Abstract
Introduction
This year's edition of the yearbook article focused on the pediatric age group we have 16 articles selected from many meritorious publications in the past year. There is a common theme of rapid advancement of diabetes technology in this age group, not only in research studies, but now also a translation to clinical implementation that is beginning to transform how pediatric diabetes care is delivered. Several articles advance our knowledge on continuous glucose monitoring (CGM) from registry studies documenting the increase in use in pediatrics to the use of remote monitoring, which is extremely well received in parents of children with diabetes. Data are accumulating on intermittently scanned CGM and CGM with real time alarms and remote notifications. Just as the field once transitioned from urine glucose testing to blood glucose testing, we now find ourselves in a transition to CGM. One open question is how soon after diagnosis of diabetes should CGM be started? Another concern is how to provide access to CGM to the pediatric population who would like to use this technology but may not be able to do so currently due to a lack of insurance or healthcare policy. Data are clear that use of CGM is associated with lower glycosylated hemoglobin (HbA1c) levels and increases in its use are a strong argument that these systems are desired by patients and their families. With the development of closed-loop delivery systems, access to diabetes technology in the pediatric population remains an important objective that will increase in urgency as data accumulate on its ability to control glycemia and reduce burden of care.
Numerous closed-loop insulin delivery studies are presented that range from advances in predicted low glucose suspend options, now clinically available for the pediatric population, to applications of hybrid closed-loop systems in adolescents with elevated HbA1c, very young children (1–7 years old), and development of new systems that will increase competition and add choice for our patients and their families. In addition, new medications have become available to treat type 2 diabetes (T2D) in youth to add to the options of metformin and insulin. Further advances in the care of youth with T2D are a major public health concern for the present and future.
To select these 16 articles focused on diabetes technology and therapeutics in the pediatric age group, we conducted a Medline search for articles dealing with the following topics: diabetes technology, insulin pump therapy (CSII), continuous glucose monitoring (CGM), closed-loop systems, and new therapies in type 1 and type 2 diabetes (T1D and T2D) relating to the pediatric age group (0–18 years). We focused on key articles that offer some insight into these issues and were published between July 1, 2018 and June 30, 2019.
Key Articles Reviewed for the Article
Battelino T, Deeb LC, Ekelund M, Kinduryte O, Klingensmith GJ, Kocova M, Kovarenko M, Shehadeh N
Blair JC, McKay A, Ridyard C, Thornborough K, Bedson E, Peak M, Didi M, Annan F, Gregory JW, Hughes DA, Gamble C for the SCIPI investigators
Hansen EA, Klee P, Dirlewanger M, Bouthors T, Elowe‐Gruau E, Stoppa‐Vaucher S, Phan‐Hug F, Antoniou MC, Pasquier J, Dwyer AA, Pitteloud N, Hauschild M
Messaaoui A, Tenoutasse S, Crenier L
Mulinacci G, Alonso GT, Snell‐Bergeon JK, Shah VN
Burckhardt MA, Roberts A, Smith GJ, Abraham MB, Davis EA, Jones TW
DeSalvo DJ, Miller KM, Hermann JM, Maahs DM, Hofer SE, Clements MA, Lilienthal E, Sherr JL, Tauschmann M, Holl RW; on behalf of the T1D Exchange and DPV Registries.
Wood MA, Shulman DI, Forlenza GP, Bode BW, Pinhas‐Hamiel O, Buckingham BA, Kaiserman KB, Liljenquist DR, Bailey TS, Shin J, Huang S, Chen X, Cordero TL, Lee SW, Kaufman FR
Biester T, Nir J, Remus K, Farfel A, Muller I, Biester S, Atlas E, Dovc K, Bratina N, Kordonouri O, Battelino T, Philip M, Danne T, Nimri R
Tauschmann M, Thabit H, Bally L, Allen JM, Hartnell S, Wilinska ME, Ruan Y, Sibayan J, Kollman C, Cheng P, Beck RW, Acerini CL, Evans ML, Dunger DB, Elleri D, Campbell F, Bergenstal RM, Criego A, Shah VN, Leelarathna L, Hovorka R; on behalf of the APCam11 Consortium
Forlenza GP, Pinhas‐Hamiel O, Liljenquist DR, Shulman DI, Bailey TS, Bode BW, Wood MA, Buckingham BA, Kaiserman KB, Shin J, Huang S, Lee SW, Kaufman FR
de Bock M, Dart J, Hancock M, Smith G, Davis EA, Jones TW
Forlenza GP, Li Z, Buckingham BA, Pinsker JE, Cengiz E, Wadwa RP, Ekhlaspour L, Church MM, Weinzimer SA, Jost E, Marcal T, Andre C, Carria L, Swanson V, Lum JW, Kollman C, Woodall W, Beck RW
Tauschmann M, Allen JM, Nagl K, Fritsch M, Yong J, Metcalfe E, Schaeffer D, Fichelle M, Schierloh U, Thiele AG, Abt D, Kojzar H, Mader JK, Slegtenhorst S, Barber N, Wilinska ME, Boughton C, Musolino G, Sibayan J, Cohen N, Kollman C, Hofer SE, Fröhlich‐Reiterer E, Kapellen TM, Acerini CL, de Beaufort C, Campbell F, Rami‐Merhar B, Hovorka R, on behalf of KidsAP Consortium
Tamborlane WV, Barrientos‐Pérez M, Fainberg U, Frimer‐Larsen H, Hafez M, Hale PM, Jalaludin MY, Kovarenko M, Libman I, Lynch JL, Rao P, Shehadeh N, Turan S, Weghuber D, Barrett T; for the Ellipse Trial Investigators
Auzanneau M, Lanzinger S, Bohn B, Kroschwald P, Kuhnle‐Krahl U, Holterhus PM, Placzek K, Hamann J, Bachran R, Rosenbauer J, Maier W; on behalf of the DPV Initiative
Efficacy and safety of a fixed combination of insulin degludec/insulin aspart in children and adolescents with type 1 diabetes: A randomized trial
Battelino T1,2, Deeb LC3, Ekelund M4, Kinduryte O5, Klingensmith GJ6, Kocova M7, Kovarenko M8, Shehadeh N9
1Department of Endocrinology, Diabetes and Metabolism, University Children's Hospital, Ljubljana, Slovenia; 2Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; 3Florida State University College of Medicine, Tallahassee, FL; 4Novo Nordisk A/S, Søborg, Denmark; 5Novo Nordisk A/S, Bagsvaerd, Denmark; 6Barbara Davis Center for Childhood Diabetes, University of Colorado and Children's Hospital Colorado, Aurora, CO; 7Department of Endocrinology and Genetics, University Pediatric Clinic–Skopje, Skopje, Republic of Macedonia; 8Pediatric Department, Novosibirsk State Medical University of The Ministry of Healthcare of the Russian Federation, Novosibirsk, Russia; 9Rambam Health Care Campus, Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
Background
Premixed analog insulins may help to reduce the number of injections when adherence is a problem. Insulin degludec/insulin aspart (IDegAsp) is a soluble, ready-to-use co-formulation in the ratio 70% insulin degludec (IDeg) to 30% insulin aspart (IAsp).
The aim of the current study was to evaluate efficacy and safety of IDegAsp in pediatric patients (aged 1–18 years) with type 1 diabetes (T1D).
Methods
A 16-week, phase 3b, treat-to-target, parallel-group, open-label, noninferiority multicenter (n=63 sites), multinational (n=14 countries) study. Eligible for inclusion were children and adolescents with T1D, previously treated with any insulin regimen for ≥3 months at a total daily insulin dose of ≤2 U/kg, and with HbA1c levels of ≤11% (≤96.7 mmol/mol). Patients were randomized 1:1 (age stratified 1 to <6 years, 6 to <12 years, and 12 to <18 years) to IDegludec Asp once daily (OD) plus insulin aspart (IAsp) for remaining meals (IDegAsp + IAsp), or IDetemir OD or twice daily (BID) plus mealtime IAsp (IDet + IAsp). The primary endpoint was the change from baseline in HbA1c after 16 weeks of treatment. Other efficacy endpoints included: fasting plasma glucose, and 4- and 8-point self-measured plasma glucose profiles. Safety endpoints included adverse events, hypoglycemic episodes, hyperglycemia, hyperglycemia with ketosis (ketones >1.5 mmol/L), insulin dose, body weight, and standard laboratory safety assessments.
Results
A total of 362 participants were randomized to IDegAsp + IAsp (n=182) or IDet + IAsp (n=180). IDegAsp + IAsp and IDet + IAsp were associated with similar changes in HbA1c from baseline. The estimated mean decrease in HbA1c was 0.27% (2.98 mmol/mol) for IDegAsp + IAsp and 0.23% (2.53 mmol/mol) for IDet + IAsp at week 16. The estimated treatment difference for IDegAsp + IAsp – IDet + IAsp at week 16 was −0.04% (95%CI −0.23, 0.15) (−0.45 mmol/mol [95%CI −2.51, 1.60]), which confirmed the noninferiority of IDegAsp+ IAsp versus IDet + IAsp. Post hoc analysis of the difference between daily doses using a mixed model for repeated measurements analysis confirmed a statistically significant reduction with IDegAsp + IAsp versus IDet + IAsp of 26% for basal dose and 15% for total insulin dose, and the mean number of injections/day was 3.6 and 4.9 with IDegAsp + IAsp and IDet + IAsp, respectively.
There were no significant differences between treatment groups in fasting or self-measured plasma glucose. Confirmed hypoglycemia rates did not significantly differ between groups. A nonsignificant higher rate of severe hypoglycemia was observed with IDegAsp + IAsp versus IDet + IAsp. The most frequent adverse events in both groups were hypoglycemia, headache, and nasopharyngitis.
Conclusions
This study has demonstrated that IDegAsp OD provides comparable glycemic control to IDet OD or BID and with similar hypoglycemia rates, both with mealtime IAsp in children with T1D. Similar glycemic control in the IDegAsp+ IAsp treatment arm was achieved with a lower insulin dose and a lower number of daily injections versus the IDet + IAsp arm.
