Peter Winocour

Simvastatin in non-insulin-dependent diabetes mellitus: Effect on serum lipids, lipoproteins and haemostatic measures

The clinical efficacy of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMGCoA) reductase inhibitor simvastatin in the treatment of hypercholesterolaemia in non-insulin-dependent diabetes (NIDDM), was examined in a double-blind placebo-controlled study of 6 months in 70 patients with NIDDM (age 25-70 years), of whom 57 were randomised to placebo (29 patients) or simvastatin for 6 months, following a 3-month run-in on diet. Patients were hypercholesterolaemic (7.8 (7.6-8.0) (mean (95% confidence intervals)) mmol/l simvastatin vs. 8.0 (7.7-8.5) mmol/l placebo) and mildly hypertriglyceridaemic (2.6 (2.2-3.0) simvastatin vs. 2.9 (2.3-3.5) placebo). Other lipid measures and estimates of glycaemic control and haemostasis were similar in both groups. There were no significant changes in lipids, haemostatic factors, or measures of glycaemic control in the placebo treatment group. Conversely by the end of 24 weeks, simvastatin produced a 28% reduction in cholesterol (to 5.6 (5.0-6.2) mmol/l (P < 0.001)), a 38% reduction in LDL cholesterol (from 5.5 (5.4-5.6) mmol/l to 3.4 (2.8-4.0) mmol/l, P < 0.001), a 15% reduction in triglyceride (to 2.2 (1.8-2.6) mmol/l, P < 0.05, and a 9% rise in HDL (from 1.16 (1.07-1.25) to 1.23 (1.14-1.32) mmol/l, P < 0.05). Improvements in apolipoprotein B (apo B) (-28%, P < 0.001), the LDL cholesterol to apo B ratio (-20%, P < 0.001), and apo A1 (+15%, P < 0.001) were recorded. There were no effects upon fibrinogen, factor VII activity, factor VIII activity, or measures of glycaemic control (fasting glucose, insulin, C-peptide, or HbA1).(ABSTRACT TRUNCATED AT 250 WORDS)

Are low erythropoietin and 1,25-dihydroxyvitamin D levels indicative of tubulo-interstitial dysfunction in diabetes without persistent microalbuminuria?

AIMSnTo investigate the relationship between Erythropoietin (EPO) and 1,25-dihydroxyvitamin D levels, and tubular damage in patients with diabetes mellitus (DM) without persistent microalbuminuria.nnnMETHODSnWe measured serum EPO and 1,25-dihydroxyvitamin D levels and tubular injury markers such as urinary N-acetyl-beta-d-glucosaminidase (NAG) and retinol binding protein (RBP) levels in 41 non-diabetic controls, 40 patients with Type 1 and 40 with Type 2 DM.nnnRESULTSnMedian serum EPO levels were lower in Type 1 (2.57 mIU/ml: p<0.001) and Type 2 DM (5.69 mIU/ml: p=0.044) than in controls (8.76 mIU/ml), though haemoglobin levels did not differ. Median 1,25-dihydroxyvitamin D levels were lower in Type 1 (41.0 pmol/l: p=0.001) and Type 2 DM (41.8 pmol/l: p=0.035) than in controls (56.1 pmol/l), though serum creatinine, calcium, phosphate and PTH levels did not differ. Median RBP excretion was higher in Type 2 DM (0.35 mg/l vs. 0.23 mg/l: p=0.013) than in controls. Median NAG excretion was higher in Type 1 DM (1,079 micromol/h vs.1,030 micromol/h: p=0.048) compared to controls.nnnCONCLUSIONSnTubulo-interstitial damage with low levels of EPO and 1,25-dihydroxyvitamin D occurs early in Type 1 and Type 2 DM before persistent microalbuminuria.

Prevalence and progression of peripheral vascular calcification in type 2 diabetes subjects with preserved kidney function

AIMSnTo determine predictors of prevalence and progression of peripheral vascular calcification (VC) in type 2 diabetes (DM) subjects with preserved kidney function.nnnMETHODSnFifty-eight subjects (age 63 ± 11.6 years) with type 2 DM and serum creatinine <125 μmol/l were studied. A CT scan of femoral, posterior tibial and dorsalis pedis arteries was carried out at baseline and at one year. Serum osteoprotegerin (OPG) and RANKL were measured along with routine biochemistry.nnnRESULTSnSeventy-eight percent of patients had baseline VC, 47% with femoral VC, 49% with VC at two sites - femoral and foot, and 4% foot VC alone. Age, ethnicity, peripheral neuropathy and eGFR were independent predictors of baseline VC. Baseline calcification was the most important predictor of VC progression and was present in all subjects with progression compared to 35% of non-progressors (p < 0.001). Exclusion of demographic factors from models revealed neuropathy and serum OPG levels as independent predictors of both; baseline VC and progression.nnnCONCLUSIONSnSubjects with type 2 DM and well-preserved renal function had a high prevalence of VC, which was rapidly progressive especially in those with baseline VC. Age, ethnicity, neuropathy, smoking and eGFR were predictors of baseline VC and progression.

