Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden

Objective To examine the association between maternal type 1 diabetes and the risk of major birth defects according to levels of glycated haemoglobin (HbA1C) within three months before or after estimated conception.

Design Population based historical cohort study using nationwide health registers.

Setting Sweden, 2003-15.

Participants 2458 singleton liveborn infants of mothers with type 1 diabetes and a glycated haemoglobin measurement within three months before or after estimated conception and 1 159 865 infants of mothers without diabetes.

Main outcome measures Major cardiac and non-cardiac birth defects according to glycated haemoglobin levels.

Results 122 cases of major cardiac defects were observed among 2458 infants of mothers with type 1 diabetes. Compared with 15 cases of major cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 33 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 2.17, 95% confidence interval 1.37 to 3.42), 49 per 1000 for 6.5% to <7.8% (3.17, 2.45 to 4.11), 44 per 1000 for 7.8% to <9.1% (2.79, 1.90 to 4.12), and 101 per 1000 for ≥9.1% (6.23, 4.32 to 9.00). The corresponding adjusted risk differences were 17 (5 to 36), 32 (21 to 46), 26 (13 to 46), and 77 (49 to 118) cases of major cardiac defects per 1000 infants, respectively. 50 cases of major non-cardiac defects were observed among infants of mothers with type 1 diabetes. Compared with 18 cases of major non-cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 22 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 1.18, 0.68 to 2.07), 19 per 1000 for 6.5% to <7.8% (1.01, 0.66 to 1.54), 17 per 1000 for 7.8% to <9.1% (0.89, 0.46 to 1.69), and 32 per 1000 for ≥9.1% (1.68, 0.85 to 3.33).

Conclusion Among liveborn infants of mothers with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects. Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only.

Reference:  BMJ 2018;362:k2638

Advertisements

Real-time continuous glucose monitoring in adults with type 1 diabetes and impaired hypoglycaemia awareness or severe hypoglycaemia treated with multiple daily insulin injections (HypoDE)

Background

The effectiveness of real-time continuous glucose monitoring (rtCGM) in avoidance of hypoglycaemia among high-risk individuals with type 1 diabetes treated with multiple daily insulin injections (MDI) is unknown. We aimed to ascertain whether the incidence and severity of hypoglycaemia can be reduced through use of rtCGM in these individuals.

Methods

The HypoDE study was a 6-month, multicentre, open-label, parallel, randomised controlled trial done at 12 diabetes practices in Germany. Eligible participants had type 1 diabetes and a history of impaired hypoglycaemia awareness or severe hypoglycaemia during the previous year. All participants wore a masked rtCGM system for 28 days and were then randomly assigned to 26 weeks of unmasked rtCGM (Dexcom G5 Mobile system) or to the control group (continuing with self-monitoring of blood glucose). Block randomisation with 1:1 allocation was done centrally, with the study site as the stratifying variable. Masking of participants and study sites was not possible. Control participants wore a masked rtCGM system during the follow-up phase (weeks 22–26). The primary outcome was the baseline-adjusted number of hypoglycaemic events (defined as glucose ≤3·0 mmol/L for ≥20 min) during the follow-up phase. The full dataset analysis comprised participants who wore the rtCGM system during the baseline and follow-up phases. The intention-to-treat analysis comprised all randomised participants. This trial is registered with ClinicalTrials.gov, number NCT02671968.

Findings

Between March 4, 2016, and Jan 12, 2017, 149 participants were randomly assigned (n=74 to the control group; n=75 to the rtCGM group) and 141 completed the follow-up phase (n=66 in the control group, n=75 in the rtCGM group). The mean number of hypoglycaemic events per 28 days among participants in the rtCGM group was reduced from 10·8 (SD 10·0) to 3·5 (4·7); reductions among control participants were negligible (from 14·4 [12·4] to 13·7 [11·6]). Incidence of hypoglycaemic events decreased by 72% for participants in the rtCGM group (incidence rate ratio 0·28 [95% CI 0·20–0·39], p<0·0001). 18 serious adverse events were reported: seven in the control group, ten in the rtCGM group, and one before randomisation. No event was considered to be related to the investigational device.

Interpretation

Usage of rtCGM reduced the number of hypoglycaemic events in individuals with type 1 diabetes treated by MDI and with impaired hypoglycaemia awareness or severe hypoglycaemia.

Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes

BACKGROUND

In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium–glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes.

METHODS

In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin.

RESULTS

A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, −0.46 percentage points), weight (−2.98 kg), systolic blood pressure (−3.5 mm Hg), and mean daily bolus dose of insulin (−2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively).

CONCLUSIONS

Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035.)

Reference: N Engl J Med 2017; 377:2337-2348 December 14, 2017

Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes

Question  Can oral insulin delay or prevent clinically diagnosed type 1 diabetes?

Findings  In this randomized clinical trial that included 389 participants in the primary analysis who were first- and second-degree relatives of patients with type 1 diabetes, oral insulin compared with placebo did not significantly reduce the risk of diabetes onset over a median of 2.7 years (insulin group, 28.5% and placebo group, 33%; hazard ratio, 0.87).

Meaning  Oral insulin as used in this study was not effective in prevention of type 1 diabetes.

Reference: JAMA. 2017;318(19):1891-1902.

Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT)

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.

Reference: The Lancet, Volume 390, No. 10110, p2347–2359, 25 November 2017

ACE Inhibitors and Statins in Adolescents with Type 1 Diabetes

BACKGROUND

Among adolescents with type 1 diabetes, rapid increases in albumin excretion during puberty precede the development of microalbuminuria and macroalbuminuria, long-term risk factors for renal and cardiovascular disease. We hypothesized that adolescents with high levels of albumin excretion might benefit from angiotensin-converting–enzyme (ACE) inhibitors and statins, drugs that have not been fully evaluated in adolescents.

METHODS

We screened 4407 adolescents with type 1 diabetes between the ages of 10 and 16 years of age and identified 1287 with values in the upper third of the albumin-to-creatinine ratios; 443 were randomly assigned in a placebo-controlled trial of an ACE inhibitor and a statin with the use of a 2-by-2 factorial design minimizing differences in baseline characteristics such as age, sex, and duration of diabetes. The primary outcome for both interventions was the change in albumin excretion, assessed according to the albumin-to-creatinine ratio calculated from three early-morning urine samples obtained every 6 months over 2 to 4 years, and expressed as the area under the curve. Key secondary outcomes included the development of microalbuminuria, progression of retinopathy, changes in the glomerular filtration rate, lipid levels, and measures of cardiovascular risk (carotid intima–media thickness and levels of high-sensitivity C-reactive protein and asymmetric dimethylarginine).

RESULTS

The primary outcome was not affected by ACE inhibitor therapy, statin therapy, or the combination of the two. The use of an ACE inhibitor was associated with a lower incidence of microalbuminuria than the use of placebo; in the context of negative findings for the primary outcome and statistical analysis plan, this lower incidence was not considered significant (hazard ratio, 0.57; 95% confidence interval, 0.35 to 0.94). Statin use resulted in significant reductions in total, low-density lipoprotein, and non–high-density lipoprotein cholesterol levels, in triglyceride levels, and in the ratio of apolipoprotein B to apolipoprotein A1, whereas neither drug had significant effects on carotid intima–media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy. Overall adherence to the drug regimen was 75%, and serious adverse events were similar across the groups.

CONCLUSIONS

The use of an ACE inhibitor and a statin did not change the albumin-to-creatinine ratio over time. (Funded by the Juvenile Diabetes Research Foundation and others; AdDIT ClinicalTrials.gov number, NCT01581476.)

Effect of Insulin Degludec vs Insulin Glargine U100 on Hypoglycemia in Patients With Type 1 Diabetes The SWITCH 1 Randomized Clinical Trial

Question  Is the rate of hypoglycemia noninferior or lower with insulin degludec vs insulin glargine U100 in insulin-treated patients with type 1 diabetes?

Findings  In this randomized crossover trial of 501 patients, insulin degludec compared with insulin glargine U100 resulted in a significantly lower rate of overall symptomatic hypoglycemic episodes over a 16-week maintenance period (2201 vs 2463 episodes per 100 patient-years of exposure).

Meaning  Patients with type 1 diabetes treated with insulin degludec, compared with insulin glargine U100, had a reduced risk of overall symptomatic hypoglycemia.

Reference: JAMA. 2017;318(1):33-44.