Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial.

BACKGROUND: Pregnant women with type 1 diabetes are a high-risk population who are recommended to strive for optimal glucose control, but neonatal outcomes attributed to maternal hyperglycaemia remain suboptimal. Our aim was to examine the effectiveness of continuous glucose monitoring (CGM) on maternal glucose control and obstetric and neonatal health outcomes. METHODS: In this multicentre, open-label, randomised controlled trial, we recruited women aged 18-40 years with type 1 diabetes for a minimum of 12 months who were receiving intensive insulin therapy. Participants were pregnant (≤13 weeks and 6 days' gestation) or planning pregnancy from 31 hospitals in Canada, England, Scotland, Spain, Italy, Ireland, and the USA. We ran two trials in parallel for pregnant participants and for participants planning pregnancy. In both trials, participants were randomly assigned to either CGM in addition to capillary glucose monitoring or capillary glucose monitoring alone. Randomisation was stratified by insulin delivery (pump or injections) and baseline glycated haemoglobin (HbA1c). The primary outcome was change in HbA1c from randomisation to 34 weeks' gestation in pregnant women and to 24 weeks or conception in women planning pregnancy, and was assessed in all randomised participants with baseline assessments. Secondary outcomes included obstetric and neonatal health outcomes, assessed with all available data without imputation. This trial is registered with ClinicalTrials.gov, number NCT01788527. FINDINGS: Between March 25, 2013, and March 22, 2016, we randomly assigned 325 women (215 pregnant, 110 planning pregnancy) to capillary glucose monitoring with CGM (108 pregnant and 53 planning pregnancy) or without (107 pregnant and 57 planning pregnancy). We found a small difference in HbA1c in pregnant women using CGM (mean difference -0·19%; 95% CI -0·34 to -0·03; p=0·0207). Pregnant CGM users spent more time in target (68% vs 61%; p=0·0034) and less time hyperglycaemic (27% vs 32%; p=0·0279) than did pregnant control participants, with comparable severe hypoglycaemia episodes (18 CGM and 21 control) and time spent hypoglycaemic (3% vs 4%; p=0·10). Neonatal health outcomes were significantly improved, with lower incidence of large for gestational age (odds ratio 0·51, 95% CI 0·28 to 0·90; p=0·0210), fewer neonatal intensive care admissions lasting more than 24 h (0·48; 0·26 to 0·86; p=0·0157), fewer incidences of neonatal hypoglycaemia (0·45; 0·22 to 0·89; p=0·0250), and 1-day shorter length of hospital stay (p=0·0091). We found no apparent benefit of CGM in women planning pregnancy. Adverse events occurred in 51 (48%) of CGM participants and 43 (40%) of control participants in the pregnancy trial, and in 12 (27%) of CGM participants and 21 (37%) of control participants in the planning pregnancy trial. Serious adverse events occurred in 13 (6%) participants in the pregnancy trial (eight [7%] CGM, five [5%] control) and in three (3%) participants in the planning pregnancy trial (two [4%] CGM and one [2%] control). The most common adverse events were skin reactions occurring in 49 (48%) of 103 CGM participants and eight (8%) of 104 control participants during pregnancy and in 23 (44%) of 52 CGM participants and five (9%) of 57 control participants in the planning pregnancy trial. The most common serious adverse events were gastrointestinal (nausea and vomiting in four participants during pregnancy and three participants planning pregnancy). INTERPRETATION: Use of CGM during pregnancy in patients with type 1 diabetes is associated with improved neonatal outcomes, which are likely to be attributed to reduced exposure to maternal hyperglycaemia. CGM should be offered to all pregnant women with type 1 diabetes using intensive insulin therapy. This study is the first to indicate potential for improvements in non-glycaemic health outcomes from CGM use. FUNDING: Juvenile Diabetes Research Foundation, Canadian Clinical Trials Network, and National Institute for Health Research.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY 2016 OUTPATIENT GLUCOSE MONITORING CONSENSUS STATEMENT.

This document represents the official position of the American Association of Clinical Endocrinologists and American College of Endocrinology. Where there were no randomized controlled trials or specific U.S. FDA labeling for issues in clinical practice, the participating clinical experts utilized their judgment and experience. Every effort was made to achieve consensus among the committee members. Position statements are meant to provide guidance, but they are not to be considered prescriptive for any individual patient and cannot replace the judgment of a clinician.

CONCEPTT: Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial: A multi-center, multi-national, randomized controlled trial - Study protocol.

