Stavroula A. Paschou

Dietary management of dyslipidaemias. Is there any evidence for cardiovascular benefit

Specific dietary strategies are the mainstay of management in most cases of dyslipidaemia, prior to or simultaneously with the initiation of a lipid-lowering agent. The exact approach differs according to the type of dyslipidaemia. In particular, a reduction in carbohydrates (mainly foods with a high glycaemic index) and their substitution with mono- and polyunsaturated fatty acids is the main strategy in patients with high levels of triglycerides (Tg) and/or low levels of high-density lipoprotein cholesterol (HDL-c). A reduction in saturated and trans fatty acids, combined with an increased intake of specific dietary components, such as plant sterols, soy protein and red yeast rice, constitutes the more efficacious dietary approach in cases where levels of total cholesterol and low-density lipoprotein cholesterol (LDL-c) are elevated. A reduction in excessive body weight is beneficial in every type of dyslipidaemia, whereas increased physical activity is mostly effective in cases with low HDL-c and high Tg levels. With respect to the potential cardiovascular benefit of these dietary interventions, there is currently evidence for the Mediterranean diet. Potential benefit may derive also from single dietary components of that diet, such as legumes, fruits, vegetables, nuts and omega-3 fatty acids, although to a lesser extent than with that general dietary pattern. The purpose of this review is to outline current knowledge regarding the recommended specific dietary pattern according to the type of dyslipidaemia and the evidence for the potential cardiovascular benefits of such approaches.

On type 1 diabetes mellitus pathogenesis

Type 1 diabetes mellitus (T1DM) results from the autoimmune destruction of β cells of the endocrine pancreas. Pathogenesis of T1DM is different from that of type 2 diabetes mellitus, where both insulin resistance and reduced secretion of insulin by the β cells play a synergistic role. We will present genetic, environmental and immunologic factors that destroy β cells of the endocrine pancreas and lead to insulin deficiency. The process of autoimmune destruction takes place in genetically susceptible individuals under the triggering effect of one or more environmental factors and usually progresses over a period of many months to years, during which period patients are asymptomatic and euglycemic, but positive for relevant autoantibodies. Symptomatic hyperglycemia and frank diabetes occur after a long latency period, which reflects the large percentage of β cells that need to be destroyed before overt diabetes become evident.

Hypertension in patients with type 2 diabetes mellitus: Targets and management

Two-thirds of patients with type 2 diabetes mellitus (T2DM) have arterial hypertension. Hypertension increases the incidence of both micro- and macrovascular complications in these patients, while the co-existence of these two major risk factors leads to a four-fold increased risk for cardiovascular disease (CVD) compared with normotensive non-diabetic controls. The aim of this article is to comprehensively review the literature and present updated information on targets for blood pressure (BP) and on the management of hypertension in patients with T2DM. A BP target of <140/90 mmHg applies to most patients, but individualization is always important. All classes of antihypertensive drugs can be used in the management of hypertension in patients with T2DM, as long as they are effective and safe and after taking co-morbidities into account. Angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are the ideal choice for initial or early treatment of hypertension in patients with T2DM and albuminuria. Combination of two or more drugs seems to be inevitable as most of these patients demonstrate resistant hypertension. The combination of ACE inhibitors with ARBs should be avoided. Thiazide and thiazide-like diuretics might be beneficial, alone or in a fixed-dose combination with ACE inhibitors or ARBs. Calcium channel blockers (CCBs) constitute an ideal option as a second- or third-line agent. Beta-blockers are not considered as first-line antihypertensive agents, except for those patients with heart failure or previous myocardial infarction. The addition of mineralocorticoid receptor antagonists to a triple-drug therapy seems the next ideal step. Gender-specific characteristics regarding BP, T2DM and CVD should be taken into consideration, even if different recommendations do not exist yet.

Metformin use during pregnancy: Is it really safe?

