Rhonda Bentley-Lewis

Gestational diabetes mellitus: postpartum opportunities for the diagnosis and prevention of type 2 diabetes mellitus

Gestational diabetes mellitus (GDM) affects approximately 4% of all pregnant women in the US and represents 90% of all cases of diabetes mellitus diagnosed during pregnancy. In addition to the adverse pregnancy outcomes associated with this complication, a history of GDM predisposes women to the future development of type 2 diabetes mellitus (T2DM). Incidence rates of GDM are increasing in the US. As a consequence, a growing number of women are now at increased risk for T2DM. Opportunities to diagnose and prevent T2DM in women with a history of GDM include early diagnosis by postpartum screening and implementation of diabetes prevention measures. In this Review, we discuss current guidelines for postpartum screening, how they might be implemented, and who should take responsibility for screening individuals at risk of T2DM. In addition, we describe measures to prevent the onset of T2DM in women with a history of GDM, focusing on lifestyle modifications, such as diet and breast-feeding.

The metabolic syndrome in women

The metabolic syndrome is estimated to be present in 47 million US residents with a similar age-adjusted prevalence in men (24%) and women (23%). The consideration of various metabolic risk factors as a single entity in the metabolic syndrome provides clinicians with a tool by which they can identify a population at increased risk for type 2 diabetes mellitus and increased cardiovascular morbidity and mortality. Cardiovascular disease is the leading cause of mortality in women in the US. To reduce the risk of cardiovascular disease, efforts have focused on modifying the metabolic risk factors that constitute the metabolic syndrome: abdominal obesity, dyslipidemia, glucose intolerance, and hypertension. In addition, because of several circumstances specific to women, including pregnancy, polycystic ovary syndrome, oral contraceptive therapy use, and menopause, there are special considerations regarding risk factor identification, modification, and clinical management. This article provides a review of diagnostic and therapeutic issues that clinicians should consider when caring for women at risk for developing or diagnosed with the metabolic syndrome.

Rationale, design, and baseline characteristics in evaluation of LIXisenatide in Acute Coronary Syndrome, a long-term cardiovascular end point trial of lixisenatide versus placebo

BACKGROUND Cardiovascular (CV) disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Furthermore, patients with T2DM and acute coronary syndrome (ACS) have a particularly high risk of CV events. The glucagon-like peptide 1 receptor agonist, lixisenatide, improves glycemia, but its effects on CV events have not been thoroughly evaluated. METHODS ELIXA (www.clinicaltrials.gov no. NCT01147250) is a randomized, double-blind, placebo-controlled, parallel-group, multicenter study of lixisenatide in patients with T2DM and a recent ACS event. The primary aim is to evaluate the effects of lixisenatide on CV morbidity and mortality in a population at high CV risk. The primary efficacy end point is a composite of time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Data are systematically collected for safety outcomes, including hypoglycemia, pancreatitis, and malignancy. RESULTS Enrollment began in July 2010 and ended in August 2013; 6,068 patients from 49 countries were randomized. Of these, 69% are men and 75% are white; at baseline, the mean ± SD age was 60.3 ± 9.7 years, body mass index was 30.2 ± 5.7 kg/m(2), and duration of T2DM was 9.3 ± 8.2 years. The qualifying ACS was a myocardial infarction in 83% and unstable angina in 17%. The study will continue until the positive adjudication of the protocol-specified number of primary CV events. CONCLUSION ELIXA will be the first trial to report the safety and efficacy of a glucagon-like peptide 1 receptor agonist in people with T2DM and high CV event risk.

