Complications and comorbidities of T2DM in adolescents: findings from the TODAY clinical trial

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Abstract

With the rise in childhood obesity, type 2 diabetes mellitus (T2DM) has been recognized to occur in adolescents with increasing frequency. Although much is known about T2DM in adults, few studies have examined the treatment and complications of T2DM in youth. The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study was designed to evaluate the efficacy of various treatments and provided a unique opportunity to study the disease progression and appearance of complications in a pediatric cohort with recent onset of the disease. In the TODAY study, hypertension was present in 11.6% of the population at baseline and increased to 33.8% by the end of the study. Prevalence of high-risk LDL-cholesterol rose from 4.5% at baseline to 10.7% at the end of the study. Microalbuminuria was found in 6.3% of the cohort at baseline and increased to 16.6%. Retinopathy was not assessed upon entry into TODAY, but was present in 13.9% of the TODAY cohort at the end of the study. Experience to date indicates that these complications and comorbidities are similar to those seen in adults, but occur on an accelerated timeline. The early manifestation of diabetes complications in youth-onset T2DM suggests that this group will be burdened with the tangible consequences of cardiovascular disease, nephropathy, and retinopathy in the third and fourth decades of life. It is hoped that through an early, aggressive approach to treatment and prevention, we may be able to curb the onset and progression of these potentially devastating outcomes.

Introduction

The prevalence of obesity has rapidly increased in the last century (Ng et al., 2014), and now ranks as one of the major causes of morbidity and mortality in the industrialized world (Calle, Thun, Petrelli, Rodriguez, & Heath, 1999). Based on CDC criteria, obesity has risen among children to its current prevalence of ~ 17% (this is slightly higher then WHO criteria), and disproportionately affects ethnic minorities (Ogden, Carroll, Kit, & Flegal, 2014). The upsurge in childhood obesity is paralleled by an increase in diseases previously seen almost exclusively in adult populations, such as hypertension, dyslipidemia, and type 2 diabetes (T2DM) (Freedman, Mei, Srinivasan, Berenson, & Dietz, 2007). In the SEARCH for Diabetes in Youth study, the prevalence of T2DM in 2009 was estimated to be 0.46 per 1000, a 35% increase compared to 2001 data (Dabelea et al., 2014). Prevalence of T2DM by ethnicity was estimated to be 0.17, 0.79, 1.06, and 1.20 per 1000 among 10- to 19-year old non-Hispanic (NH) whites, Hispanics, NH blacks and American Indians, respectively (Dabelea et al., 2014). Based on the most current data, T2DM accounts for 3% of all diabetes cases among white youth, but 23% among Hispanics, 25% among NH blacks and 64% among American-Indians in the United States (Dabelea et al., 2014).

Although numerous studies have addressed management of diabetes and its comorbidities in adults, few studies have examined the impact of T2DM in youth. The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) was designed to begin to address these issues. The primary goal of the study was to examine the effect of three different treatments (metformin alone, metformin plus rosiglitazone, and metformin plus intensive lifestyle modification) on the durability of glycemic control (Zeitler et al., 2007). The primary outcome of the TODAY study was time to treatment failure defined as either HbA1c ≥ 8% over a 6-month period or the inability to wean from insulin therapy within 3 months after an acute metabolic decompensation (Zeitler et al., 2007).

The study included 699 participants 10–17 years of age diagnosed with T2DM using the prevailing ADA criteria with illness duration of 2 years or less at the time of enrollment (Zeitler et al., 2007). Other inclusion criteria were a BMI ≥ 85% and fasting C-peptide > 0.6 ng/mL with absence of pancreatic autoantibodies (Zeitler et al., 2007). Exclusion criteria included renal or hepatic insufficiency, uncontrolled hypertension, and hypercholesterolemia despite appropriate therapy (Zeitler et al., 2007). The occurrence of comorbidities such as cardiovascular risk factors, microvascular complications, and quality of life were assessed at standard intervals throughout the study to determine the impact of diabetes control as well as other factors on their prevalence and severity (Zeitler et al., 2007).