BACKGROUND: Women with type 1 diabetes strive for optimal glycemic control before and during pregnancy to avoid adverse obstetric and perinatal outcomes. For most women, optimal glycemic control is challenging to achieve and maintain. The aim of this study is to determine whether the use of real-time continuous glucose monitoring (RT-CGM) will improve glycemic control in women with type 1 diabetes who are pregnant or planning pregnancy. METHODS/DESIGN: A multi-center, open label, randomized, controlled trial of women with type 1 diabetes who are either planning pregnancy with an HbA1c of 7.0 % to ≤10.0 % (53 to ≤ 86 mmol/mol) or are in early pregnancy (<13 weeks 6 days) with an HbA1c of 6.5 % to ≤10.0 % (48 to ≤ 86 mmol/mol). Participants will be randomized to either RT-CGM alongside conventional intermittent home glucose monitoring (HGM), or HGM alone. Eligible women will wear a CGM which does not display the glucose result for 6 days during the run-in phase. To be eligible for randomization, a minimum of 4 HGM measurements per day and a minimum of 96 hours total with 24 hours overnight (11 pm-7 am) of CGM glucose values are required. Those meeting these criteria are randomized to RT- CGM or HGM. A total of 324 women will be recruited (110 planning pregnancy, 214 pregnant). This takes into account 15 and 20 % attrition rates for the planning pregnancy and pregnant cohorts and will detect a clinically relevant 0.5 % difference between groups at 90 % power with 5 % significance. Randomization will stratify for type of insulin treatment (pump or multiple daily injections) and baseline HbA1c. Analyses will be performed according to intention to treat. The primary outcome is the change in glycemic control as measured by HbA1c from baseline to 24 weeks or conception in women planning pregnancy, and from baseline to 34 weeks gestation during pregnancy. Secondary outcomes include maternal hypoglycemia, CGM time in, above and below target (3.5-7.8 mmol/l), glucose variability measures, maternal and neonatal outcomes. DISCUSSION: This will be the first international multicenter randomized controlled trial to evaluate the impact of RT- CGM before and during pregnancy in women with type 1 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01788527 Registration Date: December 19, 2012.

Trends in the incidence of diabetes, its clinical sequelae, and associated costs in pregnancy.

BACKGROUND: Increasing diabetes prevalence affects a substantial number of pregnant women in the United States. Our aims were to evaluate health outcomes, medical costs, risks and types of complications associated with diabetes in pregnancy for mothers and newborns. METHODS: In this retrospective claims analysis, patients were identified from the Truven Health MarketScan(®) database (2004-2011 inclusive). Participants were aged 18-45 years, with ascertainable diabetes status [Yes/No], date of birth event >2005 and continuous health plan enrolment ≥21 months before and 3 months after the birth. RESULTS: In total, 839 792 pregnancies were identified, and 66 041 (7.86%) were associated with diabetes mellitus [type 1 (T1DM), 0.13%; type 2 (T2DM), 1.21%; gestational (GDM), 6.29%; and GDM progressing to T2DM (patients without prior diabetes who had a T2DM diagnosis after the birth event), 0.23%]. Relative risk (RR) of stillbirth (2.51), miscarriage (1.28) and Caesarean section (C-section) (1.77) was significantly greater with T2DM versus non-diabetes. Risk of C-section was also significantly greater for other diabetes types [RR 1.92 (T1DM); 1.37 (GDM); 1.63 (GDM progressing to T2DM)]. Risk of overall major congenital (RR ≥ 1.17), major congenital circulatory (RR ≥ 1.19) or major congenital heart (RR ≥ 1.18) complications was greater in newborns of mothers with diabetes versus without. Mothers with T2DM had significantly higher risk (RR ≥ 1.36) of anaemia, depression, hypertension, infection, migraine, or cardiac, obstetrical or respiratory complications than non-diabetes patients. Mean medical costs were higher with all diabetes types, particularly T1DM ($27 531), than non-diabetes ($14 355). CONCLUSIONS: Complications and costs of healthcare were greater with diabetes, highlighting the need to optimize diabetes management in pregnancy.

Durability of glycemic control with insulin lispro mix 75/25 versus insulin glargine for older patients with type 2 diabetes.

