Progress in understanding youth-onset type 2 diabetes in the United States: recent lessons from clinical trials
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Due to the dramatic increase in the rates of childhood obesity and youth-onset type 2 diabetes (T2D) in the late 1990s in the United States, the US government, through the National Institute of Diabetes, Digestive Disease, and Kidney (NIDDK) and the Centers for Disease Control, funded a series of large studies and trials which, together, have formed the basis for much of what we currently understand about youth-onset T2D.
The review focus on the recent results and implications of the treatment options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and the Restoring Insulin Secretion (RISE) study.
Results and Conclusions
Both TODAY and RISE studies have provided critical insight into the unique aspects of the pathophysiology of youth-onset type 2 diabetes and also provided the evidence base for our current approach to the management of this disorder.
KeywordsInsulin resistance Insulin sensitivity Obesity Type 2 diabetes
Due to the dramatic increase in the rates of childhood obesity and youth-onset type 2 diabetes (T2D) in the late 1990s in the United States, the US government, through the National Institute of Diabetes, Digestive Disease, and Kidney (NIDDK) and the Centers for Disease Control, funded a series of large studies and trials which, together, have formed the basis for much of what we currently understand about youth-onset T2D. The SEARCH for Diabetes in Youth study (SEARCH) is a population-based epidemiologic and surveillance registry of all new cases of diabetes before the age of 18 in 6 geographically and ethnically representative regions in the US, as well as a longitudinal study of the outcomes of a smaller cohort of these individuals. The results of SEARCH to date have been reviewed elsewhere [1, 2]; this study is ongoing and anticipated to continue to provide valuable information on the epidemiology and disease course of type 2 diabetes in the coming years. The HEALTHY study aimed to deliver a randomized, school-based lifestyle intervention program to 42 middle schools (6–8th grade, 12–15 years of age), including changes in the physical education programs, school meals, classroom education planning, and community involvement. The HEALTHY study has been completed and the results have been reported elsewhere .
This review will focus on the recent results and implications of the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study and the Restoring Insulin Secretion (RISE) study, both of which have provided critical insight into the unique aspects of the pathophysiology of youth-onset type 2 diabetes and also provided the evidence base for our current approach to the management of this disorder.
Lessons from TODAY
TODAY was funded by the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) in 2001 and was the first multiethnic, multicenter randomized trial examining T2D in youth and remains unique in this category; recruitment began in 2004 . The primary objective of TODAY was to compare the impact of metformin alone, metformin plus rosiglitazone, and metformin plus an intensive lifestyle program on time to treatment failure, defined as HbA1c ≥ 8% for at least 165 days, ending TODAY with HbA1c ≥ 10%, or the inability to wean from the temporary insulin therapy due to metabolic decompensation. TODAY participants were between 10 and 17 years of age, had T2D diagnosed by American Diabetes Association (ADA) criteria with a duration of less than 2 years, had a BMI at or above the 85th percentile at diagnosis, had an absence of pancreatic autoimmunity and a fasting C-peptide of at least 0.6 ng/ml. TODAY randomized 699 participants and the last study visit occurred in February 2011, leading to variable follow-up ranging from 2 to 6 years. All the diabetes care was provided by the study and diabetes-related comorbidities were managed by protocol. The TODAY cohort was predominately female (64.7%), ethnic minority (20.5% non-Hispanic White), with low socioeconomic status (41.5% had an annual household income below $25,000) and a mean T2D duration of 7.8 months . At the end of the TODAY clinical trial in 2011, participants entered TODAY2, phase 1 (T2P1) during which rosiglitazone and the lifestyle intervention were stopped, but participants continued to receive diabetes care according to protocol, including management of comorbidities, and the annual outcome assessment visits continued. In 2014, transition to TODAY2, phase 2 (T2P2) occurred and diabetes care for participants was returned to the community. However, the participants remained in a long-term observational follow-up study, consisting of quarterly telephone contact and annual in-person data collection visits. T2P2 is ongoing and is currently funded until 2020.
