NEWS & VIEWS between abnormal heart rate variability and the rate of decline in GFR in patients with or without nephropathy. A third study of the relationship between CAN and GFR was a retrospective longitu­ dinal analysis in 156 patients with T2DM who were normoalbuminuric and normo­ tensive.6 CAN was divided into four cat­ egories: normal; early; definite or severe; or atypical. During a follow-up of 9 years, GFR remained stable in the patients with normal and early patterns but declined in those with definite or severe patterns (mean change –10.3%, P = 0.047). The authors con­ cluded that definite or severe CAN might be associated with subsequent deterioration of renal function in patients with T2DM who are normoalbuminuric and normotensive. In summary, three longitudinal studies have found an association between CAN at baseline and the subsequent rate of decline of eGFR or GFR in patients with T1DM or T2DM. The one study that found no relation­ship between abnormal heart rate variability and rate of decline of GFR showed that CAN is a strong predictor of cardiovascular morbidity and mortality.5 This finding suggests that the develop­ ment of CAN might be associated with subsequent initiation of a decline in GFR and/or cardiovascular morbidity and mortality. However, no evidence supports the con­c ept that CAN is directly linked to the pathogenes­is of GFR decline. One explanation for the differing results in the relationship between CAN and GFR decline is that the methods of assessment of heart rate variability have not been standardized and CAN has been assessed qualitatively rather than quantitatively in most studies. The development in 2012 of a handheld device for calculating heart rate variation7 might simplify serial assessment of cardiac autonomic function and thereby enable identification of CAN at an early stage. Of note, patients with CAN might be asymptomatic for several years before tachycardia, exercise intolerance, postu­ ral hypotension, cardiac dysfunction and di­abetic cardiomyopathy develop.8 Once CAN has been detected, the treat­ ing clinicians need to assess whether gaps exist in the management of blood glucose, blood pressure, lipid profile, obesity, smok­ ing and other factors that might influ­ence cardiac or renal outcomes. Successful pre­vention or slowing of progression of CAN with intensive glycaemic control has been documented in patients with T1DM and T2DM. In patients with T1DM, the 382  |  JULY 2014  |  VOLUME 10

Diabetes Control and Complications Trial showed that intensive glycaemic control reduced the prevalence of abnormal func­ tion of the autonomic nervous system by 53%.9 In the STENO 2 study, multi­factorial intervention in patients with T2DM, hyper­ tension and microalbuminuria reduced the risk of progression of CAN by up to 63%.10 Early detection of CAN might there­fore be used to further motivate patients to comply with a multifactorial approach to the manage­ment of diabetes melli­tus.7 How­e ver, definitive information on the role of cardiac autonomic function as a predic­tor of early decline in GFR awaits the results of a p­lacebo-controlled intervention trial, which has not yet been initiated. In the meantime, regular measurements of albumin­uria and eGFR, coupled if neces­ sary with measurement of GFR, remain the most appro­priate approach for the detec­ tion of early GFR decline in the range of 60–90 ml/min/1.73 m2. Endocrine Centre, Austin Health, Level 2 Centaur Building Repatriation Campus, Heidelberg West, VIC 3081, Australia (G.J.). Department of Endocrinology & Diabetes, St Vincent’s Hospital, 35 Victoria Parade, Fitzroy, Melbourne, VIC 3065, Australia (R.J.M.). Correspondence to: G.J. [email protected] Competing interests The authors declare no competing interests.

1.