Metformin is the first-line drug for the treatment of patients with type 2 diabetes mellitus (T2DM). It is used as an adjunct to diet and physical activity, especially in obese individuals. Although there are suggestions from the UKPDS (UK Prospective Diabetes Study) that metformin lowers the incidence of macrovascular disease, the extent of this effect has been challenged thereafter. Nevertheless, because of its blood glucose-lowering effects, reduction of appetite, and low price, metformin plays an important role in the T2DM treatment strategy. Metformin has been also used extensively for the treatment of women with polycystic ovary syndrome (PCOS), in order to improve insulin sensitivity, reduce androgen overproduction, and improve fertility. The metabolic features of metformin make the it an attractive option for the treatment of women with gestational diabetes mellitus (GDM), the type of diabetes that presents during pregnancy. In this situation, insulin resistance develops due to the effects of placental hormones, and GDM ensues in those women whose β-cells cannot increase their insulin production to keep up with the higher demands. Indeed, several studies have shown that treatment with metformin may efficiently regulate blood glucose levels in GDM and may delay the use of insulin. However, a recent study reported that women randomized to metformin had higher blood glucose levels throughout pregnancy, and a higher percentage of largefor-gestational age (LGA) babies (21% vs 6%) compared with those on insulin therapy. These results highlight not only the effective use of insulin, but also the reluctance to escalate pharmacologic treatment when blood glucose control is not sufficient. A 2011 study had reported higher subcutaneous fat in children exposed to metformin. In addition, metformin use in PCOS pregnancies is associated with a higher risk for the child of being overweight at the age of 4 years. In obese women, metformin had no significant effect on birth weight percentile. A study in 25 children exposed to metformin during the prenatal period reported higher fasting blood glucose and systolic blood pressure, but lower low-density lipoprotein cholesterol than children not exposed to metformin. The question of the safety of metformin for pregnant women and their children then arises, because only few long-term studies have assessed its metabolic effects. However, there are other issues that need our attention too. Briones et al. extensively described the fate of metformin after it leaves our body and how it appears in wastewater and the environment. In this occasion, metformin may act as a real endocrine disruptor. There is evidence that metformin, in a concentration found in the environment, can induce a type of intersex in fish. Metformin can upregulate a number of genes associated with an endocrine-disrupting profile, including those for the androgen receptor, 3βhydroxysteroid dehydrogenase (HSD) and 17β-HSD in the male gonads. Further, metformin reduced testicular weight and testosterone production in prepubertal chickens. Metformin treatment during pregnancy caused changes in the sexual behavior of and reduced the sperm count in the male offspring of female Wistar rats. It must be acknowledged that there is still a lot of debate as to whether animal models do predict the effects of endocrine disruptors in humans. However, the number of reports in which the possible endocrinedisrupting effects of metformin have been studied in humans are very limited, because most, still few, studies have focused on anthropometric measures of the offspring. An in vitro study with human testes showed that metformin reduces testosterone production and testicular development. A study from Finland reported no difference in testicular size between boys whose mothers had been treated with metformin during pregnancy and boys whose mothers had been treated with insulin. However, in that study, the mean age of the boys was only 5 years, and specific data on puberty and the post-pubertal period are lacking. In summary, the use of metformin in GDM is gradually increasing. Arguments in favor of its use are the achievement of stable control, and possibly a reduced need to start insulin injections, which by themselves may mitigate the pregnancy-associated weight gain. The long-term effects of metformin use during pregnancy for the offspring are still unknown, and can only be fully assessed when children exposed to metformin in utero are carefully evaluated once they have reached adulthood. Metformin treatment during pregnancy should still be considered as experimental therapy and, until long-term safety data have been obtained, this must only be performed within the situation of a clinical trial. Providers of research funding should consider financing such long-term studies, or to provide funding for short-term studies with the request for long-term follow-up. It would be a good idea to start an doi: 10.1111/1753-0407.12813 Journal of Diabetes 10 (2018), 984–985

The impact of environmental temperature on the diagnosis of gestational diabetes mellitus