The TODAY clinical trial reported  that 45.6% of the cohort experienced treatment failure, with the highest rate being in the metformin monotherapy group (51.7%), which was significantly higher than that of the metformin plus rosiglitazone group (38.6%). The rate of failure for the metformin plus intensive lifestyle group was intermediate (46.6%) and was not different from either of the other groups. There were also important sex differences, with girls responding better to rosiglitazone and boys to the lifestyle intervention. Non-Hispanic Black participants had particularly poor outcomes, with more than 50% having failed the initial metformin monotherapy by 12 months. Although adherence declined gradually over time and was associated with the presence of depressive symptoms and stressful life events, adherence did not predict the loss of glycemic control in any analysis .
Beyond the primary outcome, TODAY provided enormous insight into unique aspects of T2D in youth different from those generally seen in individuals with later onset . Most importantly, TODAY demonstrated that pancreatic β-cell function declined at a rate of 20–35% per year in the youth participants , far exceeding that reported in adults in similar study designs, consistent with the much higher rates of failure of both metformin monotherapy and metformin–rosiglitazone combined therapy in youth than adults . Furthermore, this decline in β-cell function was the strongest predictor of medication failure over time in the cohort.
On the other hand, TODAY identified a substantial group of participants who did not progress to loss of glycemic control within 48 months of randomization, termed durable responders, and through multivariate analysis determined that HbA1c at the time of screening and at randomization and baseline insulinogenic index, a measure of β-cell function, were the factors that effectively distinguished between those who failed and those who did not . There was no association with medication adherence or change in BMI, nor with insulin sensitivity, suggesting that there is an underlying biological distinction related to intrinsic aspects of β-cell function between these two groups that outweighs any effect of treatment or other environmental inputs. From the analysis of receiver operator curves, an HbA1c of 6.3% or more after approximately 3 months of metformin was shown to be a predictor of loss of glycemic control; for every 0.1% increase in HbA1c, the risk of loss of glycemic control increased 16%, regardless of the treatment assignment. Girls with an HbA1c of greater than 6.3% had a fourfold increased risk of glycemic failure, with a median time of 11 months; for non-Hispanic Black girls, the increased risk was 11-fold. While the strength of the prediction was less in girls, the optimal cutoff was 5.8%. A reanalysis of this question using the data of 72 months appears to confirm these findings and this analysis is in the process of being prepared for publication. TODAY is now examining the natural history of these durable responders to determine if they are at increased risk for loss of glycemic control over time, by analogy with women who have resolution of dysglycemia after pregnancy but who are at increased risk for development of diabetes in subsequent years.
More recently, TODAY investigators have undertaken an analysis of oral glucose tolerance test response curves, which have been associated in other populations with nuanced differences in β-cell function . In this analysis, the cohort could be divided into those with monophasic, biphasic, and incessantly increasing glucose curves following oral glucose challenge. At randomization, 21.7% of the cohort had a glucose response curve characterized by incessant increase, 68.6% were monophasic, and 9.7% biphasic. The incessant increase group had similar insulin sensitivity, but significantly lower β-cell function, as measured by the C-peptide index, as well as lower disposition index (oDI), a measure of β-cell function “corrected” for the degree of insulin sensitivity, essentially reflecting whether the amount of insulin being secreted is sufficient for the demand. Furthermore, the shape of the glucose response curve predicted the course of β-cell function over time, with the 6-month decline in C-peptide index in the incessant increase group greater than the monophasic and biphasic groups (32.8% vs. 18.1% vs. 13.2%, respectively). The differences in the change in oDI were similar (32.2% vs. 11.6% vs. 9.1, respectively). Not surprisingly, given the previously demonstrated association between β-cell function and glycemic outcome, glycemic failure rates were higher in the incessant increase group than in the monophasic or biphasic groups (58.3% vs. 42.3% vs. 39.1%, respectively). These results confirm that reduced β-cell function near the time of diagnosis and after a short course of metformin is a strong predictor of the subsequent β-cell function and the course of glycemic control, again supporting the concept that intrinsic differences in β-cell function are a critical underlying component of youth-onset T2D and heterogeneity in the population response.