The International Society for Pediatric and Adolescent Diabetes (ISPAD) guidelines recommend that pediatric patients receive basal-bolus therapy to allow titration of individual insulin doses (1); however, this regimen is complex, which can negatively impact treatment adherence (2). About a third of adolescents with T1D reported omitting insulin doses (3). The ISPAD guidelines acknowledge that premixed analog insulins may help to reduce the number of injections when adherence is a problem (1).
Insulin degludec/insulin aspart (IDegAsp) is a soluble, ready-to-use co-formulation of basal and bolus insulin that retains the individual pharmacokinetic/pharmacodynamic characteristics of its components, with IDeg providing long-acting insulin coverage and IAsp providing short-acting insulin action (4).
This study has demonstrated that IDegAsp OD provides comparable glycemic control to IDet OD or BID, both with mealtime IAsp with a lower insulin dose and a lower number of daily injections and with a similar adverse events profile in children with T1D. Although confirmed hypoglycemia and nocturnal hypoglycemia rates did not significantly differ between groups, a nonsignificant higher rate of severe hypoglycemia was observed with IDegAsp + IAsp versus IDet + IAsp. On the other hand, the proportion of patients experiencing hyperglycemic episodes with ketosis and the rate of these episodes were numerically lower for IDegAsp + IAsp versus IDet + IAsp. There was also a statistically significant increase in weight standard deviation score with IDegAsp + IAsp versus IDet + IAsp, confirming the weight-sparing properties of IDet (5).
This trial is strengthened by the multinational nature of the study population and the broad age range of participants, making the results of it relevant to the global pediatric population with T1D. The study is limited by its open-label design and its relatively short duration (16 weeks).
We can conclude that IDegAsp, as the first fixed soluble co-formulation insulin, can offer the potential benefit of fewer injections compared with a traditional basal-bolus regimen, and may therefore represent an addition to the treatment options for pediatric patients with T1D for whom a treatment option with fewer injections is important or where adherence may be a challenge. However, clinicians may consider the weight-sparing effect of IDet, the ketosis benefit of IdegAsp, and the relative risk of severe hypoglycemia of IdegAsp (in patients with previous episodes of severe hypoglycemia) when choosing appropriate treatments for this patient population.
Continuous subcutaneous insulin infusion versus multiple daily injection regimens in children and young people at diagnosis of type 1 diabetes: pragmatic randomized controlled trial and economic evaluation
Blair JC1, McKay A2, Ridyard C3, Thornborough K4, Bedson E2, Peak M5, Didi M1, Annan F4, Gregory JW6, Hughes DA3, Gamble C2, for the SCIPI investigators
1Department of Endocrinology, Alder Hey Children's NHS Foundation Trust, Liverpool, UK; 2Clinical Trials Research Centre, University of Liverpool, Liverpool, UK; 3Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK; 4Department of Diabetes, Alder Hey Children's NHS Foundation Trust, Liverpool, UK; 5Department of Research, Alder Hey Children's NHS Foundation Trust, Liverpool, UK; 6Division of Population Medicine, School of Medicine, Cardiff University, Cardiff, UK
Background
Multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) are associated with superior glycemic control in patients with T1D.
The widespread adoption of CSII, with little evidence of treatment superiority compared with MDI, requires an adequately powered randomized controlled trial designed to address areas of bias inherent in previous studies. Therefore, the aim was to compare the efficacy, safety, and cost utility of CSII with MDI regimens during the first year following diagnosis of T1D in children and adolescents.
Methods
A pragmatic, multicenter (15 pediatric National Health Service [NHS] diabetes services in England and Wales), open label, parallel group, randomized controlled trial conducted in pediatric diabetes services experienced in the use of CSII. Participants aged 7 months to 15 years, with a new diagnosis of T1D were randomized to start treatment with CSII or MDI within 14 days of diagnosis. Starting doses of aspart (CSII and MDI) and glargine or detemir (MDI) were calculated according to weight and age and titrated according to blood glucose measurements and local clinical practice.
The primary outcome was glycemic control (as measured by HbA1c) at 12 months. Secondary outcomes included percentage of patients in each treatment arm with HbA1c within the national target range, incidence of severe hypoglycemia and diabetic ketoacidosis (DKA), change in height and body mass index (measured by standard deviation scores), insulin requirements (units/kg/day), partial remission rate (insulin dose adjusted HbA1c <9), pediatric quality of life inventory score (PedsQL), and cost utility based on the incremental cost per quality adjusted life year (QALY) gained from an NHS costing perspective.
Results
Two hundred ninety-three participants were included in intention to treat analyses (CSII, n=144; MDI, n=149). At 12 months, mean HbA1c was comparable between CSII and MDI participants [7.7% (60.9 mmol/mol) vs 7.5% (58.5 mmol/mol)]. Achievement of HbA1c <7.5% (58 mmol/mol) was low among the two groups (46% CSII participants vs 55% MDI participants; relative risk 0.84 [95% CI 0.67 to 1.06]). Incidence of severe hypoglycemia and DKA were low in both groups. Parents reported superior PedsQL scores for those patients treated with CSII compared with those treated with MDI. CSII was more expensive than MDI by £1,863 (€2,179; $2,474 [95% CI £1,620 to £2,137]) per patient, with no additional QALY gains (difference −0.006 [95% CI −0.031 to 0.018]).
Conclusions
In this randomized, controlled trial of pediatric patients with a new diagnosis of T1D, CSII treatment was neither more clinically effective nor more cost effective than MDI by the standards of the NHS in the UK. Both treatment regimens were suboptimal in achieving HbA1c targets.
The risk of developing diabetes complications is related to glycemic control and is lower in patients treated with intensive insulin regimens including multiple daily injections (MDI) and continuous subcutaneous insulin infusion (CSII) (6). However, there is still a debate which of these treatment regimens is preferred in real-life settings.
Over the past decade, CSII has become a standard treatment option for patients with T1D. CSII mimics physiologic insulin release better than MDI therapy and allows for greater flexibility in food intake and physical activity.
A meta-analysis of six randomized controlled trials involving 165 children reported a modest benefit of CSII treatment on glycemic control albeit below the threshold associated with better clinical outcomes (0.5%) without difference in the risk of severe hypoglycemia or DKA (7). Observational studies of national pediatric databases have reported an association between CSII treatment and superior glycemic control (8 –10), with reduced risk of severe hypoglycemia and DKA (9).
Given the benefits of CSII therapy, one might ask whether it is required to wait to offer CSII to patients with T1D only after MDI therapy has failed. Large randomized controlled trials on initiating CSII shortly after diabetes diagnosis are still sparse, with few data of metabolic parameters over the long-term in these patients. In a small randomized trial comparing CSII with MDI in patients newly diagnosed with T1D and observed for two years, researchers did not find significant differences in glycemic control or adverse events between treatment arms (11).
In the current randomized, controlled trial and economic evaluation of pediatric patients in the first year of T1D, glycemic control was suboptimal in both treatment arms. CSII treatment was not more clinically effective than treatment with MDI, and CSII was not cost effective.
We must consider that patients recruited to the study were newly diagnosed with T1D. It is noteworthy that although insulin replacement by CSII more closely resembles the normal physiology than MDI treatment, starting CSII shortly after diabetes onset can be more time-consuming and stressful for both patient and family.
In addition to teaching patients and their families about diabetes, the diabetes team also has to teach them about the pump mechanics and troubleshooting, which requires extra training hours. The patients and families are burdened not only with the need to cope with the new diagnosis but also with the need to learn new skills and techniques. Nevertheless, it can be argued that starting with MDI may be just as complicated because of the required learning about the differences between insulin duration and how to adjust the insulin dosage to food and exercise requirements. Yet in the current study, parents of children treated with CSII reported superior quality of life for their children compared with parents of children treated with MDI, which is an important aspect among parents dealing with a chronic illness of their child.
The strengths of the current study are the high retention rate, consistency of age, sex, ethnicity, and deprivation between treatment arms. Since participants were recruited at diagnosis of T1D, core diabetes education and contact with healthcare professionals was balanced across treatment arms.
As reported previously (8), glycemic control was found to be poorer in the UK than in other European and North America countries, where CSII is more commonly used. Consequently, the relative low experience of NHS practitioners in CSII treatment could have obscured the potential benefits of CSII. Therefore, conducting a multinational prospective randomized controlled study in young patients with newly diagnosed T1D with longitudinal follow-up will allow us to draw more firm Conclusions. Meanwhile, the correct treatment modality and timing of CSII initiation should be tailored for the individual patient by the diabetes care team.
Accuracy, satisfaction and usability of a flash glucose monitoring system among children and adolescents with type 1 diabetes attending a summer camp
Hansen EA1, Klee P2,3, Dirlewanger M2,3, Bouthors T4, Elowe‐Gruau E4, Stoppa‐Vaucher S4,5, Phan‐Hug F4, Antoniou MC4, Pasquier J6, Dwyer AA1,7, Pitteloud N1,4,8, Hauschild M1,4
1Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland; 2Pediatric Endocrinology and Diabetes Unit, University Hospitals of Geneva, Geneva, Switzerland; 3Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland; 4Pediatric Endocrinology, Diabetology and Obesity Unit, Lausanne University Hospital, Lausanne, Switzerland; 5Department of Pediatrics, Neuchâtel Hospitals, Neuchâtel, Switzerland; 6Institute of Social and Preventive Medicine, Lausanne, Switzerland; 7Boston College, William F. Connell School of Nursing, Chestnut Hill, MA; 8Service of Endocrinology, Diabetology and Metabolism, Lausanne University Hospital, Lausanne, Switzerland
Background
Frequent self-monitoring blood glucose (SMBG) testing is associated with improved glycemic control. A way to overcome barriers to SMBG has been the introduction of invasive CGM systems. A flash glucose monitoring system (FGM) is an alternative to CGM. The aim of the study was to assess accuracy, satisfaction, and usability of the FGM among children and adolescents with T1D in the context of a diabetes summer camp.