Tahrani, A. A. et al. Cardiac autonomic neuropathy predicts renal function decline in patients with type 2 diabetes: a cohort study. Diabetologia 57, 1249–1256 (2014). 2. Vinik, A. I. & Ziegler, D. Diabetic cardiovascular autonomic neuropathy. Circulation 115, 387–397 (2007). 3. Nasrallah, M. P. & Ziyadeh, F. N. Overview of the physiology and pathophysiology of leptin with special emphasis on its role in the kidney. Semin. Nephrol. 33, 54–65 (2013). 4. Sundkvist, G. & Lilja, B. Autonomic neuropathy predicts deterioration in glomerular filtration rate in patients with IDDM. Diabetes Care 16, 773–779 (1993). 5. Astrup, A. S. et al. Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 29, 334–339 (2006). 6. Kim, Y. K. et al. Cardiac autonomic neuropathy as a predictor of deterioration of the renal function in normoalbuminuric, normotensive patients with type 2 diabetes mellitus. J. Korean Med. Sci. 24 (Suppl.), S69–S74 (2009). 7. Gulichsen, E., Fleischer, J., Ejskjaer, N., Eldrup, E. & Tarnow, L. Screening for diabetic cardiac autonomic neuropathy using a new handheld device. J. Diabetes Sci. Technol. 6, 965–972 (2012). 8. Dimitropoulos, G., Tahrani, A. A. & Stevens, M. J. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J. Diabetes 5, 17–39 (2014). 9. [No authors listed] The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group. Ann. Intern. Med. 122, 561–568 (1995). 10. Gaede, P., Vedel, P., Parving, H. H. & Pedersen, O. Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 353, 617–622 (1999).

REPRODUCTIVE ENDOCRINOLOGY

Maternal and fetal insulin levels at birth in women with PCOS Renato Pasquali

Polycystic ovary syndrome is often associated with complications in pregnancy, which metformin does not seem to ameliorate. A recent study has investigated insulin levels in the umbilical venous blood (maternal levels) and umbilical arterial blood (fetal levels). The data seem to suggest the placenta is involved in insulin secretion during pregnancy. Pasquali, R. Nat. Rev. Endocrinol. 10, 382–384 (2014); published online 6 May 2014; doi:10.1038/nrendo.2014.61

Women with polycystic ovary syndrome (PCOS) seem to have an increased risk of complications during pregnancy, includ­ ing miscarriages, gestational diabetes mel­ litus, pregnancy-induced hypertension and preeclampsia as well as adverse neonatal outcomes. 1 Although these associations are still a matter of debate (as a result of the



heterogeneity of most studies), the find­ ings have been replicated in a meta-analysis published in 2013.2 Notably, women preg­ nant as a result of assisted reproduction technologies (especially in vitro fertiliza­ tion techniques) are also at increased risk of complications; however, multiple gesta­ tions, advanced age and underlying PCOS www.nature.com/nrendo

© 2014 Macmillan Publishers Limited. All rights reserved

NEWS & VIEWS are constant confounders of this associa­ tion.3 A new study has now explored the effects of metformin, an insulin-sensitizing drug used in the treatment of type 2 dia­ betes mellitus, on levels of insulin in the mother and fetus.4 In the past 15 years, several retrospec­ tive and nonrandomized studies have been performed to investigate the poten­ tial benefit of metformin in women with PCOS. However, a meta-analysis of ran­ domized controlled trials demonstrated no effect of metformin on the rate of spon­taneous abortions.5 Simi­larly, a ran­ domized ­placebo-controlled ­double-blind multi­centre study has evaluated whether metformin, administered from the first trimester to delivery, could reduce the rate of pregnancy complications in 257 women with PCOS (aged 18–42 years). The study found that although women treated with metformin gained less weight during preg­ nancy than those treated with placebo, no significant difference was detected in the rates of preeclampsia, preterm delivery, ges­ tational diabetes mellitus or low fetal birth weight, which suggests that treatment with metformin from the first tri­mester to deliv­ ery did not reduce pregnancy co­mplications in women with PCOS.6

‘‘

…these findings might reflect placental adaptation and/or factors related to the type of delivery

’’

On the basis of these data, the Endocrine Society Clinical Practice Guideline on diagnosis and treatment of PCOS that was published in 2013 concluded that, at present, the routine use of metformin during pregnancy in women with PCOS is unwarranted and metformin should be discontinued if a woman has a positive pregnancy test.7 Now, new data on a sub­ group of women with PCOS participating in a double-blind randomized controlled trial5 have been analysed to investigate the potential effect of metformin on insulin concentrations in the peripheral venous maternal blood and arterial and venous umbilical cord blood immediately after birth and the possi­ble association between maternal and fetal insu­lin concentrations.4 This study found that at delivery women treated with metformin (n = 57) had lower insulin concentrations than those receiv­ ing placebo (n = 61). In addition, reduced

