Metformin:A Narrative Review of Its Potential Benefits for Cardiovascular Disease, Cancer and Dementia

The biguanide metformin has been used as first-line therapy in type 2 diabetes mellitus (T2DM) treatment for several decades. In addition to its glucose-lowering properties and its prevention of weight gain, the landmark UK Prospective Diabetes Study (UKPDS) demonstrated cardioprotective properties in obese T2DM patients. Coupled with a favorable side effect profile and low cost, metformin has become the cornerstone in the treatment of T2DM worldwide. In addition, metformin is increasingly being investigated for its potential anticancer and neuroprotective properties both in T2DM patients and non-diabetic individuals. In the meantime, new drugs with powerful cardioprotective properties have been introduced and compete with metformin for its place in the treatment of T2DM. In this review we will discuss actual insights in the various working mechanisms of metformin and the evidence for its beneficial effects on (the prevention of) cardiovascular disease, cancer and dementia. In addition to observational evidence, emphasis is placed on randomized trials and recent meta-analyses to obtain an up-to-date overview of the use of metformin in clinical practice

Endothelial dysfunction contributes to renal function-associated cardiovascular mortality in a population with mild renal insufficiency: The Hoorn study

Mildly impaired renal function is associated with cardiovascular morbidity and mortality. There are indications that endothelial dysfunction and/or chronic inflammation, which play an important role in atherothrombosis, are present in early stages of renal insufficiency. This study investigated whether and to which extent endothelial dysfunction and inflammation were related to renal function and contributed to renal function-associated cardiovascular mortality in a population-based cohort (n = 613), aged 50 to 75 yr, that was followed with a median duration of 12.5 yr. During follow-up, 192 individuals died (67 of cardiovascular causes). At baseline, renal function was estimated with serum creatinine, the Cockcroft-Gault formula, and the Modification of Diet in Renal Disease equation of GFR (eGFR). Endothelial function was estimated by plasma von Willebrand factor, soluble vascular cell adhesion molecule-1, and the urinary albumin-creatinine ratio. Inflammatory activity was estimated by plasma C-reactive protein and soluble intercellular adhesion molecule-1. Renal function was mildly impaired (mean eGFR 68 ± 12 ml/min per 1.73

Both raloxifene and estrogen reduce major cardiovascular risk factors in healthy postmenopausal women; A 2 year, placebo-controlled study

Currently raloxifene, a selective estrogen receptor modulator, is being investigated as a potential alternative for postmenopausal hormone replacement to prevent osteoporosis and cardiovascular disease. We compared the 2-year effects of raloxifene on a wide range of cardiovascular risk factors with those of placebo and conjugated equine estrogens (CEEs). Analyses were based on 56 hysterectomized but otherwise-healthy postmenopausal women aged 54.8±3.5 (mean±SD) years who entered this double- blind study and who were randomly assigned to raloxifene hydrochloride 60 mg/d (n = 15) or 150 mg/d (n= 13), placebo (n= 13), or CEEs 0.625 mg/d (n = 15). At baseline and after 6, 12, and 24 months of treatment, we assessed serum lipids, blood pressure, glucose metabolism, C-reactive protein, and various hemostatic parameters. Compared with placebo, both raloxifene and CEEs lowered the level of low density lipoprotein cholesterol by 0.53 to 0.79 mmol/L (all P<0.04) and lowered, at 24 months, the level of fibrinogen by 0.71 to 0.86 g/L (all P<0.05). The effects of raloxifene and CEEs did not differ significantly. In contrast to raloxifene, from 6 months on CEEs increased high density lipoprotein cholesterol by 0.25 to 0.29 mmol/L and reduced plasminogen activator inhibitor-1 antigen by 30.6 to 48.6 ng/mL (all P<0.02 versus both placebo and raloxifene). CEEs transiently increased C- reactive protein by 1.0 mg/L at 6 months (P<0.05 versus placebo) and- prothrombin-derived fragment F1 +2 by 0.79 nmol/L at 12 months (P<0.001 versus placebo). Finally, from 12 months on, CEEs increased triglycerides by 0.33 to 0.56 mmol/L (all P<0.05 versus both placebo and raloxifene). Our findings suggest that in healthy postmenopausal women, raloxifene and estrogen monotherapy have similar beneficial effects on low density lipoprotein cholesterol and fibrinogen levels. These treatments differ, however, in their effects on high density lipoprotein cholesterol, triglycerides, and plasminogen activator inhibitor-1 and possibly in their effects on prothrombin fragment F1+2 and C-reactive protein

Hyperhomocysteinemia is associated with an increased risk of cardiovascular disease, especially in non-insulin-dependent diabetes mellitus - A population-based