Methods
In this prospective, single-arm study, children and adolescents with T1D (n=66) aged 6–17 years participating in a 7-day medically supervised summer camp were enrolled. Capillary blood glucose (BG) and flash glucose (FG) values were measured simultaneously at breakfast, lunch, and dinner and for any FG reading that was <72 mg/dL (<4.0 mmol/L) during daytime, <108 mg/dL (<6.0 mmol/L) at nighttime, >270 mg/dL (>15.0 mmol/L), or when patient symptoms were discordant with sensor readings. Any difficulties related to study sensors were documented, and patients' and healthcare professionals' (HCPs) evaluated their satisfaction with the systems.
Results
FGM demonstrated satisfactory clinical accuracy compared with reference capillary BG values, with 98.8% of values falling within the clinically acceptable zones (A and B) of the consensus error grid. Mean absolute relative difference (MARD) was 16.7%±16.1%. The FGM performed best in situations of hyperglycemia (>250 mg/dL) with a MARD at 14.4%±9.7%. Performance was the worst in hypoglycemia <0.0001. (In hypoglycemia <54 mg/dL and <54 to 70 mg/dL with a MARD at 37.1%±28.6% and 18.5%±20.7%, respectively). FGM overestimated BG values with an overall mean bias of +12.1 mg/dL (+0.67 mmol/L). Specific calculations of mean absolute difference, mean relative difference, and mean difference demonstrated that FGM overestimated BG values across all glycemic ranges. A significant influence of sex, age, and age-adjusted BMI on the MARD was identified. MARD was 15.7±14.9% in girls versus 18.0±17.5% in boys (P=0.0005). MARD was lower in younger participants (≤12.5 years) compared with patients >12.5 years (15.5±14.0% vs 18.6±18.8%; P<0.0001) and significantly differed according to age-adjusted BMI: 17.3±17.0% for <1.00 SDS 14.6±12.6% for 1–1.99 SDS, and 15.6±14.5% for ≥2.00 SDS (P=0.002). No events of ketoacidosis occurred. The only major adverse event was one hypoglycemic event requiring glucagon injection. Overall satisfaction with the FGM was high in 91.7% participants and 95.0% healthcare professionals (HCPs), although confidence in the system was low in 18.0% participants and 40.0% HCPs.
Conclusions
The present data indicate satisfactory FGM clinical accuracy compared with reference BG measurements. However, MARD was >10%, and a 29.8% missed hypoglycemia detection rate was observed, as well as situations when hyperglycemia was overestimated. As FGM values do not necessarily reflect actual glycemia, no decision should be taken on the basis of a single, nonverified FGM value alone.
Frequent self-monitoring blood glucose (SMBG) testing is associated with improved glycemic control. Despite clear evidence of its impact on metabolic control, there are several barriers to frequent SMBG including invasiveness, painful fingerpicks, and interference with daily activities.
One way to overcome barriers to SMBG has been the introduction of CGM systems that enable monitoring of glucose profiles, variability, and trends over 24 hours with alarms providing patient feedback and warnings of hypo- and hyperglycemia. A FGM is an alternative to CGM, with the advantages of FGM over CGM including longer sensor lifetime, absent need of calibration, and lower cost.
FGM offers a factory-calibrated sensor that can be worn for 14 days without manual calibration by using blood testing, a reader combined with a standard glucometer, and dedicated software. The user receives a current glucose measurement along with historic results from the preceding 8 hours by scanning the sensor with the FreeStyle reader. The glucose trends are displayed as arrows on the reader along with alerts. The device requires active scanning by the user, and it does not report alerts in real time.
Initial observations suggested that FGM users may rely solely on FGM and not perform SMBGs. This raises the question if FGM is accurate enough to replace standard glucometers, or should it be just a complementary addition to SMBG. The current study gives the opportunity to make an objective assessment relating the FGM, since it was conducted under close medical surveillance. All blood glucose measurements were performed under strict supervision thus mitigating the risk for potential inaccurate reference values. All participants underwent the same daily routine, with similar activities and the same diet. This permitted to describe the properties of the FGM in a uniform setting.
Limitations of this study include the small sample size, the limited study duration (one week), and the study setting of the camp, which differs from normal daily life due to increased glycemic variability. Thus, the computed MARD values should be evaluated in this limited context.
The study data demonstrate satisfactory FGM clinical accuracy. However, MARD was >10%, with a 29.8% missed hypoglycemia detection rate, and there were situations in which hyperglycemia was overestimated, with a risk of insulin overcorrection. As FGM values do not necessarily reflect actual glycemia, no decision should be taken on the basis of a single, nonverified, FGM value alone. This highlights the need for therapeutic education for patients/families on the integration of FGM readings in clinical decision making. Glucose trend arrows and individual experiences of clinical signs should be considered when interpreting values and use of complementary SMBG must be encouraged.
Flash glucose monitoring accepted in daily life of children and adolescents with type 1 diabetes and reduction of severe hypoglycemia in real-life use
Messaaoui A1, Tenoutasse S1, Crenier L2
1Diabetology Clinic, Hôpital Universitaire des Enfants Reine Fabiola, Brussels, Belgium–Université Libre de Bruxelles, Bruxelles, Belgium; 2Department of Endocrinology, Hôpital Erasme, Brussels, Belgium–Université Libre de Bruxelles, Bruxelles, Belgium
Background
The factory-calibrated FreeStyle Libre FGM system represents a good compromise between SMBG and CGM. By continuously measuring glucose in the interstitial fluid, it provides glucose values at any time, just by scanning the sensor. The aim of this observational prospective study was to describe the use of FGM during the first year of its reimbursement in the population of children and adolescents with T1D in Belgium.
Methods
Inclusion criteria were: patients with onset of diabetes before 16 years of age, diabetes duration of >1 year, aged 4–20 years, and followed in the Diabetology Clinic at the University Children's Hospital Queen Fabiola, Brussels, Belgium. Each patient had the choice to convert to FGM or to continue with the usual SMBG. In case they accepted to switch to FGM, the patients and their family were trained by dedicated diabetes educators for inserting the sensor and interpreting the FGM data. Patients were instructed to keep their usual insulin treatment schema. Clinical data were collected at baseline, at the next visit, and after 12 months; glucose profiles were collected at next visit and after 12 months. Regression analyses were performed to identify predictors of FGM acceptance and changes in metabolic control.
Results
A total of 334 subjects were included, of whom 83.2% switched to FGM. Patients that switched to FGM were younger (13.6 vs 15.2 years; P=0.012) and performed more SMBG testing at baseline than patients who did not switch (4.3 vs 4.1 tests daily; P=0.008). At the end of follow-up, the rate of severe hypoglycemia decreased by 53% in the group of FGM users (P=0.012) while it remained stable in SMBG users. Median HbA1c did not change significantly in either group. Among subjects who switched to FGM, 15.8% reverted to SMBG after a median time of 5.3 months. Adverse events, diabetes duration, and FGM utilization were independent predictors of the risk for reverting. FGM-related adverse events were associated with a fivefold increased risk to revert to SMBG (hazard ratio=5.12; P<0.0001).
Conclusions
FGM is relatively well accepted in the Belgian pediatric population and decreases the risk of severe hypoglycemic events. FGM was more often discontinued in patients experiencing adverse events and with diabetes of longer duration.
So far, only a few studies tested the accuracy and efficacy of FGM in the pediatric population and examined the use of FGM in home-based conditions (12 –14). In the current study, 83.2% of the included patients switched to FGM from the start. It is possible that the good reception of FGM may result from its minimal invasiveness compared with standard blood glucose measurements and its added value in the form of easily interpretable glucose trend arrows. Therefore, it can be a good compromise in young patients that do not want to use the CGM but still want to monitor their glucose levels frequently.
The organization of diabetes care in Belgium was allowed to study FGM use in their pediatric population without any financial constraints. However, 15.8% of those using FGM reverted to SMBG after a median use of 5.3 months. Those reverting to SMBG had a higher rate of FGM-related adverse events, mostly premature losses of the sensor, and skin reactions. Stopping FGM was also more frequent in patients with diabetes of longer duration and with higher HbA1c, conditions often associated with higher glucose variability, that may impact the accuracy of the FGM, which is low in hypoglycemia and during rapid change of glucose values (15). Thus, a feeling of poor reliability could have played a role in the decision to stop the FGM, although only one of the patients pointed this as the main cause of reverting to SMBG.
Nevertheless, in situations of rapid change in the glucose levels, or in situations of glucose levels in the hypoglycemic range, or when the patient's sensations are inadequate to the FGM readings, patients and parents have to be instructed to confirm the measurements with SMBG. Other main limitations of the FGM are the requirement of compliance of active scanning by the user and the lack of alarms, which may be crucial for those patients with hypoglycemic unawareness and during the night hours. However, in this study, FGM has shown to decrease the risk of severe hypoglycemic events after 1 year of follow-up.
Interestingly, in both FGM and SMBG users, median HbA1c did not change significantly during the 1-year of follow-up. Therefore, studies with longer observation times and maybe with the added feature of reported alerts in real time (as the MiaoMiao, which is a FreeStyle Libre reader that can trigger an alarm at glucose irregularity caught by the FGM) are needed to evaluate whether FGM could provide lasting improvement in glycemic outcomes.
Glycemic outcomes with early initiation of continuous glucose monitoring system in recently diagnosed patients with type 1 diabetes
Mulinacci G1, Alonso GT2, Snell‐Bergeon JK2, Shah VN2
1Università Vita‐Salute San Raffaele, Milano, Italy; 2 Barbara Davis Center for Diabetes, University of Colorado Anschutz Campus, Aurora, CO
Background
This study investigated the efficacy and safety of CGM initiation within 1 year of type 1 diabetes (T1D) diagnosis in children, adolescents, and adults.
Methods
Differences in mean A1c (primary outcome) and diabetes-related emergency visits (secondary outcome) for 2.5 years between early CGM users and non-CGM users were compared in 396 newly diagnosed patients with T1D (94% were <18 years old, 5% adults, and 46% females) between January 2013 and December 2015. The primary outcome was adjusted by age at diagnosis and by gender.
