SEARCH is a multi-ethnic, population-based registry with five sites across the U.S. ascertaining physician-diagnosed non-gestational incident diabetes cases among individuals aged 19 years or younger. More detailed information about SEARCH is published elsewhere^10-12. Each site conducts active surveillance under the Health Insurance Portability and Accountability Act (HIPAA) waivers of consent using networks of endocrinologists, healthcare providers, hospitals and community health centers, and clinical and administrative data systems along with electronic medical records. Cases are confirmed as valid after review of medical records or by the referring physician. All registered participants are asked to complete an Initial Participant Survey (IPS) (average response rate for incident cases 2006-2012, 82%). Participants diagnosed in 2006, 2008 and 2012 were invited to participate in an in-person baseline research visit (IPV) (average response rates between 46%, and 65%), where data were obtained on sociodemographic characteristics, height, weight, medications, glucose control and other risk factors for diabetes-related complications, including laboratory measurements. Blood samples (A1c) were taken and analysed at a central laboratory. For the purposes of this manuscript, the IPV baseline research visit is referred to as the baseline visit.

The YDR registry is an observational multicenter clinic-based registry enlisting all cases of physician-diagnosed diabetes, diagnosed at the age of 25 years or younger, who were registered at a designated registry reporting center on or after January 1, 2000, residing within assigned geographical areas. More detailed information about YDR is published elsewhere¹³. Individuals are classified into various diabetes categories based on the assessment of the principal investigator at the reporting center using symptom-based clinical criteria agreed upon by the registry expert group prior to initiation of data collection in 2006. YDR data collection is coordinated by the Indian Council of Medical Research through regional collaborating centers and their interacting reporting centers. All individuals have a proforma (registration and clinical extract) completed by the participant and physician to obtain information on socio-demographics, clinical profile, anthropometrics and laboratory measurements of the individual. Data from the period 2000-2006 were collected retrospectively in a structured format from medical records; while data from 2006-2012 were collected prospectively and completed by both the participant and physician at the time of registration, which is referred to here as the baseline visit. There are eight regional collaborating centers across India who provide cases to YDR. For this project, data from three of the eight regional collaborating centers (one in Chennai (Madras Diabetes Research Foundation) and two in New Delhi (All India Institute of Medical Sciences (AIIMS) and the University College of Medical Sciences, Delhi)) were used. Both previously treated and untreated cases were included. For the purposes of this manuscript, the baseline registration visit is referred to as the baseline visit.

The SEARCH and YDR data were harmonized to the structure and terminology in the Observational Medical Outcomes Partnership (OMOP) Common Data Model. Additional details of data harmonization are provided in a previous article by Hockett et al. within this special edition.

For the current analysis, we included incident T1D and T2D cases diagnosed between 2006 and 2012 among youth aged <20 years at diagnosis for YDR, and a subset of SEARCH participants diagnosed with diabetes in 2006, 2008, and 2012 and who completed a baseline visit. This sample selection aligned the clinical information in both registries.

For continuous variables, mean values ± standard deviation are presented. Two-sample t-tests were conducted to assess differences in continuous variables between the two registries. For categorical variables, counts and percentages are presented. Chi-square tests were used to determine differences in variables of interest across the two registries. All the statistical analysis was conducted using SAS statistical software v9.4 (SAS Institute, Inc, Cary, North Carolina). P-values <0.05 were considered significant.

A variety of insulin formulations and pre-mixed human insulins and analogs are available in both countries. Most patients with T1D need multiple daily injections, a basal/bolus regimen or an insulin pump^16-19. In SEARCH, 65.0% of T1D youth were on basal/bolus regimens while only 23.5% of YDR youth with T1D were using such a regimen. Moreover, there were significant differences in usage of insulin pumps between US and India (16.2% vs 1.5%, p<0.001). While in the US, paediatric patients with T1D commonly use insulin pumps for insulin delivery; in India, pumps are very expensive and the cost is not reimbursable or covered by insurance, thus limiting their use. Factors like motivation level, family support, and cognitive skills may also influence the use of insulin pumps in Indian children and adolescents²⁰. While this was not directly studied here, the main reasons for differences in the treatment pattern for youth with T1D between the two registries is likely to be related to differences in provider practices and the health care delivery systems between the two countries, and not to major differences in availability of insulin types and formulations.

Among the insulin pump users in SEARCH, a substantial proportion (45.5%) had good glycemic control (<7.5%), although this was not observed among the smaller number of YDR youth using pumps (12.5%). In a retrospective analysis of 33 patients (17 with T1D and 16 with T2D) who were on insulin pumps and were followed up for a mean duration of 3.4 years, a significant reduction in HbA1c was observed after initiating pump therapy with a reduction in frequency of severe hypoglycaemia with no instances of diabetic ketoacidosis²¹. A previous report by SEARCH found that youth with T1D that used an insulin pump had lower A1C levels and less hospitalizations without any hypoglycemic episodes²². Taken together, these findings suggest that insulin pump therapy for youth with T1D offers a better chance at adequate glycemic control.