BACKGROUND AND AIMS: Few studies have evaluated long-term durability of glycemic control in older patients. The aim of this study was to compare durability of glycemic control of twice-daily insulin lispro mix 75/25 (LM75/25; 75 % insulin lispro protamine suspension, 25 % insulin lispro) and once-daily insulin glargine (GL) added to oral antihyperglycemic medications in older patients (≥65 years of age). METHODS: Patients were participants in the maintenance phase of the DURABLE trial. During the initiation phase, patients with type 2 diabetes were randomized to LM75/25 or GL. After 6 months, patients with hemoglobin A1c (HbA1c) ≤7.0 % advanced to the 24-month maintenance phase. The primary objective was between-group comparison of duration of maintaining the HbA1c goal in older patients (≥65 years of age). A similar analysis was conducted for older patients achieving HbA1c ≤6.5 % in the initiation phase. RESULTS: Median time of maintaining HbA1c goal was longer in LM75/25 versus GL (19.6 versus 15.4 months, p = 0.007) and more LM75/25 patients maintained goal versus GL (49.2 versus 30.4 %; p = 0.003). HbA1c reduction from baseline was greater in LM75/25 versus GL (-1.56 ± 0.10 versus -1.24 ± 0.11 %; p = 0.003). Post-meal glucose was significantly lower in LM75/25 versus GL (158.86 ± 3.42 versus 171.67 ± 4.51 mg/dL; p = 0.017). No differences were observed in overall and severe hypoglycemia. LM75/25 patients had higher daily insulin doses (0.41 ± 0.02 versus 0.32 ± 0.02 units/kg/day; p < 0.001) and more weight gain (5.47 ± 0.49 versus 3.10 ± 0.53 kg; p = 0.001). Similar results were generally obtained in older patients with HbA1c ≤6.5 %. CONCLUSIONS: In our evaluation of older patients from a larger trial, LM75/25 appeared to provide longer durability of glycemic control, as well as a greater number of patients maintaining HbA1c goal versus GL.

Proposal for generating new beta cells in a muted immune environment for type 1 diabetes.

BACKGROUND: Over the past decade, many immune tolerance agents have shown promise in the non-obese diabetic mouse model for prevention and reversal of type 1 diabetes but have not been successful in clinical trials among recently diagnosed type 1 patients. The trials from decades ago using Cyclosporine A in significantly lower dosages than used for organ transplantation and in similar dosages that have increased T regulatory cell populations in conditions such as atopic dermatitis, demonstrated very high initial insulin-free remission rates when administered immediately after diagnosis. Over time, all newly diagnosed type 1 patients given Cyclosporine A required insulin. Human trials with immune tolerance agents suggest that in addition to an immune tolerance agent, a beta cell regeneration agent may also be necessary to induce long-lasting remission among patients with recent onset type 1 diabetes. METHODS: A randomized, double-blind prospective trial among recent onset type 1 diabetes patients has been designed using Cyclosporine A and a proton-pump inhibitor, which increases gastrin levels and has been shown to work through the Reg receptor to transform pancreatic duct cells into islets.

The postpartum management of women with gestational diabetes using a continuum model for health care.

Women with gestational diabetes mellitus require a continuum of care before, during, and after pregnancy for optimal management of hyperglycemia. Postpartum education and lifestyle modification should begin during pregnancy, and should continue during the postpartum period. Women should receive education on the long-term risk of type 2 diabetes mellitus, and should be encouraged to breastfeed, engage in regular physical activity, and select a highly effective contraceptive method in preparation for subsequent pregnancy. Postpartum women with gestational diabetes mellitus should be empowered to take ownership of their own health, including knowledge of health indicators such as weight, waist circumference hemoglobin A1C levels, and fasting and postprandial blood glucose levels.

Insulin pumps in pregnancy: using technology to achieve normoglycemia in women with diabetes.

Poorly controlled diabetes before conception and during pregnancy among women with pre-existing diabetes can cause major birth defects and spontaneous abortions, as wells as abnormal fetal growth and development including an offspring who is small or large for gestational age, or predisposed to obesity, type 2 diabetes, and metabolic syndrome in his/her lifetime. Conversely, for a woman with pre-existing diabetes, optimizing blood glucose levels before and during early pregnancy can reduce these risks dramatically. As insulin pump technology has evolved, continuous subcutaneous insulin infusion has become a safe and reliable method for treating diabetes during pregnancy. Although pump therapy is often preferred by patients and some experts, insulin pumps have not yet been shown to be superior to multiple daily injections of insulin during pregnancy. In this review of the literature we focus on the use of insulin pumps in the management of diabetes in pregnancy.

Pregnancy and diabetes management: advances and controversies.