Results
Gender, ethnicity, BMI, and HbA1c were similar between the groups at diagnosis. CGM users had a significantly greater improvement in glycemic control than non-CGM users at 1, 1.5, 2, and 2.5 years, irrespective of insulin delivery method. For 2.5 years of follow-up, the multiple daily injection (MDI) + CGM group (n=19) had 1.5±0.2% lower A1c than the MDI-only group (n=225) (7.7±0.2% vs 9.2±0.04%, P<0.0001), and the insulin pump (continuous subcutaneous insulin infusion [CSII] + CGM group [n=62] had 0.7%±0.1% lower A1c than the CSII only group [n=90] [8.0±0.08% vs 8.7±0.07%, P<0.0001]). The MDI+CGM group had significantly lower HbA1c than the CSII only group (7.7±0.2% vs 8.7±0.07%, P<0.0001). Diabetes-related emergency department visits was significantly lower among early CGM users compared with non-CGM users (P=0.003).
Conclusion
Early initiation of CGM within 1 year from T1D diagnosis was associated with better glucose control and fewer diabetes-related emergency visits.
After decades of research, the past few years have seen a significant increase in the clinical use of CGM. While barriers to use CGM continue to exist for some patients, particularly those with public insurance (16), the usability of current generation CGM systems has improved significantly with increased acceptance and use by people with diabetes. These data from a large clinical database at the Barbara Davis Center clearly document improved HbA1c among those who use CGM whether on an insulin pump or using injections to deliver insulin as well as a decrease in the need for diabetes-related emergency visits. CGM is rapidly becoming the standard of care for monitoring glucose values, especially in people with T1D. This report and others that describe early initiation of CGM in people newly diagnosed with T1D (17) will establish the evidence base necessary to speed the transition from blood glucose monitoring to CGM as the standard of care for people with diabetes.
The use of continuous glucose monitoring with remote monitoring improves psychosocial measures in parents of children with type 1 diabetes: a randomized crossover trial
Burckhardt MA1,2,3, Roberts A1,2, Smith GJ1, Abraham MB1,2,3, Davis EA1,2,3, Jones TW1,2,3
1Children's Diabetes Centre, Telethon Kids Institute, The University of Western Australia, Perth, Australia; 2Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Australia; 3Division of Paediatrics, The University of Western Australia School of Medicine, Perth, Australia
Background
The effect of CGM with remote monitoring on psychosocial outcomes in parents of children with T1D was investigated.
Methods
Children with T1D, aged 2–12 years, along with their parents, were included in a randomized crossover study. Participants used either conventional blood glucose monitoring (control) or the Dexcom G5 Mobile continuous glucose monitoring (CGM) system with remote monitoring (intervention) during two 3-month periods. Parental fear of hypoglycemia score (the primary outcome) was assessed using the Hypoglycemia Fear Survey.
Results
The use of CGM with remote monitoring was associated with lower Parental Hypoglycemia Fear Survey scores (P<0.001). Parental health–related quality of life and family functioning, stress, anxiety, and sleep measures also improved significantly after intervention.
Conclusions
The use of CGM with remote monitoring improved multiple measures of quality of life, reduced family stress, and improved parental sleep.
It is difficult to underestimate the benefit that parents receive from CGM systems that allow for remote monitoring of the glucose control of their young children with T1D when they are not physically with them. Young children spend a significant amount of time in schools, which have a variable ability and skill in caring for children with T1D. Moreover, in some instances, children with T1D may be restricted from activities that children without T1D would participate in (camps, sleepovers, sports, etc.) due to family (or others') concerns about the ability to care for their T1D. This important study clearly documents the effectiveness of the Dexcom G5 Mobile CGM system with remote monitoring to improve multiple measures of quality of life, reduce family stress, and improve parental sleep. More widespread use of remote monitoring in young children has the potential to reduce the burden of T1D care and to improve the lives of many families. Use of these systems in adolescents and young adults also holds promise but comes with its own age-specific challenges as children grow up and yearn to become more autonomous. Additional research is needed to help provide best practice recommendations for the adolescent and young adult population with T1D who could also benefit from remote monitoring as they balance normal developmental desire for greater autonomy from parents.
Continuous glucose monitoring and glycemic control among youth with type 1 diabetes: international comparison from the T1D Exchange and DPV Initiative
DeSalvo DJ1, Miller KM2, Hermann JM3,4, Maahs DM5, Hofer SE6, Clements MA7, Lilienthal E8, Sherr JL9, Tauschmann M10, Holl RW3,4, on behalf of the T1D Exchange and DPV Registries
1Pediatric Endocrinology and Metabolism, Texas Children's Hospital, Baylor College of Medicine, Houston, TX; 2Jaeb Center for Health Research, Tampa, FL; 3Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany; 4German Center for Diabetes Research (DZD), Munich, Germany; 5Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA; 6Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria; 7Pediatric Endocrinology and Diabetes, Children's Mercy Hospital, University of Missouri–Kansas City School of Medicine, Kansas City, MO; 8University Children's Hospital at Bochum University, Bochum, Germany; 9Department of Pediatrics, Yale University School of Medicine, New Haven, CT; 10Department of Pediatrics, Medical University of Graz, Graz, Austria
Background
Data from the U.S.–based Type 1 Diabetes Exchange (T1DX) and the German/Austrian DPV (Prospective Diabetes Follow-Up Registry) were used to investigate the change in use of pediatric real-time or intermittent scanning CGM over the past 5 years and to evaluate how it impacts glycemic control.
Methods
Data for T1DX Registry and DPV Initiative participants aged <18 years with T1D duration ≥1 year were analyzed in 2011 and again in 2016 (a total of 29,007 individuals in 2011 and 29,150 in 2016). Demographic data, CGM use, insulin modality, and most recent HbA1c for each individual were obtained from medical records. Logistic and linear regression modeling were used to compare demographic and clinical characteristics in 2011 vs 2016 within each registry.
Results
CGM use increased across all age groups in both registries from 2011 to 2016, independent of gender, ethnic minority status, or insulin delivery method. The most pronounced increase in CGM use was seen in the youngest age group (ages 1 to <6 years), and although rates of CGM use in adolescents increased from 2011, these patients still had the lowest usage rates for any age group in 2016. In 2016 for both registries, mean HbA1c was lower among CGM users regardless of insulin delivery method compared with pump only (P<0.001) and injection only (P<0.001). In addition, CGM users were more likely to achieve an HbA1c <7.5% (56% vs 43% for DPV and 30% vs 15% for T1DX; P<0.001). Compared with DPV, T1DX participants had a higher mean HbA1c regardless of whether they used CGM or not, but the difference was smaller in CGM users (P<0.001).
Conclusions
Pediatric CGM use increased in both registries and was associated with lower mean HbA1c regardless of insulin delivery modality.
The T1DX and DPV registries are used to report the dramatic increase in use of CGM in the pediatric T1D population from 2011 to 2016: from 4% to 19% in DPV and from 3% to 22% in T1DX (P<0.001 for both). The greatest increase in CGM use was in the youngest age group (<6 years of age), although all groups increased use. While the increased use of CGM would seem to be a clear validation of the benefit that patients and families gain from CGM, the data also clearly show that in all age groups those children with T1D using CGM have lower HbA1c. In addition, both registries show a stepwise decrease in HbA1c from the highest HbA1c in those who use injection + BGM (blood glucose monitoring), to those who use pump + BGM, to those who use injection + CGM, and to the lowest HbA1c in those who use pump + CGM. In these large observational datasets, use of CGM is associated with a greater effect on lower HbA1c than use of an insulin pump although patients who combine pump and CGM have the lowest HbA1c values. These data and others document the increased use and benefit of CGM to the pediatric population with T1D. Efforts to fully realize the possible benefits of CGM to improve glucose control are ongoing as is advocacy to reach all children, adolescents, and young adults with T1D who would benefit from a CGM.
In-clinic evaluation of the MiniMed 670G system “suspend before low” feature in children with type 1 diabetes
Wood MA1, Shulman DI2, Forlenza GP3, Bode BW4, Pinhas‐Hamiel O5, Buckingham BA6, Kaiserman KB7, Liljenquist DR8, Bailey TS9, Shin J10, Huang S10, Chen X10, Cordero TL10, Lee SW10, Kaufman FR10
1Division of Pediatric Endocrinology, University of Michigan Medical School, Ann Arbor, MI; 2USF Diabetes Center, Morsani College of Medicine, University of South Florida, Tampa, FL; 3Barbara Davis Center for Childhood Diabetes, Aurora, CO; 4Atlanta Diabetes Associates, Atlanta, GA; 5Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Aviv, Israel; 6Department of Pediatric Endocrinology, Stanford University, Stanford, CA; 7SoCal Diabetes, Torrance, CA; 8Rocky Mountain Diabetes and Osteoporosis Center, Idaho Falls, ID; 9AMCR Institute, Escondido, CA; 10Medtronic, Northridge, CA
Background
Predictive low-glucose management (PLGM) algorithms have been shown to mitigate and prevent hypoglycemia in several in-clinic and observational studies. Performance evaluations on both the investigational PLGM algorithm and that of the MiniMed 640G system SmartGuard “suspend before low” feature have reported hypoglycemia avoidance success rates of 60%–80% or significant reductions in treatment for hypoglycemia compared with control in patients with type 1 diabetes (T1D). The Manual Mode function of the MiniMed 670G system automatically stops insulin delivery when sensor glucose is predicted to reach or fall below a preset low-glucose value within the next 30 minutes and resumes delivery after hypoglycemia recovery. In the present study, the overnight performance of the MiniMed 670G “suspend before low” feature was evaluated in children with T1D aged 7–13 years.
