The incidence of youth-onset type 2 diabetes has increased in parallel with the increase in the number of children with obesity in the United States.1,2 In the period from 2002 to 2012, the incidence of type 2 diabetes increased by 4.8% each year.3
Disease processes associated with diabetes, including the development of insulin resistance and impairment of beta cell function, progress more rapidly in youth-onset type 2 diabetes than in adult-onset diabetes . These factors result in worse glycemic control and a higher risk of diabetes-related complications.1,4-7
The SEARCH Diabetes in Youth Registry Study and a registry study in the Canadian province of Manitoba showed a higher prevalence of diabetic kidney disease, hypertension, retinal disease, and peripheral nerve disease among youth with type 2 diabetes than among those with type 1 diabetes.4,8
Both studies were cross-sectional; the SEARCH study reported post hoc diagnoses and the Canadian study identified results in an administrative database. Additionally, the burden of complications at age 21 years in the cohort in the SEARCH study was estimated using modeling.
After calculation of a standardized mortality rate, data from the Australian National Death Index and the Australian National Diabetes Services Scheme showed an inverse relationship between age of onset of type 2 diabetes and long-term risk of disease. terminal kidney.1,9
The lack of prospective longitudinal data challenged the development of evidence-based guidelines for the prevention and treatment of complications in youth-onset type 2 diabetes.
The authors hypothesize that longitudinal follow-up of participants in the Treatment Options for Type 2 Diabetes in Adolescents and Young People (TODAY) clinical trial would show a rapid accumulation of diabetes-related complications, including the development of damage in life-threatening end organs.
They present here the general incidence and the grouping of complications. Subsequent analyzes will provide a deeper exploration of the risk factors, treatments, and associations for each complication.
| Methods |
> Clinical trial design
The analysis of the primary outcome of the TODAY clinical trial and the protocol were published previously.10 In summary, 699 participants were enrolled at 15 centers in the United States from 2004 to 2009.
Participants were between 10 and 17 years old and had a duration of type 2 diabetes (defined according to the American Diabetes Association 200210 criteria) of less than 2 years, a body mass index (BMI [weight in kilograms divided by square of height in meters]) equal to or greater than the 85th percentile, a fasting C-peptide level of more than 0.6 ng per milliliter, and a negative pancreatic antibody test.
Eligible participants were randomly assigned to receive metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention. Participants were followed for an average of 3.9 years (range, 2 to 6.5).
A total of 319 participants (45.6%) had lack of glycemic control (primary outcome): 51.7% of participants who received metformin alone, 38.6% of those who received metformin plus rosiglitazone, and 46.6% of those who received metformin plus rosiglitazone. % of those who received metformin plus a lifestyle intervention.10 Data on adverse events that occurred during the trial were previously published.10
| Follow-up study design |
In 2011, they enrolled 572 participants (81.8%) from the TODAY trial in the follow-up TODAY2 study, which was conducted in two phases. In the first phase (March 2011 to February 2014), participants received all study diabetes care and were treated with metformin with or without insulin to maintain glycemic control; Data on adverse events were collected in the same way as in the TODAY trial.
From March 2014 to January 2020, a total of 518 participants were transferred to the second observational phase of the study; There were annual study visits, but medical monitoring was carried out by the participants’ health providers.
Because the study offered no treatment or intervention in this phase, only adverse events related to the study procedures were evaluated. The two phases of the study provided a combined mean duration of follow-up of 10.2 years. Participants who had a positive genetic test result for onset of juvenile diabetes were excluded from all analyses.
| Surveillance |
The study was approved by the institutional review board of each participating center. All participants and their parents or guardians provided written informed consent or assent, as appropriate to the participant’s age, in accordance with local guidelines.
The study was designed by the TODAY Study Group, which collected and analyzed the data and endorses the accuracy of the data and analysis. The first draft of the manuscript was written by the manuscript writing group, and the steering committee made the decision to submit the manuscript for publication. No confidentiality agreements were imposed by the primary sponsor (the National Institute of Diabetes and Digestive and Kidney Diseases).
| Definitions of complications |
Similar algorithms were used for classification of diabetes-related complications in the clinical trial and in both phases of the follow-up study, with differences in the frequency of data collection incorporated into the algorithms.
