Density Lipoprotein Cholesterol and Microvascular Kidney Disease and Retinopathy in Type 2 Diabetes Mellitus A Global Case–Control Study in 13 Countries

Background— Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. Methods and Results— The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A1c, hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11–1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88–0.96) for every 0.2 mmol/L (≈1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16–1.31) with triglycerides and decreased by 0.86 (0.82–0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. Conclusions— Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.

Association Between Plasma Triglycerides and HDL-Cholesterol and Microvascular Kidney Disease and Retinopathy in Type 2 Diabetes: A Global Case-Control Study in 13 Countries

Background— Microvascular renal and retinal diseases are common major complications of type 2 diabetes mellitus. The relation between plasma lipids and microvascular disease is not well established. Methods and Results— The case subjects were 2535 patients with type 2 diabetes mellitus with an average duration of 14 years, 1891 of whom had kidney disease and 1218 with retinopathy. The case subjects were matched for diabetes mellitus duration, age, sex, and low-density lipoprotein cholesterol to 3683 control subjects with type 2 diabetes mellitus who did not have kidney disease or retinopathy. The study was conducted in 24 sites in 13 countries. The primary analysis included kidney disease and retinopathy cases. Matched analysis was performed by use of site-specific conditional logistic regression in multivariable models that adjusted for hemoglobin A1c, hypertension, and statin treatment. Mean low-density lipoprotein cholesterol concentration was 2.3 mmol/L. The microvascular disease odds ratio increased by a factor of 1.16 (95% confidence interval, 1.11–1.22) for every 0.5 mmol/L (≈1 quintile) increase in triglycerides or decreased by a factor of 0.92 (0.88–0.96) for every 0.2 mmol/L (≈1 quintile) increase in high-density lipoprotein cholesterol. For kidney disease, the odds ratio increased by 1.23 (1.16–1.31) with triglycerides and decreased by 0.86 (0.82–0.91) with high-density lipoprotein cholesterol. Retinopathy was associated with triglycerides and high-density lipoprotein cholesterol in matched analysis but not significantly after additional adjustment. Conclusions— Diabetic kidney disease is associated worldwide with higher levels of plasma triglycerides and lower levels of high-density lipoprotein cholesterol among patients with good control of low-density lipoprotein cholesterol. Retinopathy was less robustly associated with these lipids. These results strengthen the rationale for studying dyslipidemia treatment to prevent diabetic microvascular disease.

Centralized Pan-European survey on the under-treatment of hypercholesterolaemia (CEPHEUS): overall findings from eight countries

Abstract Background: Surveys evaluating plasma lipid goal attainment in patients with coronary heart disease have shown that hypercholesterolaemia is inadequately treated. Limited data account for the reasons behind this. The aim of the CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS) survey was to evaluate the current use and efficacy of lipid-lowering drugs (LLD), and to identify possible patient/physician characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets recommended by the 2003 European guidelines (Third Joint Task Force). Methods: CEPHEUS was a European, multi-centre, cross-sectional survey conducted in eight countries and involved patients on LLD for >3 months (stable medication >6 weeks). One visit was scheduled for data collection, including fasting lipids. In all but one country, physicians and patients filled in a questionnaire about aspects of hypercholesterolaemia and treatment. Clinical trial registration: Trial registration: ClinicalTrials.gov identifier: NCT00542867. Results: Of the 15 199 patients recruited, 14 478 were included in the final analyses. The mean age was 63.2 years, and 45% of patients were female. Overall, 55.3% of the patients achieved their LDL-C target. In multivariate analyses, the factors identified as positive predictors for achieving LDL-C goals included normal body mass index, not smoking, not having metabolic syndrome, being on statin therapy and good treatment adherence. Limitations: The population was a selected group of subjects treated with LLD, and the results cannot be extrapolated to the general population. Patient consent was obtained, which may have selected more motivated patients and induced a positive bias. The physician and patient questionnaires were not validated, but were only used for exploratory purposes. Conclusion: Only 55.3% of patients using LLD achieved the LDL-C target recommended in the 2003 European guidelines.

log(TG)/HDL-C is related to both residual cardiometabolic risk and β-cell function loss in type 2 diabetes males.