BACKGROUND: The treatment of diabetes in pregnancy has potentially far-reaching benefits for both pregnant women with diabetes and their children and may provide a cost-effective approach to the prevention of obesity, type 2 diabetes mellitus, and metabolic syndrome. Early and accurate diagnosis of diabetes in pregnancy is necessary for optimizing maternal and fetal outcomes. CONTENT: Optimal control of diabetes in pregnancy requires achieving normoglycemia at all stages of a woman's pregnancy, including preconception and the postpartum period. In this review we focus on new universal guidelines for the screening and diagnosis of diabetes in pregnancy, including the 75-g oral glucose tolerance test, as well as the controversy surrounding the guidelines. We review the best diagnostic and treatment strategies for the pregestational and intrapartum periods, labor and delivery, and the postpartum period, and discuss management algorithms as well as the safety and efficacy of diabetic medications for use in pregnancy. SUMMARY: Global guidelines for screening, diagnosis, and classification have been established, and offer the potential to stop the cycle of diabetes and obesity caused by hyperglycemia in pregnancy. Normoglycemia is the goal in all aspects of pregnancy and offers the benefits of decreased short-term and long-term complications of diabetes.

Oral anti-CD3 monoclonal antibody delays diabetes in non-obese diabetic (NOD) mice: effects on pregnancy and offspring--a preliminary report.

BACKGROUND: The objective was to observe the effect of oral anti-CD3 monoclonal antibody (mAb) on non-obese diabetic mice, pregnancy, and offspring. METHODS: Three protocols are classified as: (1) Twenty non-obese diabetic/ShiLtJ female mice were monitored for type 1 diabetes mellitus. If the blood glucose level was ≥ 250 mg/dL, the mice were treated for 8 days with either 50 or 100 µg oral anti-CD3 monoclonal antibody. If the diabetes resolved, the mice were bred. (2) F1 offspring were monitored for diabetes; 15 female mice became diabetic. Non-diabetic F1 female mice were divided into two groups [ten antibody (Ab) and ten control (C)] and bred. Ab female mice were given 100 µg monoclonal antibody before diabetes development and during pregnancy for 6 weeks. (3) Twenty-five F2 Ab and 23 F2 C mice were monitored. At 15-17 weeks, Ab mice, both female and male, were given 100 µg monoclonal antibody for 8 weeks. RESULTS: (1) The diabetes in four female mice treated with 50 µg did not resolve; in three of the six diabetic female mice treated with 100 µg, the diabetes resolved and the mice were bred. The remaining ten non-diabetic female mice were given 100 µg oral monoclonal antibody and then bred. No diabetes developed during pregnancy; 13 litters were born. (2) Three diabetic Ab female mice sustained their pregnancies versus one diabetic C female mouse (p ≤ 0.05). (3) At 30 weeks, six Ab female and three Ab male mice and seven C female and three C male mice developed diabetes. The number of diabetic Ab and C mice was not different; diagnosis age was significantly different-Ab 23.3 ± 5.1 and C 18.8 ± 3.7 weeks (p ≤ 0.05). CONCLUSIONS: In female non-obese diabetic mice, oral anti-CD3 monoclonal antibody was effective in reversing diabetes and allowing pregnancy and extending longevity, but it did not prevent diabetes in the offspring.

Basal insulin analogues in diabetic pregnancy: a literature review and baseline results of a randomised, controlled trial in type 1 diabetes.

As basal insulin analogues are being used off-label, there is a need to evaluate their safety (maternal hypoglycaemia and fetal and perinatal outcomes) and efficacy [haemoglobin A1c(HbA1c), fasting plasma glucose, and maternal weight gain]. The aim of this review is to provide an overview of the current literature concerning basal insulin analogue use in diabetic pregnancy, and to present the design and preliminary, non-validated baseline characteristics of a currently ongoing randomized, controlled, open-label, multicentre, multinational trial comparing insulin detemir with neutral protamine hagedorn insulin, both with insulin aspart, in women with type 1 diabetes planning a pregnancy (n = 306) or are already pregnant (n = 164). Inclusion criteria include type 1 diabetes > 12 months' duration; screening HbA1c ≤ 9.0% (women recruited prepregnancy), or pregnant with gestational age 8-12 weeks and HbA1c ≤ 8.0% at randomization. At confirmation of pregnancy all subjects must have HbA1c ≤ 8.0%. Exclusion criteria include impaired hepatic function, cardiac problems, and uncontrolled hypertension. Subjects are randomized to either insulin detemir or neutral protamine hagedorn insulin, both with prandial insulin aspart. The results are expected mid-2011 with full publications expected later this year. Baseline characteristics show that basal insulin analogues are already frequently used in pregnant women with type 1 diabetes. This study will hopefully elucidate the safety and efficacy of the basal insulin analogue detemir in diabetic pregnancy.