Of the 699 participants in the TODAY study, 319 (45.6%) reached the primary endpoint (glycemic failure) over an average follow-up time of 3.86 years (Zeitler et al., 2012). Failure rates for all of the treatment arms were high (51.7% in the metformin only group, 38.6% in the metformin plus rosiglitazone group, and 46.6% in the metformin plus intensive lifestyle group), demonstrating the aggressive nature of youth-onset T2DM (Zeitler et al., 2012). Metformin plus rosiglitazone was superior to metformin alone, while metformin plus lifestyle modification was not different from either of the other two groups, suggesting that multiple drug therapy may be necessary early in the disease process for youths with T2DM (Zeitler et al., 2012).

The goal of this review is to describe the complications and comorbidities of T2DM observed during the TODAY study. Although the incidence of various complications and comorbid conditions has been established in adults (Anderson et al., 2001, Bilous, 2008, Cameron and Cruickshank, 2007, Lin et al., 2010, Stratton et al., 2001), very few studies have examined comorbidities in youth-onset type 2 diabetes, and none have done so in the context of a randomized treatment trial. The following is a comprehensive review of these findings from the study.

Section snippets

Cardiovascular risk factors

Previous studies have established T2DM as a major independent risk factor for cardiovascular disease (Anonymous, 1999). According to the Framingham cardiovascular risk assessment, T2DM is equivalent in risk to an increase in age of 10 years in adults, and when combined with other risk factors (e.g., dyslipidemia, hypertension), T2DM increases the risk of cardiovascular disease by an additional three to four fold above that predicted for each risk factor alone (Wilson et al., 1998).

Renal complications and hypertension

The leading causes of end-stage renal disease in the United States are diabetes and hypertension, and diabetic kidney disease continues to increase in prevalence in concert with the increasing prevalence of diabetes (de Boer et al., 2011).

Hypertension (defined as blood pressure ≥ 130/80 mmHg or ≥ 95% for age, height, and sex on at least three confirmed blood pressure reading) at presentation in adolescents with T2DM has been reported to be between 10% and 32% (Pinhas-Hamiel & Zeitler, 2007). In a

Ophthalmologic complications

Diabetic retinopathy (the leading cause of blindness in Americans aged 20–74) is characterized by gradual alterations in the microvasculature that disrupt retinal perfusion by increasing vascular permeability. Diabetic retinopathy has four stages: mild nonproliferative retinopathy, moderate nonproliferative retinopathy, severe nonproliferative retinopathy, and proliferative retinopathy. The ultimate consequence of this process when unchecked is vascular proliferation that disrupts retinal

Psychosocial functioning

Psychosocial functioning has been shown to have an impact on one’s ability to self-manage a chronic disease, such as diabetes (de Ridder, Geenen, Kuijer, & van Middendorp, 2008). Studies in adults with T2DM have shown that major depression is associated with increased risk of microvascular complications, even after controlling for disease severity and self-care activities (Lin et al., 2010). In a meta-analysis of 20 adult studies (3 with T1DM only, 8 with T2DM only, and 9 with both T1DM and

Summary of findings

The TODAY study is the first and only large-scale, randomized trial to assess the impact of intensive therapy on youth-onset T2DM. Metformin alone resulted in durable glycemic control in only half of the participants over a 5-year period, but a combination of metformin and rosiglitazone improved the durability of glycemic control (Zeitler et al., 2012). From the ADOPT trial in adults, the treatment failure on metformin and rosiglitazone monotherapy over a 5-year period was 21% and 15%,

Grant support

This work was completed with funding from NIDDK and the NIH Office of the Director through grants U01-DK61212, U01-DK61230, U01-DK61239, U01-DK61242, and U01-DK61254. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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    Conflict of interest: JBT has no disclosures. SMW receives grant funding from Novo-Nordisk, Bristol-Myers Squibb, and Takeda Global R&D.

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