Late Cardiovascular Consequences of Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM), defined as carbohydrate intolerance of any degree first recognized during pregnancy, complicates approximately 4% of all pregnancies in the United States. Several factors can increase ones risk of developing GDM, including obesity, family history of type 2 diabetes mellitus (T2DM), and race/ethnicity. Conversely, a history of GDM can increase the risk of developing not only T2DM but also cardiovascular disease (CVD) independent of a diagnosis of T2DM. Several investigations have explored GDM relationships with CVD risk factors, CVD surrogate markers, and clinically evident CVD. These studies have included evaluations of biochemical parameters, such as inflammatory and endothelial biomarkers; endothelial dysfunction, such as that seen in impaired brachial artery flow-mediated vasodilation; and vascular dysfunction, manifest as cardiac dysfunction or in diseases such as hypertension. This article will review these studies and examine factors considered to be responsible for promoting CVD in women with a history of GDM, such as T2DM and metabolic syndrome and its components. In addition, studies evidencing CVD in women with a history of GDM will be explored.

Barriers to follow-up for women with a history of gestational diabetes.

Women with gestational diabetes (GDM) are at increased risk for type 2 diabetes (T2DM), but many do not receive recommended follow-up. We sought to identify barriers to follow-up screening. We surveyed primary care providers (PCPs) and obstetric and gynecology care providers (OBCPs) in a large health system. We also assessed documentation of GDM history in the health care systems electronic medical record. Four hundred seventy-eight clinicians were surveyed, among whom 207 responded. Most participants (81.1%) gave an accurate estimate of risk of progression to T2DM. PCPs were less likely than OBCPs to ask patients about history of GDM (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.20 to 0.90), but they were far more likely to indicate that they order glucose screening for women with a known history (OR 4.31, 95% CI 2.01 to 9.26). Providers identified poor communication between OBCPs and PCPs as a major barrier to screening. Fewer than half (45.8%) of 450 women with GDM by glucose tolerance test criteria had that history documented on their electronic problem list. Clinicians are aware that women with GDM are at high risk of developing type 2 diabetes, but they do not routinely assess and screen patients, and communication between OBCPs and PCPs can be improved.

A systematic review of metabolite profiling in gestational diabetes mellitus

Aims/hypothesisGestational diabetes mellitus is associated with adverse maternal and fetal outcomes during, as well as subsequent to, pregnancy, including increased risk of type 2 diabetes and cardiovascular disease. Because of the importance of early risk stratification in preventing these complications, improved first-trimester biomarker determination for diagnosing gestational diabetes would enhance our ability to optimise both maternal and fetal health. Metabolomic profiling, the systematic study of small molecule products of biochemical pathways, has shown promise in the identification of key metabolites associated with the pathogenesis of several metabolic diseases, including gestational diabetes. This article provides a systematic review of the current state of research on biomarkers and gestational diabetes and discusses the clinical relevance of metabolomics in the prediction, diagnosis and management of gestational diabetes.MethodsWe conducted a systematic search of MEDLINE (PubMed) up to the end of February 2014 using the key term combinations of ‘metabolomics,’ ‘metabonomics,’ ‘nuclear magnetic spectroscopy,’ ‘mass spectrometry,’ ‘metabolic profiling’ and ‘amino acid profile’ combined (AND) with ‘gestational diabetes’. Additional articles were identified through searching the reference lists from included studies. Quality assessment of included articles was conducted through the use of QUADOMICS.ResultsThis systematic review included 17 articles. The biomarkers most consistently associated with gestational diabetes were asymmetric dimethylarginine and NEFAs. After QUADOMICS analysis, 13 of the 17 included studies were classified as ‘high quality’.Conclusions/interpretationExisting metabolomic studies of gestational diabetes present inconsistent findings regarding metabolite profile characteristics. Further studies are needed in larger, more racially/ethnically diverse populations.

Ovarian Hypertension: Polycystic Ovary Syndrome

Hypertension is a significant contributor to the risk for cardiovascular disease. The increased prevalence of hypertension in women with polycystic ovary syndrome (PCOS) may contribute to the increased risk of cardiovascular disease in these women. Whether hypertension is associated with PCOS independent of obesity remains controversial. Nevertheless, detection and subsequent treatment of hypertension in this population should decrease the adverse sequelae from hypertensive cardiovascular disease. Treatment of risk factors inherent to PCOS, such as hyperandrogenism, insulin resistance, and obesity, may minimize the risk not only for the development of hypertension but also for incident cardiovascular disease independent of hypertension.