Continuous glucose monitoring during pregnancy.

Diabetes throughout gestation presents challenges that greatly influence maternal and fetal outcomes. Since the degree of maternal hyperglycemia is the most deterministic of these risks, glucose monitoring has become a fundamental tool in the management of diabetes in pregnancy. While most patients with diabetes are in need of improved glucose control, certain circumstances beg for more detailed glucose information than is available by conventional methods alone. In this article, we will review the state of diabetes during pregnancy and the serious outcomes that persist despite the overall improvement in glycemic control today. We will discuss the advantages of incorporating continuous glucose monitoring (CGM), specifically in the treatment of pregnancies complicated by diabetes. In addition to its clinical utility, CGM can advance our understanding and classification of normoglycemia during pregnancy. Demarcation of the normal glucose profile that is present during gestation better defines the therapeutic goals for women with diabetes and ultimately promotes success in pregnancy.

In silico evaluation platform for artificial pancreatic beta-cell development--a dynamic simulator for closed-loop control with hardware-in-the-loop.

BACKGROUND: A critical step in algorithm development for an artificial beta-cell is extensive in silico testing. Computer simulations usually involve only the controller software, leaving untested the hardware elements, including the critical communication interface between the controller and the glucose sensor and insulin pump. METHODS: An in silico simulation platform has been developed that uses all of the components of the clinical system. At the core is a comprehensive in silico population model that covers the variability of principal metabolic parameters observed in vivo, to replace the human subject, with the ability to use historical clinical data. A continuous glucose monitor, in this case either the Abbott Diabetes Care (Alameda, CA) FreeStyle Navigator or the DexCom (San Diego, CA) STS7, is supplied with a glucose signal provided by the simulator. The Insulet (Bedford, MA) OmniPod insulin pump is also interfaced with the simulator to provide insulin delivery data. These hardware elements are an integral part of the system under testing, which also includes the algorithm components. RESULTS: The system is unique in that it uses the same hardware components for simulations as are required in clinical trials, allowing for full-system level verification and validation. With a detailed mathematical model, a suite of patients can be simulated to reflect various conditions. Because all hardware is used, their related limitations are automatically included. CONCLUSIONS: A complete artificial beta-cell evaluation platform was realized with the flexibility to interface various algorithms and patient models, allowing for the systematic analysis of monitoring and control algorithms. The system facilitates a variety of tests and challenges to the software and the component devices, streamlining preclinical validation trials.

New modalities in the treatment of pregnancies complicated by diabetes: drugs and devices.

The development of drugs and devices in the treatment of pregnancies complicated by diabetes is in constant forward progression to compensate for pancreatic beta cell insufficiency. Maternal hyperglycemia during pregnancy is of particular interest due to the severe consequences that surface when a fetus is in development. The drugs that are currently recommended for use during pregnancy include rapid-acting insulin analogs lispro and aspart for meal-related bolus insulin and intermediate-acting NPH for basal insulin. Oral anti-diabetic agents are not recommended for use during pregnancy. Better control may be achieved with the incorporation of real-time glucose sensors and new insulin pumps with hopes of improving pregnancy outcome.

Bolus calculator: a review of four "smart" insulin pumps.

Abstract The use of continuous subcutaneous insulin infusion (CSII) pumps has been gaining popularity since 1979, when the first research report on insulin pumps was published. Insulin pumps-small medical devices that are programmed to infuse insulin through a catheter placed under the skin-are a replacement for multiple daily injections of insulin. They are currently being used by 375,000 people with type 1 diabetes, many of whom prefer CSII to multiple daily injections because of the increased flexibility of diet and exercise, increased convenience and precision when dosing, and better predictability of blood glucose levels that insulin pumps can provide when used correctly. Recent pump manufacturers have engineered a new feature called a bolus calculator, which calculates bolus insulin doses based on input from the pump wearer, which functions to help patients obtain optimum control over blood glucose levels. The bolus calculator takes into account the patient's current blood glucose, target blood glucose, amount of carbohydrate consumed, and other factors such as insulin sensitivity and insulin-to-carbohydrate ratio as well as duration of insulin action ("insulin on board"). Each pump company calculates insulin doses in a slightly different way. This article will review differences in bolus calculator recommendations between four insulin pumps, as well as errors that may occur when using bolus calculators. It will also include an in silico simulation of a meal followed by a snack using multiple insulin decay curves.