This significant heterogeneity in the population suggests that there may be two overall forms of youth-onset T2D—one that is easily controlled and may remit, at least temporarily, as the insulin resistance of puberty wanes and one that is rapidly progressive. Broadly, these two groups appear to differ in function both early in the onset of T2D and over time. This heterogeneity in treatment response, as well as the longitudinal changes in insulin sensitivity, β-cell function, and related mechanisms, suggest that differences in the ability of the β-cell, and potentially other pathways, to adapt to obesity and the stress of the insulin resistance of puberty likely underlie the observed differences in the development and course of youth-onset T2D.
TODAY demonstrated that complications and comorbidities are highly prevalent in this population of individuals: By 36 months, 23.3% had triglycerides of at least 150 mg/dl or were on lipid-lowering medications and 10.7% had LDL-C of at least 130 mg/dl or were on lipid-lowering medications . During the last year of TODAY, all of the cohort underwent eye exams and the prevalence of any retinopathy was 13.7%, at a mean T2D duration of 4.8 years, although no participant had more than mild non-proliferative diabetic retinopathy (NPDR) or macular edema . Utilizing the National Cholesterol Education Program’s Adult Treatment Panel III definition of metabolic syndrome, 75.8% of participants were classified as having metabolic syndrome at randomization, with no change in prevalence during the first 24 months of TODAY .
The TODAY study performed multiple measures of cardiovascular function. Echocardiography was performed in the last year of TODAY (median 4½ years from diagnosis of T2D, average age 18 years) and identified overall high/normal left ventricular (LV) mass, but 16.2% of the participants had adverse LV geometry (8.1% concentric geometry, 4.5% LV hypertrophy and 3.6% both) . Of most concern, echocardiography was repeated approximately 5 years after the initial exam and left ventricular mass increased by 1.5% and ejection fraction fell by 1.3%, a highly concerning rate of change portending major cardiovascular risk. TODAY also demonstrated associations between glycemic control and RV function (via tricuspid annular excursion) and fitness with LV mass . Adipokines also correlated with cardiac strain, showing the interrelationship between cardiac and metabolic measures.
Youth with T2D have significantly lower maximal exercise capacity, decreased work rate, increased left ventricular mass, and lower cardiac circumferential strain compared to both lean control youth and obese youth of similar BMI [17, 18]. In addition, T2D youth had prolonged VO2 kinetics during submaximal exercise, reflecting poor adaptation to exercise and suggesting defects that have an impact on activities of daily life. The low VO2 peak correlated independently with insulin resistance, free fatty acids, forearm blood flow, cardiac circumferential strain, and adiponectin, illustrating the impacts of lipid, adipokine, vascular, and cardiac abnormalities on functional exercise capacity.
At an average of 7.6 years after diagnosis, arterial stiffness was assessed using pulse wave velocity (PWV), augmentation index (Aix) and brachial distensibility (BrachD). In a comparison with lean controls, 22% (radial) to 50% (femoral) of the TODAY participants had abnormal arterial stiffness overall and their mean arterial stiffness was significantly worse than controls for femoral and radial PWV, Aix, and BrachD .
Diabetic kidney disease (DKD) remains a leading cause of morbidity and mortality in people with T2D [20, 21]. Longitudinal data from the TODAY study found that the prevalence of increased albumin excretion rose from 6.3% of participants at baseline to 16.6% at 3.9 years of follow-up, at the time of glycemic failure prior to the initiation of insulin, and to 18.0% at 5 years of follow-up [22, 23]. Similarly, 11.6% had hypertension at baseline, increasing to 33.8% by the end of the TODAY clinical trial in 2011 .
Perhaps most importantly, hyper-filtration (GFR ≥ 135 ml/min/1.73m2), is prevalent in youth with T2D and predicts rapid GFR decline [17, 18, 19, 20, 21, 22], which is also prevalent in the TODAY cohort using estimated GFR trajectories. Furthermore, TODAY has demonstrated that a strong relationship exists between IR and hyper-filtration in adolescents with youth-onset T2D . GFR is hypothesized to fall progressively after hyper-filtration and leads, in the long run, to end-stage renal disease . Therefore, a rapid decline in GFR ( ≥ 3 mL/min/1.73m2/year) may be the most clinically relevant measure of DKD.