Effect of Race/Ethnicity on Hypertension Risk Subsequent to Gestational Diabetes Mellitus

Gestational diabetes mellitus (GDM) prevalence is greater in racially/ethnically diverse groups compared with non-Hispanic white populations. Although race has been shown to modify other cardiovascular disease risk factors in postpartum women, the role of race/ethnicity on GDM and subsequent hypertension has yet to be examined. The aim of this study was to evaluate the impact of race/ethnicity in relation to GDM and subsequent hypertension in a retrospective analysis of women who delivered at Massachusetts General Hospital from 1998 to 2007. Multivariate analyses were used to determine the associations between GDM and (1) race/ethnicity, (2) hypertension, and (3) the interaction with hypertension and race/ethnicity. Women were monitored for a median of 3.8 years from the date of delivery. In our population of 4,010 women, GDM was more common in nonwhite participants (p<0.0001). GDM was also associated with hypertension subsequent to delivery after adjusting for age, race, parity, first-trimester systolic blood pressure, body mass index, maternal gestational weight gain, and preeclampsia (hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.28 to 2.37, p=0.0004). Moreover, Hispanic (HR 3.25, 95% CI 1.85 to 5.72, p<0.0001) and white (HR 1.68, 95% CI 1.10 to 2.57, p=0.02) women with GDM had greater hypertension risk relative to their race/ethnicity-specific counterparts without GDM in race-stratified multivariable analyses. In conclusion, Hispanic women compared with white women have an increased risk of hypertension. Hispanic and white women with GDM are at a greater risk for hypertension compared with those without GDM. Because the present study may have had limited power to detect effects among black and Asian women with GDM, further research is warranted to elucidate the need for enhanced hypertension risk surveillance in these young women.

Gestational diabetes mellitus: an opportunity of a lifetime.