OBJECTIVE To investigate a probable impact of seasons on the diagnosis of GDM, as well as the specific effect of the environmental temperature on the diagnosis of this clinical entity. PATIENTS AND METHODS Two observational studies, one retrospective and one prospective, were conducted in a referral center. Study A included retrospectively 7618 pregnant women who underwent a 3-h 100 g OGTT during the 3rd trimester of gestation. Study B prospectively included 768 pregnant women tested in the 3rd trimester of gestation with a 75 g OGTT. Temperature was recorded every day at 09:00 h. RESULTS Retrospective Study A: GDM prevalence differed significantly by season: winter = 28.1%, summer = 39.2%, spring = 32.4% and autumn = 32.4% (P < 0.0001). The odds ratio for being diagnosed with GDM was much higher during summer 1.65 (95% CI: 1.43-1.90), with spring and autumn following with 1.23 (95% CI: 1.08-1.39) compared to winter. Glucose levels during OGTT were measured: significantly increased blood glucose values were observed at 60, 120 and 180 min in summer, which remained significant after adjustment for age, gestational age, BMI, weight gain during pregnancy and blood pressure. Prospective Study B: At temperatures above 25°C, the average glucose 60-min and 120-min levels were increased. The relative risk for abnormal glucose values at 60 min, when the environmental temperature increased over 25°C, was 2.2 (1.5-3.3). CONCLUSIONS GDM prevalence in Greece presents seasonal variation, with higher risk during summer due to post glucose load level variations. These variations could be attributed to differences in environmental temperature.

Correction to: Adrenocortical incidentalomas and bone: from molecular insights to clinical perspectives

The original version of this article unfortunately contained a mistake in Figure 1. There is a typo in the word “osteoclastogenesis” and the word “activity” is missing in the same entity. It should be “osteoclastogenesis” instead of “osteoclestogenesis”.

Association between age at menopause and fracture risk: a systematic review and meta-analysis

PurposeEarly menopause (EM, age at menopause < 45 years) and premature ovarian insufficiency (POI, age at menopause < 40 years) are associated with an increased risk of osteoporosis. However, their association with increased fracture risk has not been established, with studies yielding conflicting results. The primary aim of this systematic review and meta-analysis was to synthesize studies evaluating the association between age at menopause and fracture risk. The secondary aim was to evaluate this effect concerning the site of fractures.MethodsA comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to 31 January 2018. Data were expressed as odds ratio (OR) with 95% confidence intervals (CI). The I2 index was employed for quantifying heterogeneity.ResultsEighteen studies were included in the qualitative and quantitative analysis (462,393 postmenopausal women, 12,130 fractures). Compared with women with age at menopause > 45 years, women with EM demonstrated higher fracture risk (OR 1.36, 95% CI 1.11–1.66, p < 0.002, I² 81.5%). Women with POI did not display any difference in fracture risk compared either with women with age at menopause > 40 (OR 1.23, 95% CI 0.72–2.09, p = 0.436, I² 62.5%) or >45 years (OR 0.54, 95% CI 0.22–1.29, p = 0.17, I2 0%). No difference was evident when a separate analysis was performed for vertebral, non-vertebral and hip fractures.ConclusionsThis is the first meta-analysis showing that EM is associated with increased fracture risk compared with normal age at menopause, without any distinct effect on the site of the fracture.

Efficacy of anti-osteoporotic medications in patients with type 1 and 2 diabetes mellitus: a systematic review