The primary objective of T2P2 is to track the progression of T2D and related comorbidities and complications in the TODAY cohort as they transition to young adulthood. The underlying hypothesis of T2P2 is that youth-onset T2D would progress rapidly and result in high rates of diabetes-related medical complications and comorbidities and that this rapid rate of progression would be related to increased insulin resistance characteristic of puberty, worsening β-cell function, the degree of glycemic control, control of non-glycemic factors, and obesity itself. All participants in TODAY are eligible for enrollment in T2P2, regardless of their participation in T2P1. At the beginning of T2P2 in 2014, the average age of the participants was 21.1 years (range 15–27 years), with a mean of 8.1 years (range 5.5–11.6 years) since diagnosis. Surveillance for the development and progression of diabetes-related complications and comorbidities includes annual physical exams by study staff, protocol-driven study procedures, and events reported by participants at annual visits upon scripted questioning of interim medical history. During T2P2, several procedures (e.g., echocardiography, retinal imaging, pulse wave velocity) were repeated to provide longitudinal comparison with prior procedures performed during TODAY. A sleep study was also performed on 115 representative participants. Information regarding deaths, serious adverse events, and pre-defined medical events and conditions in study participants has been solicited and reviewed by the T2P2 Comorbidity Assessment Committee (CAC) according to pre-established criteria for each diagnosis based on evidence-based national guidelines. The complications dataset will be locked on March 1, 2019, with analysis and reporting expected in the subsequent months. Preliminary review of the data for internal purposes in June 2018 showed strikingly high rates of cardiovascular, renal, retinal, and neural abnormalities, including multiple amputations and two cardiac deaths at a median age of approximately 25 years. These findings, if confirmed in the formal analysis, portend very poor health outcomes in these young adults with youth-onset T2D.
TODAY undertook a collaboration with the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) to compare medical and surgical outcomes in youth-onset T2D . Teen-LABS is a prospective, multicenter, observational study designed to evaluate the efficacy and safety of bariatric surgery in adolescents at one of five participating centers in the United States. There were 30 Teen-LABS participants with type 2 diabetes at the time of surgery; 24 underwent Roux-en-Y gastric bypass and 6 underwent vertical sleeve gastrectomy. Data from these 30 Teen-LABS participants were frequency matched to 63 TODAY participants based on baseline age, race/ethnicity, sex, and BMI. Although this is a secondary analysis, a strength of this comparison is that the two studies used the same central laboratory for all analyses and the definitions of comorbidities were sufficiently similar to be harmonizable. At baseline, the Teen-LABS participants were slightly older, more likely to be female, and had substantially higher BMI and waist circumference, but the cohorts were racially and ethnically similar. At baseline, Teen-LABS participants had higher systolic and diastolic blood pressure, LDL cholesterol, and triglycerides, but the cohorts did not differ by average HbA1c, fasting glucose, insulin, albuminuria, serum creatinine, or estimated glomerular filtration rate. At baseline, 23 of the Teen-LABS participants were on oral medications and 7 on injected therapy, while all TODAY participants were on metformin alone at baseline by protocol.
Over 2 years, BMI in the Teen-LABS cohort declined by 28% but increased by 3.5% in TODAY participants. Similarly, waist circumference decreased by 29 cm in Teen-LABS but increased by 5 cm in TODAY. Most importantly, mean HbA1c declined from 6.8 to 5.5% in Teen-LABS but increased from 6.3 to 7.6% in TODAY participants; after adjustment for BMI change, follow-up HbA1c values remained significantly lower in the Teen-LABS cohort. Looked at in another way, the proportion of Teen-LABS participants with HbA1c < 5.7% increased from 38% at baseline to 77% after 2 years, but decreased from 27% at baseline to 13% in TODAY participants. Furthermore, after 2 years, 95% of Teen-LABS participants and 37% of TODAY participants had HbA1c values < 6.5. None of the Teen-LABS participants were using medication for control of type 2 diabetes at 2 years, while all the TODAY participants remained on intensive medical therapy. Regarding comorbidities, the prevalence of elevated blood pressure decreased from 67% at baseline to 19% at 2 years in the Teen-LABS group, but doubled from 21 to 42% in TODAY participants. Similarly, the prevalence of dyslipidemia decreased from 72% at baseline to 43% at 2 years in Teen-LABS, while there was no change in TODAY participants. Finally, the prevalence of low GFR decreased from 24% at baseline to 0% at 2 years, while the proportion with elevated urinary albumin/creatinine ratio decreased from 26% at baseline to 5% at 2 years. No changes were seen in GFR or albumin/creatinine ratio in the TODAY participants. An analysis of the impact of surgery on hyper-filtration is ongoing. On the other hand, 40% of the Teen-LABS participants experienced reoperation or hospital admission in the 2 years of follow-up, compared to 3% of TODAY participants.