All laboratory analyzes were performed at the Northwest Lipid Research Laboratory according to methods described previously.11 A detailed description of the analysis methods and definitions of complications is briefly provided below.
| Hypertension |
Blood pressure was measured at each visit. Hypertension was defined as blood pressure at or above the 95th percentile for age, sex, and height; a systolic blood pressure of at least 130 mm Hg or a diastolic blood pressure of at least 80 mm Hg on three consecutive occasions; or elevated blood pressure followed by initiation of antihypertensive therapy.12
| Dyslipidemia |
Fasting lipid profiles were obtained annually. Low-density lipoprotein (LDL) cholesterol dyslipidemia was defined as consecutive levels of at least 130 mg per deciliter (3.37 mmol per liter), calculated using the Friedewald equation.
Triglyceride dyslipidemia was defined as consecutive triglyceride values of at least 150 mg per deciliter (1.69 mmol per liter) or a single elevated lipid value followed by initiation of lipid-lowering therapy.13
| Albuminuria as a marker of diabetic kidney disease |
Urine samples were collected annually. If abnormal values were found, the test was repeated on the first sample obtained in the morning. Moderate albuminuria was defined as a ratio of urinary albumin (in milligrams) to creatinine (in grams) of 30, and severe albuminuria as a ratio of at least 300 in at least two of the three measurements.14
| Diabetic neuropathy |
Michigan Neuropathy Screening Instrument (MNSI) and Semmes–Weinstein Monofilament Screening Scores were performed annually.15 Scores on the MNSI range from 0 to 8, with higher scores indicating more severe symptoms of neuropathy.
The MNSI examination was considered abnormal if the score was greater than 2 in at least two consecutive evaluations. The Semmes-Weinstein monofilament examination was considered abnormal if fewer than 8 of 10 answers were correct on at least two consecutive examinations.15
| Diabetic eye disease |
Fundus photography was performed twice for research purposes (in 2010 or 2011 and in 2017 or 2018) and was graded at a centralized reading center by examiners who were unaware of the treatment assigned to the participants.16
Ocular disease was defined as a score of at least 20 according to the Early Treatment of Diabetic Retinopathy Study protocol criteria (grades range from 10 to 85, with higher values indicating a greater degree of retinopathy), or edema clinically significant macular, or both.
| Adjudication of events that occurred outside the study |
During the semiannual follow-up, participants underwent a structured interview to identify events that had occurred since the previous visit. Medical records were obtained for adjudication by the comorbidity evaluation committee according to the prespecified criteria of the guidelines.
| Statistic analysis |
Demographic, metabolic, and nonmetabolic characteristics are presented as means and standard deviations or percentages. The percentages of participants in each phase of the study who did not achieve glycemic control or who had hypertension, LDL or triglyceride dyslipidemia, or moderate or severe albuminuria are reported at the end of the clinical trial.
Complications were grouped to obtain overall classifications: moderate and severe albuminuria were classified as renal disease, abnormal MNSI and monofilament examination results were classified as neuropathy, and LDL or triglyceride dyslipidemia as dyslipidemia.
The percentage of participants with ocular disease was calculated. Microvascular events (nerve, retina, and kidney disease) were added to identify the first occurrence of any event.
Kaplan-Meier estimates were used to estimate all cumulative incidences. Separate univariate and multivariable Cox proportional hazards regression models including available data from all participants were used to estimate the overall risk of any microvascular complication for selected covariates.
Covariates that were prespecified based on known associations were included in the Cox models as fixed or time-varying covariates, including time-weighted arithmetic mean values for glycated hemoglobin, BMI, and insulin sensitivity ( 1 ÷ fasting insulin).
For participants with a missing covariate value, the previously observed value was carried forward. All enrolled participants, regardless of follow-up duration, were grouped according to the number and type of complications.
Associations between the number of microvascular complications and risk factors were evaluated with the use of a cumulative logistic proportional odds model. Complications that occurred during the study were counted, and corresponding event rates were calculated. Analyzes were performed with SAS Software, version 9.4 (SAS Institute).
All analyzes were repeated using a sensitivity cohort that included participants who completed an end-of-study visit for whom laboratory values were available.
| Results |
Complications are more common among patients with hyperglycemia, hypertension, and dyslipidemia.