Methods
Patients (n=105) of a mean age of 10.8±1.8 years who have been using an insulin pump (with or without CGM) for >6 months before screening underwent an overnight in-clinic evaluation of the “suspend before low” feature with a preset low limit of 65 mg/dL. Before wearing study devices, all participants and their parent(s)/guardian(s)/ companions were trained on the devices as well as diabetes management principles. Each experiment during the evaluation was considered successful if the “suspend before low” feature was activated. After exercise, frequent sample testing (FST) was conducted every 5 minutes if values were <70 mg/dL; every 15 minutes if 70–80 mg/dL; and every 30 minutes if >80 mg/dL. Hypoglycemia avoidance was defined as all FST reference glucose values >65 mg/dL after “suspend before low” activation. The PLGM algorithm performance was evaluated based on the percentage of hypoglycemia avoidance (i.e., the number of participants whose glucose did not fall <65 mg/dL/total number of participants in whom “suspend before low” activated); the FST reference glucose values before and after “suspend before low” activation, as well as before and after insulin resumption; the rates of FST reference glucose change before and after “suspend before low” activation as well as before and after insulin resumption; and the duration of insulin delivery suspension (the elapsed time from initial “suspend before low” activation to insulin delivery resumption). An episode of hypoglycemia was defined as the occurrence of two or more consecutive FST reference glucose values <65 mg/dL. First-day performance of the Guardian Sensor 3 glucose sensor and CGM system, as demonstrated by the mean absolute relative difference (ARD) between the sensor glucose values and FST reference glucose values and the percentage of within −20% agreement between sensor-FST paired points (20%/20 agreement rate) were also evaluated. The safety outcomes measured during the “suspend before low” evaluation included: serious adverse events, device-related adverse events, unanticipated device effects, severe hypoglycemia, diabetic ketoacidosis (DKA), and the number of treatments for hypoglycemia.
Results
Activation of the “suspend before low” feature occurred in 79 of the 105 participants, 79.7% (63/79) did not result in sensor glucose falling <65 mg/dL. Mean glucose at activation was 102±19 mg/dL, and the initial insulin suspension duration was 87.5±32.7 minutes. Four hours after insulin resumption, mean reference glucose was 130±42 mg/dL. Mean absolute relative difference between the FST reference glucose and sensor glucose values on the first day of sensor wear was 11.4%. For the 26 participants in whom the “suspend before low” feature did not activate, none involved a reference glucose value ≤65 mg/dL, suggesting that the PLGM algorithm performed as intended.
Conclusions
PLGM algorithms within sensor-integrated insulin delivery systems can help avoid hypoglycemia exposure and reduce the fear of hypoglycemia in a population in which hypoglycemia management remains a challenge.
Hypoglycemia avoidance is very important, as increased frequency and duration of hypoglycemia with intensive insulin treatment can lead to impaired hypoglycemia awareness.
Sensor-integrated pump systems with glucose-responsive insulin delivery were developed to respond to low glucose levels by suspending insulin at a preset low limit. The long-term, in-home use of the low glucose or low threshold suspend feature reduced the frequency and severity of daytime and nighttime hypoglycemia exposure and severe hypoglycemia compared with controls, without increasing HbA1c levels (18). Beyond low glucose or low threshold suspend, PLGM algorithms have been shown to prevent hypoglycemia in several in-clinic and observational studies (19,20). The Manual Mode function of the MiniMed 670G system allows activation of the “suspend before low” feature to provide an additional means of reducing hypoglycemia exposure in the open-loop setting. The present study demonstrates the algorithm's hypoglycemia avoidance capability in the Smart-Guard “suspend before low” feature of the MiniMed 670G system tested in a large group of children.
The limitation of the present study is the lack of a control group by which to directly compare the effects of the PLGM algorithm and the very short time duration. However, regarding long-term performance and safety of the PLGM algorithm, a recent randomized in-home study in the pediatric age group compared the effects of 3-month PLGM use versus control (“suspend on low” and “suspend before low” off) and determined that use of the PLGM algorithm was associated with fewer hypoglycemic events (21).
These data demonstrate the ability of an insulin delivery system to mitigate the onset, frequency, or severity of hypoglycemia.
DREAM5: An open-label, randomized, cross-over study to evaluate the safety and efficacy of day and night closed-loop control by comparing the MD-Logic automated insulin delivery system to sensor augmented pump therapy in patients with type 1 diabetes at home
Biester T1, Nir J2, Remus K1, Farfel A2, Muller I3, Biester S1, Atlas E3, Dovc K4, Bratina N4, Kordonouri O1, Battelino T4, Philip M2, Danne T1, Nimri R2
1Children's Hospital “Auf der Bult,” Diabetes Center for Children and Adolescents, Hannover, Germany; 2Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikvah, Israel; 3DreaMed Diabetes Ltd, Petah Tikvah, Israel; 4Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children's Hospital, UMC Ljubljana, Ljubljana, Slovenia
Background
There is a growing body of evidence that closed-loop systems improve glycemic control while simultaneously decreasing rates of hypoglycemic events. The MD-Logic closed-loop system, uses fuzzy logic algorithms to modulate insulin delivery based on a set of rules that imitates the line of reasoning of diabetes practitioners, which are based on common medical knowledge and the experience of traditional treatment. The MD-Logic controller combines a basal-bolus approach of insulin delivery with event-driven treatment. The present study aimed to evaluate the MD-Logic closed-loop system for day and night use for 60 hours during the weekend at home compared with sensor-augmented pump (SAP) therapy in participants with T1D.
Methods
A prospective, multicenter, crossover, controlled study of patients aged 16 years and older with T1D. Participants were instructed and encouraged to continue with their usual daily routine, with no specific restrictions regarding meals, physical activity, or time connected to the system. All participants were connected in randomized order for one weekend to SAP therapy or the MD-Logic System. In the intervention arm only, the amount of carbohydrate was entered into the bolus calculator; the rest of insulin delivery was automated and wireless via a tablet computer. The primary efficacy outcome was percentage of glucose sensor readings within target range 70 to 180 mg/dL (3.9–10 mmol/L). Secondary efficacy and safety outcomes included percentage of glucose sensor readings <60, 70 mg/dL (3.3, 3.9 mmol/L), percentage of glucose sensor readings >180, 240 mg/dL (10, 13.3 mmol/L), average and SD of glucose sensor readings, and overnight percentage of readings <70 mg/dL (3.9 mmol/L).
Results
The study participants (n=34) were of median age (interquartile range) of 16.7 years (13.5–18.9), with median diabetes duration of 9.4 years (5.0–12.7), median pump use of 5.4 years (3.1–9.4), and median baseline HbA1c 7.6% (7.0–8.1). With the closed-loop system versus control weekends, there was a significant increase in the percentage of time within target range (66.6% vs 59.9%, P=0.002) with unchanged percentage of time <70 mg/dL (2.3% vs 1.5%, P=0.369). Mean weekend glucose level per participant was significantly lower [153 (142–175) vs 164 (150–186) mg/dL, P=0.003]. Measures of glycemic variability did not differ between control and closed loop weekends, whether analyzed over the entire weekend, during the day or the night. No serious adverse events were reported during the study. No events of ketosis or severe hypoglycemia were observed.
Conclusions
This study provided evidence that MD-Logic closed-loop control with automatic bolus is safe and effective for daytime and overnight use during the weekend at home and was associated with better glycemic control than SAP. The closed-loop control increased the time within range with no change in hypoglycemia compared with state-of-the-art SAP therapy and without safety issues.
Achievement of recommended glycemic control remains challenging across all age groups (22). Fear of hypoglycemia, particularly overnight, has a major adverse impact on the quality of life of children with T1D and their families (23). Therefore, high overnight glycemic targets are set, resulting in substantial periods of hyperglycemia, and nocturnal hypoglycemia is a major impediment to tight glycemic control.
Reported recent data from the Type 1 Diabetes Exchange shows that only a minority of individuals meet HbA1c goals and HbA1c levels remain particularly high in adolescents and young adults, despite the substantial increase in diabetes technologies, and especially the use of CGM in recent years (24). Therefore, a better novel approach is required that is less dependent on human factors in order to try to improve glycemic control and quality of life of patients with T1D. Closed-loop systems may represent a tangible treatment option. There have been a number of advances in developing automated insulin delivery systems for optimizing glucose control with the ultimate aim of reducing the burden of care. Several prototypes of control algorithms have evolved and have been tested throughout the world. Two commonly used algorithms are the proportional-integral-derivative and the model predictive controller (25,26), that use mathematical models that link insulin delivery with glucose excursions.
The MD-Logic uses fuzzy logic algorithms to modulate insulin delivery based on a set of rules that imitates the line of reasoning of diabetes practitioners, which in turn are based on common medical knowledge and the experience of traditional treatment (27). The MD-Logic controller combines a basal bolus approach of insulin delivery with event driven treatment (the closed loop raises continuous insulin infusion in the case of a high-value prediction and also gives larger amounts of insulin immediately as a bolus without raising the basal) and a personalized system with learning capacity, safety alerts, and embedded insulin safety layers (28). The controller algorithms combine control to range and control to target.
Despite the relatively small number of participants, the current study broadens the knowledge acquired from previous home studies using the MD-Logic closed-loop which included only the evening and overnight period. In previous overnight studies, the use of the system showed increased time within range and reduced time in hyperglycemia, along with a reduction of time in hypoglycemia during closed loop control compared with SAP therapy (29). In the current study, improved glycemic control was demonstrated also during the daytime (which is more challenging due to food intake and physical exercise) without serious adverse events. Also, the algorithm was tested during the weekends that is a challenging period for maintaining good glycemic control. However, there was a relatively high rate of communication errors between the tablet computer running the algorithm and the insulin pump.
Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: a multicenter, 12-week randomized trial
Tauschmann M1,2, Thabit H1,3,4, Bally L1,3, Allen JM1,2, Hartnell S3, Wilinska ME1,2, Ruan Y1, Sibayan J5, Kollman C5, Cheng P5, Beck RW5, Acerini CL1,2, Evans ML1,3, Dunger DB1,2, Elleri D6, Campbell F7, Bergenstal RM8, Criego A8, Shah VN9, Leelarathna L4, Hovorka R1,2, on behalf of the APCam11 Consortium
1Wellcome Trust‐MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2Department of Pediatrics, University of Cambridge, Cambridge, UK; 3Department of Diabetes and Endocrinology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 4Manchester University NHS Foundation Trust and University of Manchester, Manchester, UK; 5Jaeb Center for Health Research, Tampa, FL; 6Royal Hospital for Sick Children, Edinburgh, UK; 7Leeds Children's Hospital, Leeds, UK; 8International Diabetes Center, Minneapolis, MN; 9Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO
Background
Two meta-analyses of randomized trials reported that outpatient use of closed-loop systems increases the length of time that sensor-measured glucose is near-normoglycemia and reduces the risk of hyperglycemia and hypoglycemia. This study aimed to assess the effectiveness of day-and-night hybrid closed-loop insulin delivery compared with SAP therapy in patients aged 6 years and older with suboptimally controlled T1D.