Although a secondary analysis of only a small group of individuals was performed, the comparative outcomes for youth with T2D treated surgically demonstrated by this collaboration were substantially better than those treated medically, with achievement of degrees of glycemic control and reduction in cardiovascular risk burden unattainable despite intensive medical therapy and labor-intensive staff support in TODAY. These outcomes suggest that bariatric/metabolic surgery is likely to play an important role in the management of youth with T2D, at least until the mechanism of action of surgery is clearly defined and achieved through non-surgical means. However, further research is required to understand the impact of the increasing popularity of vertical sleeve gastrectomy on metabolic outcomes and complication rates and to understand and reduce the high rates of post-operative complications in these individuals.
Lessons from RISE
The Restoring Insulin Secretion study is the most recent of the clinical trials that has contributed to our understanding of youth-onset T2D . The first results from RISE were reported at the Annual Meeting of the American Diabetes Association in 2018 and published in companion articles in Diabetes Care [28, 29, 30]. Additional results comparing adult and youth outcomes will be presented at the American Diabetes Association Annual Meeting in 2019 with companion papers expected in Diabetes Care.
The progressive decline in β-cell function is increasingly recognized as critical to the pathophysiology of T2D and, as noted, appears to be substantially more rapid in individuals with youth-onset T2D than when the disorder occurs later in life. β-cell dysfunction leads to loss of control of both fasting and post-prandial glucose and fatty acid metabolism and, since excess glucose and fatty acid exposure can result in further β-cell dysfunction , there is an accelerating cycle of dysfunction and toxicity. Therefore, the initial dysregulation of glucose and fat metabolism would appear to be primary targets for preservation of β-cell function in prediabetes and early stages of T2D. Previous studies of the progression from prediabetes to diabetes in adults have provided evidence that such an approach can improve β-cell function, including studies of thiazolidinediones, metformin and insulin. For example, metformin reduced the risk progression to T2D among adults with prediabetes in the Diabetes Prevention Program (DPP), associated with improvements in both insulin sensitivity and β-cell function [32, 33]. The Outcome Reduction with Initial Glargine Intervention (ORIGIN) study found that the long-acting insulin glargine reduced the risk of progression to type 2 diabetes at the conclusion of active therapy, with persistent benefits after withdrawal of therapy. Furthermore, studies indicate that normalization of glucose metabolism with a short course of intensive insulin therapy, including a large trial from China , can lead to sustained remission of diabetes and improvement in β-cell function.
Based on these previous studies, NIDDK supported exploratory trials to examine strategies to preserve and/or improve β-cell function in youth (metformin, insulin) and adults (metformin, insulin, glucagon-like peptide-1 receptor agonist, gastric banding) during active therapy and to test whether these effects can be sustained after treatment withdrawal. Ninety-one youth with prediabetes or recently diagnosed T2D participated in a randomized open-label clinical trial comparing insulin glargine (3 months) to lower fasting glucose to < 90 mg/dL followed by metformin (9 months) against metformin (12 months). At 12 months, treatments were discontinued and the participants retested at 15 months. β-cell function and insulin sensitivity were rigorously tested using hyperglycemic clamp methodology. Furthermore, although the treatment interventions used in the adult trial were not exactly the same, there was substantial overlap and outcomes measure protocols were identical, allowing direct comparison, for the first time, of T2D pathophysiology and treatment response in youth and adults.