A high serum total homocysteine (tHcy) level is an independent risk factor for cardiovascular disease. Because it is not known whether the strength of the association between hyperhomocysteinemia and cardiovascular disease is similar for peripheral arterial, coronary artery, and cerebrovascular disease, we compared the three separate risk estimates in an age-, sex-, and glucose tolerance-stratified random sample (n=631) from a 50- to 75-year-old general white population. Furthermore, we investigated the combined effect of hyperhomocysteinemia and diabetes mellitus with regard to cardiovascular disease. The prevalence of fasting hyperhomocysteinemia (>14.0 micromol/L) was 25.8%. After adjustment for age, sex, hypertension, hypercholesterolemia, diabetes, and smoking, the odds ratios (ORs; 95% confidence intervals) per 5-micromol/L increment in tHcy were 1.44 (1.10 to 1.87) for peripheral arterial, 1.25 (1.03 to 1.51) for coronary artery, 1.24 (0.97 to 1.58) for cerebrovascular, and 1.39 (1.15 to 1.68) for any cardiovascular disease. After stratification by glucose tolerance category and adjustment for the classic risk factors and serum creatinine, the ORs per 5-micromol/L increment in tHcy for any cardiovascular disease were 1.38 (1.03 to 1.85) in normal glucose tolerance, 1.55 (1.01 to 2.38) in impaired glucose tolerance, and 2.33 (1.11 to 4.90) in non-insulin-dependent diabetes mellitus (P=.07 for interaction). We conclude that the magnitude of the association between hyperhomocysteinemia and cardiovascular disease is similar for peripheral arterial, coronary artery, and cerebrovascular disease in a 50- to 75-year-old general population. High serum tHcy may be a stronger (1.6-fold) risk factor for cardiovascular disease in subjects with non-insulin-dependent diabetes mellitus than in nondiabetic subjects

Use of clean coal technology by-products as agricultural liming techniques

Dry flue gas desulfurization (FGD) by-products are mixtures of coal fly-ash, anhydrite (CaCO{sub 4}), and unspent lime- or limestone-based sorbent. Dry FGD by-products frequently have neutralizing values greater than 50% CaCO{sub 3} equivalency and thus have potential for neutralizing acidic soils. Owing to the presence of soluble salts and various trace elements, however, soil application of dry FGD by-products may have adverse effects on plant growth and soil quality. The use of a dry FGD by-product as a limestone substitute was investigated in a field study on three acidic agricultural soils (pH 4.6, 4.8, and 5.8) in eastern Ohio. The by-product (60% CaCO{sub 3} equivalency) was applied in September, 1992, at rates of 0, 0.5, 1.0, and 2.0 times the lime requirement of the soils, and alfalfa (Medicago sativa L.) and corn (Zea mays L.) were planted. Soils were sampled immediately after FGD application and three more times every six months thereafter. Samples were analyzed for pH and water soluble concentrations of 28 elements. Soil pH was increased by all FGD rates in the zone of incorporation (0--10 cm), with the highest rates giving a pH slightly above 7. Within one year pH increases could be detected at depths up to 30 cm. Calcium, Mg, and S increased, and Al, Mn, and Fe decreased with increasing dry FGD application rates. No trace element concentrations were changed by dry FGD application except B which was increased in the zone of incorporation. Dry FGD increased alfalfa yield on all three soils, and had no effect on corn yield. No detrimental effects on soil quality were observed

Microvascular dysfunction as a link between obesity, insulin resistance and hypertension

Impaired microvascular dilatation from any cause and impaired insulin-mediated capillary recruitment in particular result in suboptimal delivery of glucose and insulin to skeletal muscle, and subsequently impairment of glucose disposal (insulin resistance). In addition, microvascular dysfunction, through functional and/or structural arteriolar and capillary drop-out, and arteriolar constriction, increases peripheral resistance and thus blood pressure. Microvascular dysfunction may thus constitute a pathway that links insulin resistance and hypertension. Overweight and obesity may be an important cause of microvascular dysfunction. Mechanisms linking overweight and obesity to microvascular dysfunction include changes in the secretion of adipokines leading to increased levels of free fatty acids and inflammatory mediators, and decreased levels of adiponectin all of which may impair endothelial insulin signaling. Microvascular dysfunction may thus constitute a new treatment target in the prevention of type 2 diabetes mellitus and hypertension

Both resistance- and endurance-type exercise reduce the prevalence of hyperglycaemia in individuals with impaired glucose tolerance and in insulin-treated and non-insulin-treated type 2 diabetic patients

Aims/hypothesis The present study compares the impact of endurance- vs resistance-type exercise on subsequent 24 h blood glucose homeostasis in individuals with impaired glucose tolerance (IGT) and type 2 diabetes. Methods Fifteen individuals with IGT, 15 type 2 diabetic patients treated with exogenous insulin (INS), and 15 type 2 diabetic patients treated with oral glucose-lowering medication (OGLM) participated in a randomised crossover experiment. Participants were studied on three occasions for 3 days under strict dietary standardisation, but otherwise free-living conditions. Blood glucose homeostasis was assessed by ambulatory continuous glucose monitoring over the 24 h period following a 45 min session of resistance-type exercise (75% one repetition maximum), endurance-type exercise (50% maximum workload capacity) or no exercise at all. Results Average 24 h blood glucose concentrations were reduced from 7.4±0.2, 9.6±0.5 and 9.2±0.7 mmol/l during the control experiment to 6.9±0.2, 8.6±0.4 and 8.1±0.5 mmol/l (resistance-type exercise) and 6.8±0.2, 8.6±0.5 and 8.5±0.5 mmol/l (endurance-type exercise) over the 24 h period following a single bout of exercise in the IGT, OGLM and INS groups, respectively (p 10 mmol/l) was reduced by 35±7 and 33±11% over the 24 h period following a single session of resistanceand endurance-type exercise, respectively (p< 0.001 for both treatments). Conclusions/interpretation A single session of resistanceor endurance-type exercise substantially reduces the prevalence of hyperglycaemia during the subsequent 24 h period in individuals with IGT, and in insulin-treated and non-insulin-treated type 2 diabetic patients. Both resistance- and endurance-type exercise can be integrated in exercise intervention programmes designed to improve glycaemic control. Trial registration: Clinicaltrials.gov NCT00945165 Funding: The Netherlands Organization for Health Research and Development (ZonMw, the Netherlands). © 2011 The Author(s)