BackgroundT2DM is associated with atherogenic dyslipidemia (AD), defined as decreased HDL-C plus raised triglycerides (TG). AD confers increased risk for CAD, even when LDL-C is at target. AD is rarely assessed due to lack of screening methods consensus.AimTo establish the prevalence and severity of AD from log(TG)/HDL-C in T2DM males, and to determine how it relates to cardiometabolic phenotype, glucose homeostasis, micro- and macrovascular complications, and 10-year UKPDS CV risk.Methods585 T2DM males divided according to quintiles (Q) of log(TG)/HDL-C. AD prevalence defined as HDL-C <40 mg.dL-1 plus TG ≥150 mg.dL-1. β-cell function assessed with HOMA.ResultsMean HDL-C and TG were 44 (13) and 204 (155) mg.dL-1. AD prevalence was 35%. AD correlated with lower β-cell function, with accelerated loss of insulin secretion, and with poorer HbA1c levels. AD was related to a high prevalence of CAD, and also to 10-year absolute CAD risk.Conclusionslog(TG)/HDL-C is a simple means to estimate AD and the residual CV risk it confers in T2DM. AD closely associates with major cardiometabolic and glucose homeostasis determinants and poorer metabolic control. The ratio also relates to macroangiopathy prevalence and ranks future CAD risk, and is well-suited to capture non-LDL-related macrovascular residual risk and major glycemic determinants.

Insulin sensitivity, adjusted β-cell function and adiponectinaemia among lean drug-naive schizophrenic patients treated with atypical antipsychotic drugs: A nine-month prospective study

Atypical antipsychotic drugs (AADs) induce weight gain and truncal adiposity, and even the metabolic syndrome (MetS), which may progress to IFG/IGT or DM. AAD effects in lean schizophrenic patients without MetS have not been documented, especially in terms of weight gain and changes in insulin sensitivity (S), beta-cell function (beta) and adiponectinaemia. We prospectively determined the effects of nine-month therapy with AADs on anthropometrics, metabolism and adiponectinaemia, including homoeostasis model assessment (HOMA) modelling of S, beta and betaxS (hyperbolic product, assessing individual beta adjusted for S). We analyzed 36 schizophrenic subjects (M/F: 24/12; Caucasian: n=23, North African: n=12, South Asian: n=1) aged 35+/- years (mean+/-one S.D.) free of MetS (NCEP-ATPIII), of whom 19 study completers were evaluated following AAD treatment. S, beta, betaxS and adiponectin were measured at zero, three and nine months. At nine months, BMI had risen from 22+/-2 to 25+/-2kg/m(2) (P<0.001) and waist circumference from 85+/-8 to 91+/-11cm (P<0.001), while adiponectin decreased from 10.4+/-5.1 to 7.4+/-3.8mug/mL (P<0.001). Blood pressure and lipids were unaffected. S decreased from 138+/-49 to 110+/-58% (P=0.006) and beta increased from 83+/-24 to 100+/-40% (P=0.034). As a result, betaxS decreased from 106+/-19 to 91+/-27% (P=0.015). Fasting glycaemia rose from 89+/-5 to 96+/-9mg/dL (P=0.007). On study completion, 21% had IFG. Long-term use of AADs in lean, drug-naive, schizophrenics initially free of MetS induced weight gain and truncal fat accumulation associated with decreases in adiponectin and hyperbolic product, explaining the increased fasting glycaemia and impaired fasting glucose seen in predisposed individuals.

MRI of cervical cord lesions and their resolution in Toxocara canis myelopathy

Abstract We report serial MRI findings in a 58-year-old man with cervical cord involvement by Toxocara canis, in whom antihelminthic chemotherapy yielded improvement of the neurological deficits and cord lesions seen on MRI.