The first important results from RISE come from an examination of the baseline measures of insulin sensitivity and secretion in youth and adults. Although profound insulin resistance in youth was anticipated by clinical observations of severe acanthosis nigricans and very high insulin requirements in youth with T2D, using hyperglycemic clamp methodology, a robust approach for determining both insulin sensitivity and secretion, RISE demonstrated that insulin sensitivity was approximately 50% lower than in adults, even when adjusted for BMI [28, 29]. This means that even at the same degree of adiposity, the youth had substantially more insulin resistance than the adults, likely reflecting the combination of both obesity-related insulin resistance and puberty-related insulin resistance, along with other potential contributors. Furthermore, insulin secretion in the youth was two to threefold greater in the youth than in the adults. To some extent, increased insulin secretion would be expected given the more profound insulin resistance, but the increased secretion was still present even when adjusting for the degree of insulin sensitivity, meaning that the youth were, in fact, hypersecreting relative to their insulin resistance at least in these early stages of T2D. Given evidence that sustained demand on the β-cell may be an important predictor of progression of β-cell dysfunction, it is logical to assume that this hypersecretion is a critical contributor to the unique pathophysiology of youth-onset T2D. Furthermore, these results suggest that understanding the causes of this hypersecretion and identifying effective strategies to protect the β-cell from the consequences of severe insulin resistance in youth will be important areas for future research.
The primary outcome of RISE also provides important insight into youth-onset T2D . AT the end of 3 months, the glargine dose in those randomized to insulin was 0.6 ± 0.4 units/kg/day, a surprisingly high dose in these adolescents with relatively minor abnormalities in glucose regulation prior to treatment. The mean fasting glucose attained was 93 ± 12 mg/dL; 50% of the participants achieved the goal of 80–90 mg/dL. BMI declined in the metformin group over the first 9 months, but was not different between the groups at 12 or 15 months. HbA1c declined in the glargine group at 3 months and in both groups at 6 months, but returned to baseline by 9 months and was significantly above baseline at 15 months (3 months off therapy); the HbA1c was not significantly different between the groups at any time point. Similar results were seen for both fasting and 2 h glucose by oral glucose tolerance test. These results indicate small but unsustained improvements in both adiposity and glycemia with either glargine followed by metformin or metformin alone, different than expected from previous adult studies.
There was no difference at 12 or 15 months in any measure of β-cell function. Furthermore, neither treatment improved or maintained β-cell function during or after active treatment. Indeed, β-cell function declined significantly from baseline while on active treatment and was significantly worse than baseline at 15 months (3 months off treatment). Therefore, neither treatment previously shown to be effective in adults, was able to halt the progressive deterioration of β-cell function in youth.
These results from RISE demonstrate that youth with T2D have more severe insulin resistance than adults, are hypersecreting insulin even when their insulin resistance is taken into account, and do not have slowing down of β-cell deterioration even with effective lowering of glycemic demand. Taken together, these results support the view that youth-onset T2D reflects a more serious β-cell defect for which more aggressive interventions will be required.
Implications for the evaluation and management of youth-onset T2D
Between them, SEARCH, HEALTHY, TODAY and RISE have contributed to a substantial and growing understanding of the epidemiology, disease course, risk factors, presentation, treatment responses, and complications in youth-onset T2D in the United States, as well as important insights into the differences in pathophysiology between youth-onset T2D and T2D occurring in older individuals. These studies provide a perspective on youth-onset T2D as an aggressive disorder characterized by severe insulin resistance and rapid β-cell deterioration following a period of insulin hypersecretion, poor response to current therapies, accelerated development of comorbidities, and serious health consequences in young adulthood. At the same time, these studies have now provided sufficient evidence base to develop well-supported approaches to the evaluation and initial and subsequent management of glycemia in individuals with youth-onset T2D, as well as the surveillance for and treatment of comorbidities and complications in this population. These evidence-based approaches are reflected in the just rereleased American Diabetes Association Statement on the Evaluation and Management of Type 2 diabetes in youth . Similar guidelines that take into account a more international perspective have also been recently published by the International Society for Pediatric and Adolescent Diabetes .
Compliance with ethical standards
Conflict of interest
No financial or nonfinancial benefits have been received or will be received from any party related directly or indirectly to the subject of this article.
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