Methods
An open-label, multicenter, multinational, parallel randomized controlled trial of patients with T1D aged 6 years and older treated with insulin pump and with suboptimal glycemic control (HbA1c 7.5–10.0%) that were recruited from diabetes outpatient clinics in the UK and in the United States. Patients were randomly assigned to receive either hybrid closed-loop therapy or SAP therapy over 12 weeks of free living. Patients were trained on study insulin pump and continuous glucose monitoring (CGM) use over a 4-week run-in period. Allocation to the study groups was unblinded, and randomization was stratified within center by low (<8.5%) or high (≥8.5%) HbA1c. The primary endpoint was the proportion of time with glucose levels within the target range of 70–180 mg/dL (3.9–10.0 mmol/L) at 12 weeks after randomization.
Results
Patients eligible to participate were randomly assigned to receive hybrid closed-loop therapy (n=46) or SAP therapy (n=40; control group). The proportion of time that glucose levels were within the target range was significantly higher in the closed-loop group compared with the control group (65±8 % vs 54±9%; P<0.0001). In the closed-loop group, HbA1c was reduced from a screening value of 8.3±0.6% to 8.0±0.6% after the 4-week run-in, and to 7.4±0.6% after the 12-week intervention period. In the control group, the HbA1c values were 8.2±0.5% at screening, 7.8±0.6% after run-in, and 7.7±0.5% after intervention. The reductions in HbA1c percentages were significantly greater in the closed-loop group compared with the control group (mean difference in change 0.36% [95% CI 0.19–0.53]; P<0.0001). The time spent with glucose concentrations <70 mg/dL (3.9 mmol/L; mean difference in change −0.83% [–1.40 to −0.16]; P=0.0013) and >180 mg/dL (10.0 mmol/L; mean difference in change −10.3% [–13.2 to −7.5]; P<0.0001) was shorter in the closed-loop group than the control group. The coefficient of variation of sensor-measured glucose, total daily insulin dose and body weight were not different between interventions. No severe hypoglycemia occurred. One diabetic ketoacidosis occurred in the closed-loop group due to infusion set failure. Two participants in each study group had significant hyperglycemia, and there were 13 other adverse events in the closed-loop group and 3 in the control group.
Conclusions
In a wide age range of patients with suboptimally controlled T1D, hybrid closed-loop insulin delivery improved glucose control with reduction of the risk of hypoglycemia.
Hybrid closed-loop systems are characterized by automated insulin delivery, apart from when the user administers insulin boosts at mealtime. The current study shows that compared with SAP therapy, 12-week use of a day-and-night hybrid closed-loop insulin delivery system was associated with an improvement in overall glycemic control and a reduction in hypoglycemia risk in suboptimally controlled type 1 diabetes patients. Day-and-night closed-loop therapy was used for a median of 71% (63–83) of the time over the 12-week period. The hybrid closed-loop system was used safely during daily living without supervision or remote monitoring.
The strength of this study is its multinational, multicenter randomized design of closed-loop use in outpatient settings with a large number of patients. It is also the longest randomized outpatient closed-loop use study of 24 hours per day, 7 days per week, including a wide age range of participants (pediatric and adult patients). Since the study was done without remote monitoring or close supervision in free-living settings, it allows assessment of performance of closed-loop systems per se in the real world. Nevertheless, one limitation is the number of devices comprising the hybrid closed-loop system, which increased the risk of device and connectivity problems. However, the use of the closed-loop system was not associated with any additional burden, as assessed by the participant version of PedsQL.
Since the study objective was to compare algorithmic and nonalgorithmic insulin delivery approaches, threshold suspend and predictive low glucose suspend features were not enabled in the control group, which may impact the results relating rate and time spent with hypoglycemia.
The study limitations include exclusion of participants which might benefit from use of the closed-loop system, as patients with poor diabetes control, patients with impaired hypoglycemia awareness or a history of recurrent severe hypoglycemia, and patients younger than 6 years.
Safety evaluation of the MiniMed 670G system in children 7–13 years of age with type 1 diabetes
Forlenza GP1, Pinhas‐Hamiel O2, Liljenquist DR3, Shulman DI4, Bailey TS5, Bode BW6, Wood MA7, Buckingham BA8, Kaiserman KB9, Shin J10, Huang S10, Lee SW10, Kaufman FR10
1Barbara Davis Center for Childhood Diabetes, Aurora, CO; 2Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Aviv, Israel; 3Rocky Mountain Diabetes and Osteoporosis Center, Idaho Falls, ID; 4USF Diabetes Center, Morsani College of Medicine, University of South Florida, Tampa, FL; 5AMCR Institute, Escondido, CA; 6Atlanta Diabetes Associates, Atlanta, GA; 7University of Michigan Medical School, Ann Arbor, MI; 8Department of Pediatric Endocrinology, Stanford University, Stanford, CA; 9SoCal Diabetes, Torrance, CA; 10Medtronic, Northridge, CA
Objective
To evaluate the outpatient safety of the MiniMed™ 670G system with SmartGuard™ technology in children with type 1 diabetes (T1D).
Methods
Participants (n=105, age=10.8±1.8 years, range 7–13 years) were enrolled at nine centers and first completed a 2-week baseline run-in phase in Manual Mode and then a 3-month study phase with Auto Mode enabled. Sensor glucose (SG), HbA1c, SG variability, and percentage of SG values in glucose ranges were compared. Frequent sample testing with i-STAT® venous reference measurement during a hotel period (6 days/5 nights) evaluated the system's CGM performance.
Results
Auto mode was used 81% (median) of the time. Over the course of the study, overall SG dropped by 6.9±17.2 mg/dL (P<0.001), HbA1c decreased from 7.9±0.8% to 7.5±0.6% (P<0.001), percentage of time in range (70–180 mg/dL) increased from 56.2±11.4% to 65.0%±7.7% (P<0.001), and the SG CV decreased from 39.6±5.4% to 38.5±3.8% (P=0.009). The percentage of SG values within target glucose range was 68.2±9.1% and that of i-STAT reference values was 65.6±17.7%. The percentage of values within 20%/20 of the i-STAT reference was 85.2%. There were no episodes of severe hypoglycemia or diabetic ketoacidosis.
Conclusion
In-home use of MiniMed 670G system Auto Mode for 3 months by 7- to 13-year-old patients with T1D, as in adolescents and adults with T1D, was safe and associated with reduced HbA1c levels and increased time in range compared with baseline.
Following the initial U.S. Food and Drug Administration (FDA) approval of the MiniMed 670G system in people with T1D down to 14 years of age (30), this first hybrid closed-loop system was then evaluated in children 7–13 years of age in this study that included a 2-week run phase in Manual Mode followed by a 3-month study with Auto Mode. Use of Auto Mode was 81% in this study population, and all CGM metrics of interest showed improvement. In addition, sensor performance was evaluated and 85.2% of sensor glucose values were within 20%/20 of the iSTAT reference. Safety was also documented. The next few years will likely witness the rapid progression of additional hybrid closed-loop insulin delivery systems that will follow this same path to regulatory approval, first in adults and older adolescents, and then moving in younger children. It remains to be seen what types of studies will be required for regulatory approval (and insurance approval) for future iterations of approved systems. Adequate evaluation to assure safety and improved efficacy will be balanced with the burden of large and expensive clinical trials. Additional versions of automated insulin delivery systems and advances in the performance of all systems as well as expansion into younger age groups will be a common theme for future issues of this yearbook.
Performance of Medtronic hybrid closed-loop iterations: Results from a randomized trial in adolescents with type 1 diabetes
de Bock M1,2,3, Dart J2, Hancock M1, Smith G2, Davis EA1,2,3, Jones TW1,2,3
1Department of Endocrinology of Diabetes, Perth Children's Hospital, Nedlands, Australia; 2Children's Diabetes Centre, Telethon Kids Institute, Perth, Western Australia; 3Division of Paediatrics, The University of Western Australia School of Medicine, Perth, Australia
Background
This study investigated the performance of an enhanced Medtronic hybrid closed-loop (HCL) algorithm. The system utilized sensor glucose values nonadjunctively for bolus advice, recognized sustained hyperglycemia, suggested insulin bolus correction, and included more accommodative SmartGuard automode parameters that aim to improve function and usability.
Methods
Twelve adolescents aged 13–17 years (mean age 15 years; 5 males, 5 females; mean HbA1c 8.55%) with type 1 diabetes >1 year, HbA1c 7.0%–10%, currently using an insulin pump were randomized to the control Medtronic standard HCL algorithm or to the enhanced intervention Medtronic HCL. Participants attended a 7-day and 7-night nonstructured camp setting.
Results
For the control group, time in target range (3.9–10 mmol/L) was 63.68±10.74% at baseline and increased to 75.85±8.49% during the study (relative Δ19%). Time spent <2.8 mmol/L was 0.61±0.79% at baseline for the control group and decreased to 0.32±0.31% during the study for the control group (relative change 48%). In the intervention group, time in target range (3.9–10 mmol/L) was 52.15±9.55% at baseline and increased to 74.32±8.41% during the study (relative change 42%). Time spent <2.8 mmol/L was 1.07%±1.77% at baseline for the intervention group and decreased to 0.24±0.14% during the study for the intervention group (relative change 78%). Mean sensor glucose was 8.05±0.73 mmol/L versus 8.22±0.56 mmol/L for the control and intervention groups. SmartGuard automode exit frequency was 0.54 exits/person/day for control and 0.12 exits/person/day for the intervention. Participants were in active SmartGuard automode 97.1% and 98.8% of the time for the control and intervention, respectively. Alarm frequency was 2.1 alarms/person/day for the control arm, and 0.26 alarms/person/day in the intervention arm.