Low serum osteoprotegerin levels in normoalbuminuric type 1 diabetes mellitus

The aim of this study is to establish whether abnormal mineral metabolism is present in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. Serum levels of 1,25-dihydroxyvitamin D, osteoprotegerin (OPG) and receptor activator for nuclear factor kappa β ligand (RANKL) and other determinants of bone metabolism were measured in 35 patients with type 1 DM and in 25 age-, sex- and ethnicity-matched healthy controls. Serum OPG (1.98 vs. 2.98xa0pmol/l: Pxa0=xa00.001), 1,25-dihydroxyvitamin D (41.1 vs. 48.2xa0pmol/l: Pxa0=xa00.035) and magnesium (0.84 vs. 0.89xa0mmol/l Pxa0=xa00.029) levels were significantly lower in patients with type 1 DM compared to normal controls. RANKL levels were similar in both groups. The groups did not differ with respect to calcium, phosphate, PTH, 25-hydroxyvitamin D, tubular reabsorption of phosphate and cross-linked N-telopeptides of type 1-collagen levels. Abnormalities of mineral metabolism including low serum OPG and 1,25-dihydroxyvitamin D levels occur in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. These abnormalities may promote altered bone metabolism and vascular pathology.

The foot in type 2 diabetes: Is there a link between vascular calcification and bone mineral density?

AIMSnTo examine the relationship between vascular calcification in the foot (FVC) and bone mineral density (BMD) in the heel of type 2 diabetes mellitus (DM) subjects.nnnMETHODSn65 subjects with type 2 DM and serum creatinine<125 μmol/l underwent CT scanning of the foot to assess FVC and dual energy X ray absorptiometry (DEXA) scan to assess heel BMD. Routine biochemistry including osteoprotegerin (OPG) and Receptor activator of nuclear factor kappa-B ligand (RANKL) was also carried out.nnnRESULTSnThe proportion of subjects with FVC was 43%, whilst 40% had low BMD (T score<-1.0). Age, neuropathy and 25 hydroxyvitamin D were independent predictors of FVC. Body-weight, eGFR, 25 hydroxyvitamin D, OPG, and total cholesterol were independent predictors of low heel BMD. There was no correlation between albuminuria and BMD or FVC. There was no difference in heel BMD between those with FVC and those without, but those with frank osteoporosis were significantly more likely to have FVC than those with higher BMD.nnnCONCLUSIONSnThere is no clear-cut association between FVC and low BMD in type 2 DM with relatively well-preserved renal function. Age, neuropathy, eGFR, hyperlipidemia, body-weight, 25 hydroxyvitamin D and OPG play a complex role in their pathogenesis.

Spring 2006 Meeting of the Association of British Clinical Diabetologists

Professor Paul Durrington, Professor of Medicine, University of Manchester Proposing the motion, Professor Paul Durrington said that the attitude to cholesterol-lowering of the meeting, which opposed the motion by more than three to one in the preliminary vote, was nothing new. In 1990, it was pronounced that ‘cholesterol lowering was ineffective, particularly in secondary prevention’. Even after the 4S Study, people were still maintaining that statins were dangerous. By 2000, the position had shifted slightly and the line was now that ‘statins are highly effective and extremely safe but have not been shown to work in type 2 diabetes’. Throughout it was claimed that statins were too expensive. Now there was greater willingness to act on the very considerable evidence. Statins were the most evidence-based drugs ever. They reduced CVD risk safely (they were safer than aspirin or insulin and there had been no fatal cases of rhabdomyolysis from statins) and effectively, regardless of level or source of risk. They cost £154 per year, according to NICE Technical Assessment 94 in 2006. The Oxford Group Meta-analysis of 14 RCTs (with 90 056 participants) had demonstrated that every 1% decrease in LDL cholesterol produced a 1.25% decrease in CVD risk, irrespective of factors such as age, previous disease, treated hypertension, diabetes or level of LDL. This meant a 21% decrease in vascular endpoints in people with and without diabetes. Professor Durrington pointed out that more than 70% of those with type 1 and 90% of those with type 2 diabetes were over 40. And the absolute CVD risk in type 1 diabetes rose exponentially after 40. A 40-yearold person with diabetes had the same risk as a non-diabetic 60-year-old. On the basis of these facts, he suggested that all those aged over 40 with type 1 or type 2 diabetes should be started on statins, as well as those aged 18–39 with diabetes and at least one other risk factor. Do not wait, he pleaded, until people with a high life-time risk had an event, before putting them onto a statin.