insulin levels were only observed in women receiving metformin who had a vaginal delivery; insulin levels were not reduced in those who underwent operative deliv­ ery. More interest­ingly, the researchers also observed that the two groups had similar levels of insu­lin in the umbilical venous blood (that is, the mother’s blood) and in the ar­terial blood (that is, blood from the fetus) and similar arterio–venous differ­ ences. However, for each mother–neonate pair, insulin values were higher in blood from the umbilical vein than in that from the umbilical artery, regardless of whether metformin or placebo was given (totals for both treatment groups, 70 ± 51 pmol/l versus 45 ± 48 pmol/l; P 97,000 visits to emergency departments in the USA each year. Patients with diabetes mellitus aged >80 years have twice the rate of such visits than those in midlife, highlighting the need to improve management strategies for elderly patients with diabetes mellitus. Moheet, A. & Seaquist, E. R. Nat. Rev. Endocrinol. 10, 384–385 (2014); published online 6 May 2014; doi:10.1038/nrendo.2014.67

Iatrogenic hypoglycaemia is a common adverse effect of insulin therapy for patients with diabetes mellitus. Hypoglycaemic events are associated with considerable mor­ bidity, which can limit the ability of patients to achieve a level of glycaemic control that can prevent long-term complications of dia­ betes mellitus. Hypoglycaemic events can also be fatal. In addition, these events are a common cause of visits to the emergency department and subsequent hospitalizations, as demonstrated in a recent study by Geller and colleagues.1 These episodes of hypo­ glycaemia, which are costly with respect to both health-care resources and patient outcomes, are presumably avoidable. The responsibility lies with clinicians to effec­ tively manage treatment protocols to pre­vent patients from having such severe hypo­ glycaemia that they require the as­sistance of emergency personnel. In their investigation, Geller and col­ leagues used data from two nationally rep­ resentative surveys to estimate the rates of 384  |  JULY 2014  |  VOLUME 10

‘‘

Glycaemic targets and diabetic therapy should be individualized...

’’

insulin-related hypoglycaemia that resulted in visits to emergency departments and subsequent hospitalizations in the USA between 1 January 2007 and 31 December 2011. Data to estimate the number of visits to emergency departments and hospitaliza­ tions due to insulin-related hypoglycaemia were taken from the National Electronic Injury Surveillance System–Cooperative Adverse Drug Event Surveillance Project.2 The National Health Interview Survey was used to estimate the total number of patients with diabetes mellitus who were treated with insulin or an oral antidiabetic agent.3 From these data, Geller and col­ leagues estimated that >97,000 visits to emer­gency departments resulted from iatro­ genic hypo­glycaemia each year, which rep­ resents almost 10% of all of the emer­gency



department visits as a result of adverse drug reactions during the period of the survey. The number of visits was particularly high in the elderly. In patients taking insulin, those ≥80 years old were more than twice as likely as those aged 45–64 years to visit the emergency department (rate ratio of 2.5; 95% CI 1.5–4.3) and nearly five times more likely to then be hospitalized (rate ratio of 4.9; 95% CI 2.6–9.1) as a result of a hypo­glycaemic episode. The most common reasons identified for patients having experi­ enced a hypoglycaemic event were reduced food intake and administration of the wrong insulin product. This important and clinically relevant finding agrees with those of previous studies, which have shown that the numbers of emergency department visits related to hypoglycaemia are higher in older patients with diabetes mellitus than in the general population with diabetes mellitus.4 The work also complements a study by Fu and co-workers, in which one in four hospital admissions of patients with type 2 diabetes mellitus (T2DM) was found to be related to hypoglycaemia, and statistically significant associations were found with age >65 years and with the use of insulin.5 The risk of hypoglycaemia is believed to be increased in patients striving to achieve near-normal glycaemic levels; however, few clinical trials have examined the risks and benefits of intensive glycaemic control in patients with diabetes mellitus >70 years old.4 Large clinical trials in patients with dia­betes mellitus have demonstrated bene­ ficial effects of intensive glycaemic con­trol on rates of microvascular complica­tions; how­ever, these results are not directly appli­ c­able to patients >70 years old with dia­betes mellitus and multiple comorbidities. The Action to Control Cardiovascu­lar Risk in Diabetes (ACCORD) trial6 was designed to study the effects of inten­sive glycaemic control (targeting circulat­ing levels of HbA1c