The use of sodium-glucose co-transporter-2 inhibitors or glucagon-like peptide-1 receptor agonists versus sulfonylureas and the risk of lower limb amputations:a nation-wide cohort study

Background: Numerous studies have investigated the potential association of sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) with an increased risk of lower limb amputations (LLAs), but have produced conflicting results. Particularly studies comparing SGLT2-Is to glucagon-like peptide-1 receptor agonists (GLP1-RAs) seem to find a higher LLA risk with SGLT2-I use. This raises the question whether the results are driven by a protective GLP1-RA-effect rather than a harmful SGLT2-I-effect. GLP1-RAs could promote wound healing and therefore reduce the risk of LLAs, but the associations between both drug classes and LLA remain uncertain. Therefore, the aim of the current study was to investigate the risk of LLA and diabetic foot ulcer (DFU) with SGLT2-I use and GLP1-RA use versus sulfonylurea use. Methods: A retrospective population-based cohort study was conducted using data from the Danish National Health Service (2013–2018). The study population (N = 74,475) consisted of type 2 diabetes patients aged 18 + who received a first ever prescription of an SGLT2-I, GLP1-RA or sulfonylurea. The date of the first prescription defined the start of follow-up. Time-varying Cox proportional hazards models estimated the hazard ratios (HRs) of LLA and DFU with current SGLT2-I use and GLP1-RA use versus current SU use. The models were adjusted for age, sex, socio-economic variables, comorbidities and concomitant drug use. Results: Current SGLT2-I use was not associated with a higher risk of LLA versus sulfonylureas {adjusted HR 1.10 [95% confidence interval (CI) 0.71–1.70]}. Current GLP1-RA use, on the other hand, was associated with a lower risk of LLA [adjusted HR 0.57 (95%CI 0.39–0.84)] compared to sulfonylureas. The risk of DFU was similar to that with sulfonylureas with both exposures of interest. Conclusion: SGLT2-I use was not associated with a higher risk of LLA, but GLP1-RAs with a lower risk of LLA. Previous studies reporting a higher risk of LLA with SGLT2-I use compared to GLP1-RA use might have been looking at a protective GLP1-RA effect, rather than a harmful SGLT2-I effect

The association of early life socioeconomic conditions with prediabetes and type 2 diabetes: results from the Maastricht study

markdownabstractBackground: Using cross-sectional data from The Maastricht Study, we examined the association of socioeconomic conditions in early life with prediabetes and T2DM in adulthood. We also examined potential mediating pathways via both adulthood socioeconomic conditions and adult BMI and health behaviours. Methods: Of the 3263 participants (aged 40-75 years), 493 had prediabetes and 906 were diagnosed with T2DM. By using logistic regression analyses, the associations and possible mediating pathways were examined. Results: Participants with low early life socioeconomic conditions had a 1.56 times higher odds of prediabetes (95% confidence interval (CI) = 1.21-2.02) and a 1.61 times higher odds of T2DM (95% CI = 1.31-1.99). The relation between low early life socioeconomic conditions and prediabetes was independent of current socioeconomic conditions (OR = 1.38, 95% CI = 1.05-1.80), whereas the relation with T2DM was not independent of current socioeconomic conditions (OR = 1.10, 95% CI = 0.87-1.37). BMI party mediated the association between early life socioeconomic conditions and prediabetes. Conclusions: Socioeconomic inequalities starting in early life were associated with diabetes-related outcomes in adulthood and suggest the usefulness of early life interventions aimed at tackling these inequalities

Large Epidemiologic Studies of Gout: Challenges in Diagnosis and Diagnostic Criteria

Large epidemiologic studies of gout can improve insight into the etiology, pathology, impact, and management of the disease. Identification of monosodium urate monohydrate crystals is considered the gold standard for diagnosis, but its application is often not possible in large studies. Therefore, under such circumstances, several proxy approaches are used to classify patients as having gout, including ICD coding in several types of databases or questionnaires that are usually based on the existing classification criteria. However, agreement among these methods is disappointing. Moreover, studies use the terms acute, recurrent, and chronic gout in different ways and without clear definitions. Better definitions of the different manifestations and stages of gout may provide better insight into the natural course and burden of disease and can be the basis for valid approaches to correctly classifying patients within large epidemiologic studies