Gestational diabetes mellitus is defined as carbohydrate intolerance of any degree that begins or is first recognized during pregnancy.1 It complicates approximately 4% of all pregnancies in the United States1 and 3-5% in the United Kingdom.2 Notably, variable prevalence rates between 1-14%1 have been reported due to factors including differences in the diagnostic criteria used to define both gestational diabetes and Type 2 diabetes mellitus,3-6 as well as the heterogeneous racial/ethnic populations studied.7 Despite controversy over diagnostic criteria, the risks associated with gestational diabetes in pregnancy have been well-recognized. These have included neonatal risks such as macrosomia, maternal risks such as increased Cesarean delivery rate,8 and their respective comorbidities. Additionally, the impact of gestational diabetes after the pregnancy has been appreciated. The incidence rate of Type 2 diabetes after a pregnancy complicated by gestational diabetes has ranged from 2.6% to over 70% in studies examining women from 6 weeks to 28 years postpartum.9 Difficulty in precisely defining the incidence of Type 2 diabetes in women with a history of gestational diabetes has been attributed to factors such as varied diagnostic criteria for both gestational diabetes and Type 2 diabetes,3-6 insulin use during pregnancy, longer periods of postpartum follow-up,9 as well as missed opportunities in identifying and diagnosing these women through education and screening efforts.10 In today’s Lancet, Leanne Bellamy and colleagues11 report findings from their meta-analysis of cohort studies examining the correlation between gestational diabetes and subsequent development of Type 2 diabetes. Their analysis included 20 studies representing 675,455 women and 10,859 cases of Type 2 diabetes. They observed a nearly 7.5 fold increased risk of developing Type 2 diabetes for women who had gestational diabetes during pregnancy. Moreover, when considering the duration of follow-up, women within 5 years of a pregnancy complicated by gestational diabetes had a relative risk of 4.69 which more than doubled to 9.34 among women who were examined more than 5 years postpartum. Because of differences in diagnostic criteria for both gestational diabetes and Type 2 diabetes across studies, as well as variable distributions of gestational diabetes risk factors among the studies, the authors conducted several subgroup analyses in order to discover potential sources of heterogeneity. They did not uncover heterogeneity resulting from duration of follow-up, ethnicity, maternal age, maternal BMI during pregnancy or postpartum, or diagnostic criteria for gestational diabetes and Type 2 diabetes. However, other potential sources of heterogeneity were not examined in subgroup analyses, possibly due to an inability to gather complete data in the setting of a meta-analysis. Parity is potentially a risk factor for both gestational diabetes12 and Type 2 diabetes13 and is often handled as an adjusted covariate in the setting of a multivariate analysis. Therefore, dichotomizing this parameter, if parity data could indeed be captured from the relevant studies, may provide insight into sources of heterogeneity. Additionally, lifestyle information, which cannot always be gleaned from study descriptions of patient characteristics, would also provide beneficial information when considering sources of heterogeneity. For example, lactation has been demonstrated to decrease the risk of developing Type 2 diabetes among women with a history of gestational diabetes.14 Nevertheless, I recognize that a meta-analysis is inherently limited by the data contained in the studies under examination and, given the significant multicollinearity among risk factors for gestational diabetes and Type 2 diabetes, teasing out specific attributable risk will prove challenging if not impossible. Sufficient evidence has been accumulated to support the assertion that gestational diabetes is a harbinger of Type 2 diabetes in women who are presumably predisposed to Type 2 diabetes and are faced with the metabolic challenges of pregnancy. The current task is to ensure that this information is disseminated to clinicians, and that they use this information to target women who have experienced gestational diabetes for Type 2 diabetes prevention efforts. Consequently, future studies should address how the progression from gestational diabetes to Type 2 diabetes can be arrested in order to develop evidence-based approaches to the health care of this population. Given the compelling data evidencing the link between gestational diabetes and the development of Type 2 diabetes, we as clinicians are afforded the rare opportunity to alter the natural course of disease and impact a woman’s future health today. Carpe diem!

Metabolomic analysis reveals amino-acid responses to an oral glucose tolerance test in women with prior history of gestational diabetes mellitus

Objective Although gestational diabetes mellitus (GDM) is associated with an increased risk of type 2 diabetes mellitus (T2DM) compared to normoglycemic pregnancies, the biochemical pathways underlying the progression of GDM to T2DM are not fully elucidated. The purpose of this exploratory study was to utilize metabolomics with an oral glucose tolerance test (OGTT) to examine the amino acid response in women with prior GDM to determine if a relationship between these metabolites and established risk factors for T2DM exists. Materials/methods Thirty-eight non-pregnant women without diabetes but with prior GDM within the previous 3 years were recruited from a community-based population. A 75 g-OGTT was administered; fasting and 2-h plasma samples were obtained. Metabolite profiles of 23 amino acids or amino acid derivatives were measured with gas chromatography-mass spectrometry. Measures of insulin resistance were derived from the OGTT and risk factors for T2DM were obtained by self-report. Results Twenty-two metabolite levels decreased significantly in response to the OGTT (p < 0.05). The clinical covariates most powerfully associated with metabolite level changes included race, body mass index (BMI), and duration of prior breastfeeding, (mean ± SD of standardized β-coefficients, β = −0.38 ± 0.05, 0.25 ± 0.08, and 0.44 ± 0.03, respectively, all p < 0.05). Notably, a prior history of breastfeeding was associated with the greatest number of metabolite changes. Conclusions Greater change in metabolite levels after a glucose challenge was significantly associated with a longer duration of breastfeeding and higher BMI. Further exploration of these preliminary observations and closer examination of the specific pathways implicated are warranted.