Conclusions
Feasibility of the enhanced HCL algorithm was demonstrated with a high proportion of time spent in SmartGuard automode and target glucose range. The iterative changes resulted in fewer SmartGuard automode exits without compromising glucose control.
Although this was a short-term study in a small group of individuals with T1D, it documents a potential next version of hybrid closed-loop system from Medtronic and includes nonadjunctive use of sensor glucose values for bolus decisions (instead of using blood glucose meter values) and iterations to the control algorithm to address sustained hyperglycemia and more user friendly Auto Mode parameters. Staying in Auto Mode in the initial 670G system can be a challenge for some people, especially those with higher HbA1c or who are less attentive to Auto Mode requirements, and the benefits of Auto Mode can only be gained if the user of the system is able to remain in Auto Mode. Therefore, improvements to the 670G—a first-generation technology that was constrained by safety and regulatory concerns as the first FDA-approved system—that allow users to stay in Auto Mode for more time will lead to better glycemic outcomes. Increased usability of diabetes technology has been a major theme over the past few years and will continue to have a very strong influence on what systems succeed in the marketplace.
Predictive low-glucose suspend reduces hypoglycemia in adults, adolescents and children with type 1 diabetes in an at-home randomized crossover study: Results of the PROLOG trial
Forlenza GP1, Li Z2, Buckingham BA3, Pinsker JE4, Cengiz E5, Wadwa RP1, Ekhlaspour L3, Church MM4, Weinzimer SA5, Jost E1, Marcal T3, Andre C4, Carria L5, Swanson V6, Lum JW2, Kollman C2, Woodall W2, Beck RW2
1Barbara Davis Center for Diabetes, University of Colorado Denver, Aurora, CO; 2Diabetes Study Group, Jaeb Center for Health Research, Tampa, FL; 3Division of Pediatric Endocrinology and Diabetes, Stanford University, Stanford, CA; 4Clinical Research, Sansum Diabetes Research Institute, Santa Barbara, CA; 5Division of Pediatric Endocrinology and Diabetes, Yale University, New Haven, CT; 6Clinical Affairs, Tandem Diabetes Care, San Diego, CA
This manuscript is also discussed in the article on Decision Support Systems and Closed Loop, page S-47.
Background
The safety and efficacy of a new insulin delivery system designed to reduce insulin delivery when trends in CGM glucose concentrations predict future hypoglycemia was evaluated.
Methods
A 6-week randomized crossover trial was conducted in people with tT1D (n=103, age 6–72 years, mean HbA1c 7.3% [56 mmol/mol]) to evaluate the efficacy and safety of a Tandem Diabetes Care t:slim X2 pump with Basal-IQ integrated with a Dexcom G5 sensor and a PLGS algorithm compared with SAP therapy. CGM-measured time <70 mg/dL was the primary outcome.
Results
Both study periods were completed by 99% of participants with median CGM use >90% in both arms. Median time <70 mg/dL was reduced from 3.6% at baseline to 2.6% during the 3-week period in the PLGS arm compared with 3.2% in the SAP arm (difference [PLGS − SAP]=−0.8% [95% CI −1.1 to −0.5]; P<0.001). The corresponding mean values were 4.4%, 3.1%, and 4.5%, respectively, indicating a 31% reduction in the time <70 mg/dL with PLGS. Mean glucose concentration did not increase (159 vs 159 mg/dL; P=0.40), nor did percentage of time spent >180 mg/dL (32% vs 33%; P=0.12). Mean pump suspension time was 104 min/day. One severe hypoglycemic event occurred in the SAP arm but none occurred in the PLGS arm.
Conclusions
The Tandem Diabetes Care Basal-IQ PLGS system significantly reduced hypoglycemia without subsequent hyperglycemia. The Results for this study indicate that the system can improve glycemic control to the benefit of both adults and youth with T1D.
This study contributed to the FDA approval of the second company with an automated insulin delivery system, the Tandem Diabetes Care Basal-IQ PLGS system. In contrast to the Medtronic 530G (low glucose suspend) or the Medtronic 670G (hybrid closed loop), this system reduces insulin delivery when CGM glucose concentrations predict future hypoglycemia. CGM use with this system was greater than 90% and time spent below 70 mg/dL was reduced by 31% without an increase in mean CGM glucose, similar to previous studies, despite a mean pump suspension of 104 minutes daily in people with T1D as young as 6 years of age. Increased choice of automated insulin delivery systems is likely over the next few years and this should spur competition, improve system performance, and lead to improved outcomes (glucose control and quality of life) for people with diabetes. Whether the presence of multiple diabetes technology options leads to lower cost for these systems remains to be seen as, at least in the United States, cost for insulin has increased dramatically in the past. Moreover, as diabetes technology demonstrates improved outcomes, access to these systems for all people should be a goal to avoid tiered care based on ability to pay for care.
Home use of day-and-night hybrid closed-loop insulin delivery in very young children: a multicenter, 3-week, randomized trial
Tauschmann M1,2,3, Allen JM1,2, Nagl K3, Fritsch M3, Yong J4, Metcalfe E4, Schaeffer D5, Fichelle M5, Schierloh U5, Thiele AG6, Abt D7, Kojzar H8, Mader JK8, Slegtenhorst S9, Barber N1, Wilinska ME1,2, Boughton C1, Musolino G1, Sibayan J10, Cohen N10, Kollman C10, Hofer SE7, Fröhlich‐Reiterer E11, Kapellen TM6, Acerini CL2, de Beaufort C5, Campbell F4, Rami‐Merhar B3, Hovorka R1,2, on behalf of KidsAP Consortium
1Wellcome Trust‐MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2Department of Paediatrics, University of Cambridge, Cambridge, UK; 3Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria; 4Department of Paediatric Diabetes, Leeds Children's Hospital, Leeds, UK; 5Department of Pediatric Diabetes and Endocrinology, Clinique Pédiatrique, Centre Hospitalier de Luxembourg, Luxembourg City, Luxembourg; 6Division for Paediatric Diabetology, University of Leipzig, Leipzig, Germany; 7Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria; 8Department of Internal Medicine, Medical University of Graz, Graz, Austria; 9Department of Nutrition and Dietetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; 10Jaeb Center for Health Research, Tampa, FL; 11Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
Background
The feasibility and safety of hybrid closed-loop insulin delivery in children with T1D aged 1–7 years was investigated, along with the role of diluted insulin in glucose control was investigated.
Methods
Twenty-four children with T1D on insulin pump therapy (median age 5 years [interquartile range 3–6], HbA1c 7.4±0.7% [57±8 mmol/mol], and total daily insulin 13.2±4.8 units/day) underwent two 21-day periods of unrestricted living in an open-label, multicenter, multinational, randomized crossover study. Hybrid closed-loop with diluted insulin (U20) and hybrid closed-loop with standard strength insulin (U100) in random order were compared. The Cambridge model predictive control algorithm was used during both interventions.
Results
The primary endpoint was proportion of time that sensor glucose was in the target range (3.9–10 mmol/L) was not different between interventions (mean±SD 72±8% vs 70±7% for closed-loop with diluted insulin vs closed-loop with standard insulin, respectively; P=0.16). No difference was found in mean glucose levels (8.0±0.8 vs 8.2±0.6 mmol/L; P=0.14), glucose variability (SD of sensor glucose 3.1±0.5 vs 3.2±0.4 mmol/L; P=0.16), the proportion of time spent with sensor glucose <3.9 mmol/L (4.5±1.7% vs 4.7±1.4%; P=0.47) or <2.8 mmol/L (0.6±0.5% vs 0.6±0.4%; P>0.99), or total daily insulin delivery (17.3±.6 vs 18.9±6.9 units/day; P=0.07). There were no incidences of closed-loop-related severe hypoglycemia or ketoacidosis.
Conclusion
Results of the study indicate that unrestricted home use of day-and-night closed-loop insulin delivery in very young children with T1D to be both feasible and safe. Using diluted insulin during closed-loop delivery provided no additional benefits compared with the use of standard-strength insulin.
This study advances access to hybrid closed-loop insulin delivery systems to children with T1D aged 1–7 years. In addition to demonstrating that home use of day and night closed-loop systems in very young children with T1D is feasible and safe, the investigators also compared the effect of using standard insulin (U100) versus diluted insulin (U20). They tested the hypothesis that in very young children with low insulin requirements and increased sensitivity to insulin, the diluted insulin would result in improved glucose control including a reduced risk of hypoglycemia which is a particular concern in this patient population given many of these children's inability to effectively communicate about hypoglycemia due to their development stage. The study had 90% power to determine a 10% increase in time in range with dilute insulin, but the difference in time in range was not statistically significant (72 vs 70%; P=0.16). The only variable that differed was a lower amount of total daily bolus in the dilute insulin arm of the study (10.4±3.5 vs 11.8±4.2 units/day; P=0.006). This study demonstrates that these young children with T1D who can be very challenging for parents (and healthcare teams) to care may benefit from closed-loop systems. Further testing and expansion of these systems into this population remains a research and clinical care imperative. More studies on how best to achieve optimal control in very young children are needed, including more data on diluted insulin and other variables pertinent to this population.