PurposeBoth type 1 (T1DM) and type 2 diabetes mellitus (T2DM) have been associated with bone fragility and increased fracture risk. However, little is known regarding the effect of anti-osteoporotic treatment on bone mineral density (BMD) and/or fracture risk in these patients. We aimed to systematically investigate the efficacy of anti-osteoporotic medications in patients with diabetes in comparison with non-diabetic subjects.MethodsMEDLINE and Scopus databases were searched (up to 31st October 2017).ResultsNine studies fulfilled the pre-defined inclusion criteria [patients with T2DM (n = 8) or either T1DM or T2DM (n = 1)]. Regarding fracture risk, five studies were identified. Alendronate demonstrated comparable vertebral anti-fracture efficacy in patients with and without diabetes (n = 2), whereas non-vertebral fracture risk was either the same (n = 1) or higher in diabetic patients (n = 1). Raloxifene also demonstrated comparable vertebral anti-fracture efficacy in both groups (n = 2), without any effect on non-vertebral fractures in either group. In one study, diabetic patients exposed to raloxifene demonstrated the same vertebral and non-vertebral fracture risk with non-diabetic patients. Teriparatide (n = 1) demonstrated the same non-vertebral fracture rates in both patients with and without T2DM. Regarding BMD, equal increases in spine BMD were observed with alendronate (n = 4), risedronate (n = 1), and teriparatide (n = 1). With respect to hip BMD, similar increases were observed with teriparatide (n = 1), whereas data regarding alendronate were controversial (n = 3). No eligible study was found for zoledronic acid, ibandronate, strontium ranelate, denosumab, or bazedoxifene.ConclusionsThe presence of diabetes does not alter anti-osteoporotic treatment response, regarding BMD increase and vertebral fracture risk reduction.

Adrenocortical incidentalomas and bone: from molecular insights to clinical perspectives

Adrenal incidentalomas constitute a common clinical problem with an overall prevalence of around 2–3%, but are more common with advancing age being present in 10% of those aged 70 years. The majority of these lesions are benign adrenocortical adenomas (80%), characterized in 10–40% of the cases by autonomous cortisol hypersecretion, and in 1–10% by aldosterone hypersecretion. Several observational studies have shown that autonomous cortisol and aldosterone hypersecretion are more prevalent than expected in patients with osteopenia and osteoporosis: these patients have accelerated bone loss and an increased incidence of vertebral fractures. In contrast to glucocorticoid action, the effects of aldosterone on bone are less well understood. Recent data, demonstrating a concomitant co-secretion of glucocorticoid metabolites in patients with primary aldosteronism, could explain some of the metabolic abnormalities seen in patients with aldosterone hypersecretion. In clinical practice, patients with unexplained osteoporosis, particularly when associated with other features such as impaired glucose tolerance or hypertension, should be investigated for the possible presence of autonomous cortisol or aldosterone secretion due to an adrenal adenoma. Randomized intervention studies are needed, however, to investigate the optimum interventions for osteoporosis and other co-morbidities in these patients.

Menopausal hormone therapy and cardiovascular risk. Where are we now

Transition to menopause is associated with an increase in cardiovascular disease (CVD) risk, mainly attributed to lipid and glucose metabolism dysregulation, as well as to body fat redistribution, leading to abdominal obesity. Indeed, epidemiological evidence suggests that both early menopause (EM, defined as age at menopause <45 years) and premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with 1.5-2-fold increase in CVD risk. Menopausal hormone therapy (MHT) exerts a favorable effect on CVD risk factors (with subtle differences regarding estrogen dose, route of administration, monotherapy or combination with progestogen and type of progestogen). Concerning CVD morbidity and mortality, most studies have shown a beneficial effect of MHT in women at early menopausal age [<10 years since the final menstrual period (FMP)] or younger than 60 years. MHT is strongly recommended in women with EM and POI, as these women, if left untreated, are at risk of CVD, osteoporosis, dementia, depression and premature death. MHT has also a favourable benefit/risk profile in perimenopausal and early postmenopausal women, provided that the patient is not at a high CVD risk (as assessed by 10-year calculation tools). Transdermal estrogens have a lower risk of thrombosis compared with oral regimens. Concerning progestogens, natural progesterone and dydrogesterone has a neutral effect on CVD risk factors. In any case, the decision for MHT should be individualized, tailored according to the symptoms, patient preference and the risk of CVD, thrombotic episodes and breast cancer.