The majority of youth with T2D in both registries were on approved treatment regimens (i.e. metformin and insulin). More than 30% of the SEARCH and YDR youth with T2D were on insulin or insulin + any OHAs. Unlike T1D, an insulin-containing regimen is generally not the first-line of treatment for T2D, unless the patient presents in diabetic ketoacidosis (DKA) or has a high A1c (>10%) at the time of diagnosis²³. When oral treatment fails, insulin is recommended to improve glycemic control. Studies in adults have suggested that early insulin treatment in T2D reduces the risk of chronic vascular complications^24,25, but long-term data in youth are limited.

In SEARCH, 60-70% of T2D youth were at the recommended glycemic target of <7.5%, whereas in YDR, 20 to 30% met the target regardless of the treatment regimen used. In both the registries, the recommended glycemic control target could not be reached by all, which may be due to their pubertal status. Glycemic control deteriorates during puberty due to increase in lean body mass, which increases insulin requirement leading to insulin resistance. Certain behavioural changes and psychosocial issues occurring during adolescence also further worsens glycemic control²⁶. Therefore, physicians need to identify barriers to achieving optimal glycemic control in order to prevent the development of vascular complications. It is recommended that adolescents with T2D should have two to four A1c measurements per year because adolescents may require insulin therapy more rapidly than adults²⁷. SEARCH had a higher percentage of youth in the insulin + any OHAs group which may be one of the reasons for the lower A1c levels in SEARCH compared to YDR. Among YDR youth, the mean A1c levels were greater than 7.5% for all treatment regimens.

The TODAY study, a clinical trial of U.S. adolescents with T2D, reported that metformin monotherapy maintained optimal glycemic control only in half of the youth and demonstrated that the addition of rosiglitazone, but not intensive lifestyle intervention, was superior to metformin alone^23,28. In another study, glimepiride was shown to reduce A1c levels but was not equivalent to metformin. Moreover, it stimulated weight gain; it is not approved by the Food and Drug Administration for youth with T2D^29,30. There are clinical trials on new oral hypoglycemic agents including DPP-4 inhibitors (sitagliptin, saxagliptin, and linagliptin), and several of the new injectable agents, including GLP-1 agonists (such as exenatide and liraglutide). However, these drugs are not yet approved for youth with T2D. Our study suggests that more aggressive treatments are needed in youth with T2D to bring their glycemic control within target range.

A nationwide Indian study of adults (ICMR-INDIAB) covering four Indian states, showed that higher A1c levels were observed in the oldest age group studied (20–24 years)³¹. In the U.S., the T1D Exchange, a large registry of youth diagnosed with T1D from 67 centers across the U.S., showed glycemic control among patients 8–18yrs old worsened over time³². In this paper, we found that more than 40% of youth with T1D or T2D (aged 19 years or younger) had A1c levels above 7.5%, indicating a substantial burden of suboptimal glycemic control, almost regardless of treatment regimen.

There are several limitations to our study. First, in both registries, the treatment regimens captured at the time of the baseline visit were self-reported and did not capture adherence and compliance. In YDR, data from only three centers (Chennai and two in New Delhi) were included and results may not be fully representative of the larger population of youth with diabetes in India. Since data were not shared across registries, we were not able to conduct multivariate analyses, which would have allowed us to control for differences between the two registries (such as the longer diabetes duration to baseline visit in SEARCH vs YDR). These findings only reflect the treatment patterns and A1c levels of youth at the time of inclusion into the registries, within the first year of diagnosis. In some centers in the U.S., for example, over time, up to 50-70% of T1D youths are being treated with pumps and this later treatment is not captured in this analysis³³. Additionally, ADA targets of care were updated in 2014 and the findings reported here reflect glycemic control during a period of time with slightly different standards of care in the U.S. Finally, and importantly, A1c levels were not standardized across registries. While SEARCH used standardized techniques and a central certified laboratory³⁴, this was not the case for YDR and could explain some of the differences seen in A1c levels between SEARCH and YDR. It is however, likely that the more aggressive treatment regimens in the U.S. explain the relatively more optimal A1c levels achieved among SEARCH youth. The major strength of our study rests on the fact that this is the first attempt to harmonize and compare two youth diabetes registries internationally, including youth with both T1D and T2D.

Development of microvascular complications is closely linked to suboptimal glycemic control in both T1D and T2D. The high A1c levels in youth with both forms of diabetes is of concern, as these individuals are likely to be exposed to a longer period of hyperglycaemia, compared with subjects with onset of diabetes later in life. Indeed, among youth with T2D, complications may sometimes be present even at the time of diagnosis of diabetes^1,35-37. Moreover, in such youth, rapid progression of complications is sometimes observed within 5 years of diagnosis^38-40. Regardless of treatment regimens used, A1c levels for the majority of youth in SEARCH and YDR are above the ADA recommended levels, particularly in YDR. This glycemic burden may put them at high risk of developing complications during the prime of their life unless immediate steps are taken to improve diabetes care in youth and lower the A1c levels. Treatment efforts should aim for better glycemic control in both countries in order to prevent long term complications.