Liraglutide in children and adolescents with type 2 diabetes
Tamborlane WV1, Barrientos‐Pérez M2, Fainberg U3, Frimer‐Larsen H3, Hafez M4, Hale PM5, Jalaludin MY6, Kovarenko M7, Libman I8, Lynch JL9, Rao P10, Shehadeh N11, Turan S12, Weghuber D13, Barrett T14; for the Ellipse Trial Investigators
1Department of Pediatrics, Yale University, New Haven, CT; 2Pediatric Endocrinology, Angeles Hospital of Puebla, Puebla City, Mexico; 3Novo Nordisk, Søborg, Denmark; 4Diabetes and Endocrinology Unit, Department of Paediatrics, Cairo University, Cairo; 5Novo Nordisk, Plainsboro, NJ; 6Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia; 7Novosibirsk Medical University, Novosibirsk, Russia; 8Division of Pediatric Endocrinology and Diabetes, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA; 9University of Texas Health Science Center at San Antonio, San Antonio, TX; 10Diabetes Research Society, Hyderabad, India; 11Endocrinology, Diabetes and Metabolism Institute, Rambam Health Care Campus, Haifa, Israel; 12Department of Pediatrics, Subdivision of Endocrinology and Diabetes, Marmara University School of Medicine, Istanbul, Turkey; 13Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria; 14Institute of Cancer and Genomic Sciences, University of Birmingham, and Birmingham Women's and Children's Hospital, Birmingham, UK
Background
For most pediatric patients with early T2D, metformin is the regulatory-approved treatment of choice. However, rapid decline in β-cell function combined with severe insulin resistance contributes to early loss of glycemic control with metformin monotherapy. Insulin is the only drug approved for use in youth who do not have an adequate response to metformin monotherapy, whereas a large number of oral and injectable agents are approved for adults. The aim of this study was to confirm the superiority of liraglutide to placebo in controlling glycemia in children and adolescents with T2D when added to treatment with metformin with or without insulin.
Methods
A phase 3, randomized, parallel-group, placebo-controlled trial, with a 26-week double-blind period followed by a 26-week open-label extension period at 84 sites in 25 countries. Inclusion criteria were as follows: patients aged 10 to <17 years with T2D, a body-mass index >85th percentile, and a glycated hemoglobin level 7.0%–11.0% if the patients were being treated with diet and exercise alone or 6.5%–11.0% if they were being treated with metformin (with or without insulin). All patients received metformin during the trial. Patients were randomly assigned, in a 1:1 ratio, to receive subcutaneous liraglutide (up to 1.8 mg/day) or placebo for a 26-week double-blind period, followed by a 26-week open-label extension period. The primary efficacy endpoint was the change from baseline in glycated hemoglobin level at week 26. Secondary efficacy end points were change in fasting plasma glucose levels from baseline, the percentage of patients who reached a glycated hemoglobin level of <7.0%, and change from baseline in the BMI z-score, all at week 26. Additional secondary endpoints included the changes from baseline in body weight, fasting lipid levels, and systolic and diastolic blood pressure. Adverse events were assessed throughout the trial.
Results
Of 135 pediatric patients who underwent randomization, 134 received at least one dose of liraglutide (n=66) or placebo (n=68). Both groups had similar demographic characteristics. At 26 weeks, analysis revealed a mean decrease in HbA1c of 0.64% with liraglutide and an increase of 0.42% with placebo, for an estimated treatment difference of −1.06% (P<0.001); the difference increased to −1.30% at 52 weeks. The fasting plasma glucose level decreased at both 26 and 52 weeks in the liraglutide group, although the level increased in the placebo group. Both groups reported a similar number of patients experiencing adverse events, but overall rates of adverse events and gastrointestinal adverse events were higher with liraglutide.
Conclusions
The current study showed the superiority of liraglutide to placebo when added to metformin, with or without basal insulin, with respect to glycemic control in children and adolescents with T2D. Gastrointestinal adverse events were more common in the liraglutide group.
The number of young patients with T2D is increasing. Lifestyle modification including diet and exercise is only successful in a small proportion of patients; therefore, pharmacotherapy approaches are needed to treat T2D among youth. The current therapeutic options for these patients are limited to insulin and metformin.
However, a high proportion of youth with T2D fail to maintain glycemic control when treated with metformin either alone or in conjunction with lifestyle interventions (31, 32). Insulin therapy, well known to be associated with hypoglycemia and weight gain (33), is often required soon after diagnosis. Thus, there is a need for more treatment options for youth with T2D.
Glucagon-like peptide-1 is secreted from the gut after meals and enhances glucose-induced insulin secretion, inhibits glucagon secretion, suppresses appetite, and delays the gastric-emptying rate. Glucagon-like peptide-1 receptor analogs are already widely used in the adult population to improve glycemic control and induce weight loss in overweight subjects with T2D.
A previous randomized, double-blind, placebo-controlled trial reported that liraglutide once daily in youth (10–17 years old) with T2D was well tolerated, with safety, tolerability, and pharmacokinetic profiles similar to profiles in adults (34). The current study data supports these findings and demonstrated that in children and adolescents with T2D, liraglutide, at a dose of up to 1.8 mg/day (added to metformin, with or without basal insulin), was efficacious in improving glycemic control over 52 weeks. The relatively high incidence of gastrointestinal adverse events may impact the compliance rate in daily life, although they were observed especially during the initial 8 weeks of therapy, and the majority were mild in severity. Interestingly, the statistical superiority of liraglutide to placebo in lowering the BMI z score was not shown in the pediatric population, which may be explained by the fact that only approximately 50% of the liraglutide group received the full dose of 1.8 mg/day during the trial. The study strengths are the large number of patients included from different countries and different ethnic groups. A potential limitation of this trial is the dose escalation schedule that was used, and the fact that only approximately 50% of the patients received the highest dose of liraglutide. This fact may have limited data collection related to the safety profile of liraglutide.
Recently the results of another randomized, placebo-controlled, double-blind single-dose pharmacokinetics, pharmacodynamics, and safety study of treatment with sitagliptin (a dipeptidyl peptidase-4 inhibitor) in pediatric patients (10–17 years old) with T2D have shown that the trends in pharmacodynamics observations are generally consistent with the mechanism of action as a dipeptidyl peptidase-4 inhibitor and its effects on glycemic indices as demonstrated previously in adults (35), which may be another option for oral therapy in pediatric patients with T2D. The addition of other potential medications for the treatment of young patients with T2D may help to better achieve the target glycemic control.
Area deprivation and regional disparities in treatment and outcome quality of 29,284 pediatric patients with type 1 diabetes in Germany: a cross-sectional multicenter DPV analysis
Auzanneau M1,2, Lanzinger S1,2, Bohn B1,2, Kroschwald P3, Kuhnle‐Krahl U4, Holterhus PM5, Placzek K6, Hamann J7, Bachran R8, Rosenbauer J2,9, Maier W2,10, on behalf of the DPV Initiative
1Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany; 2German Center for Diabetes Research (DZD), Neuherberg, Germany; 3Children's Hospital, Ruppiner Kliniken GmbH, Hochschulklinikum der Medizinischen Hochschule Brandenburg, Neuruppin, Germany; 4Practice for Pediatric Endocrinology and Diabetology, Gauting, Germany; 5Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University Hospital of Schleswig‐Holstein, Campus Kiel/Christian‐Albrechts University of Kiel, Kiel, Germany; 6Pediatric and Adolescent Medicine, University Hospital, Martin‐Luther University, Halle, Germany; 7Department of Pediatrics, St. Marien Hospital Landshut, Landshut, Germany; 8Pediatric Practice, Oberhausen, Germany; 9Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany; 10Institute of Health Economics and Health Care Management, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
Background
This study evaluated the association of area deprivation with disparities in healthcare for pediatric patients with T1D in Germany.
Methods
Patients <20 years of age with T1D and German residence documented in the 2015/2016 “diabetes patient follow-up” (Diabetes-Patienten-Verlaufsdokumentation [DPV]) registry were included. Area deprivation was assessed by quintiles of the German Index of Multiple Deprivation (GIMD 2010) at the district level and was assigned to patients. Multivariable regression models (linear, logistic, and Poisson) adjusting for sex, age, migration background, diabetes duration, and German federal state were used to analyze associations between GIMD 2010 and indicators of diabetes care.
Results
In 29,284 patients, from the least deprived to the most deprived quintile, use of continuous glucose monitors (CGM) decreased from 6.3% to 3.4%, and use of long-acting insulin analogs decreased from 80.8% to 64.3%. The use of rapid-acting insulin analogs rose from 74.7% to 79.0%; mean HbA1c increased as well, from 7.84% to 8.07% (62 to 65 mmol/mol), and the prevalence of overweight went from 11.8% to 15.5%; however, the rate of severe hypoglycemia decreased from 12.1 to 6.9 events per 100 patient-years. Associations between area deprivation and other parameters showed more complex pattern (use of CSII) or were not significant.
Conclusions
The study found area deprivation to be associated with key outcomes in pediatric T1D and with treatment modalities as well. The results of our investigation also show that access to CGM and CSII could be improved in the most deprived regions in Germany.
This paper from the DPV Initiative in Germany serves as a reminder that disparities in health remain even in countries with healthcare delivery systems that provide universal healthcare to their citizens. The authors use a measure of deprivation based on geographic location and found a continuum of key measures of diabetes care (HbA1c, CGM use, insulin analogues, and BMI) based on area deprivation (GIMD), such that those living in the most deprived regions have the poorest outcomes. The GMID includes seven domains of deprivation with different weights: income, employment, education, municipal/district revenue, social capital, environment, and security. The GMID has been validated in multiple studies and in this publication serves as an instrument to determine whether area deprivation is associated with regional disparities in the treatment and quality of pediatric T1D outcomes. Studies such as these can be used by healthcare systems to target interventions to improve the health of people in areas with more deprivation and poorer health outcomes. This line of research will become increasingly important as diabetes technology in the pediatric age group becomes more effective to reduce the burden of T1D and to improve glucose outcomes. This also raises the question of equity in pediatric diabetes care in countries where access to care depends on insurance status and those without insurance or with lesser forms of insurance have poorer outcomes. Further study on this topic in additional countries is vital to lead to policy changes to improve access to diabetes technology that promises to improve outcomes for children with diabetes worldwide.
Footnotes
Author Disclosure Statement
No competing financial interests exist for S.S. D.M. has had research support from the NIH, JDRF, NSF, and the Helmsley Charitable Trust, and his institution has had research support from Medtronic, Dexcom, Insulet, Bigfoot Biomedical, Tandem, and Roche. D.M. has consulted for Abbott, the Helmsley Charitable Trust, Sanofi, Novo Nordisk, Eli Lilly, Medtronic, and Insulet.