> Demographic and metabolic characteristics
Cohort characteristics were similar in the TODAY trial and in both phases of the TODAY2 study. At the end of the study, the mean age (± SD) of the 500 participants who were evaluated from March 2014 to January 2020 and included in the analysis was 26.4 ± 2.8 years, and the mean time since diagnosis of diabetes was 13.3 ± 1.8 years. A total of 22 participants who had confirmed midlife onset diabetes were excluded from the analyses.
The median glycated hemoglobin level increased over time and the percentage of participants with a glycated hemoglobin level in the nondiabetic range (<6% [48 mmol per mol]) decreased from 75% at baseline (i.e. i.e., the time of entry into the clinical trial) to 19% at 15 years (i.e., the end of the follow-up study), and the percentage with a glycated hemoglobin level of at least 10% (86 mmol per mol ) was 0% at the beginning of the study and 34% at 15 years.
BMI increased from baseline (reaching a plateau from 3 to 9 years), followed by a gradual decrease; but the overall mean BMI remained in the narrow range of 35 to 37.5. The diabetes medications participants were taking at the end of the study remained almost exclusively insulin and metformin, both of which were prescribed to almost 50% of participants at the time of their final visit; more than a quarter of the participants were not taking medication.
> Hypertension and dyslipidemia
The prevalence of hypertension at the beginning of the study was 19.2%, and the cumulative incidence at 15 years was 67.5%. Dyslipidemia was present in 20.8% of participants at the beginning of the study, and the cumulative incidence at 15 years was 51.6%. There were no differences in the incidences of hypertension or dyslipidemia according to original treatment assignment.
> Kidney, nerve and eye disease
The prevalence of kidney disease at the beginning of the study was 8%, and the cumulative incidence at 15 years was 54.8%. At baseline, 1% of participants had neuropathy, and the cumulative incidence at 15 years was 32.4%.
Retinal disease was assessed twice, precluding determination of cumulative incidence. At the first evaluation (in 2010 or 2011), 13.7% had very mild nonproliferative diabetic retinopathy. After an additional 7 years (in 2017 or 2018), 51% had eye disease, including 8.8% with moderate to severe retinal changes and 3.5% with macular edema.
The cumulative incidence of any microvascular complication was 50% at 9 years and 80.1% at 15 years.
In unadjusted models and models adjusted for sex, race and ethnicity, and age at randomization, factors associated with an increased risk of developing any microvascular complication were race or minority ethnic group, a high glycated hemoglobin level, low sensitivity to insulin, hypertension and dyslipidemia.
There were no differences by original treatment assignment. A sensitivity analysis using the same unadjusted and adjusted models produced similar results.
> Grouping of complications
At the time of the last visit, 270 of 677 participants (39.9%) had no diabetes complications, 215 (31.8%) had one complication, 144 (21.3%) had two, and 48 (7, 1%) had three. In univariate analyses, factors that were strongly associated with increased risk for accrual of complications were race/minority ethnic group, hyperglycemia, high BMI, low insulin sensitivity, hypertension, and dyslipidemia. After adjustment for sex, race and ethnicity, age, and duration of diabetes at randomization, BMI was no longer a risk factor.
> Event rates of clinically identified adjudicated complications
The frequency of all adjudicated cardiac, vascular, and cerebrovascular events was 3.73 per 1000 person-years; there were 17 serious cardiovascular events (myocardial infarction [4 events], congestive heart failure [6 events], coronary artery disease [3 events], and stroke [4 events]).
The rate of all eye disease events, including 60 advanced events, was 12.17 per 1000 person-years. The rate of all liver, pancreas, or gallbladder events was 6.70 per 1000 person-years.
The rate of all nervous events was 2.35 per 1000 person-years. For all kidney events, including end-stage kidney disease, the rate was 0.44 per 1,000 person-years. Six deaths were reported (one from myocardial infarction, one from kidney failure, one from drug overdose, one from sepsis, and two from sepsis with multiple organ failure).
| Discussion |
These prospective longitudinal data indicate that diabetes-related complications appear early in youth-onset type 2 diabetes and accumulate rapidly; At least one microvascular complication developed in 60.1% of study participants.
Additionally, clustering of complications was observed, with 28.4% of participants having two or more diabetes complications at an average age of 26.4 years; Among these participants, the average time since diabetes diagnosis was 13.3 years.
In addition, serious but rare cardiovascular diseases occurred despite the young age of the participants. Taken together, these data illustrate the serious personal and public health consequences of the onset of type 2 diabetes in youth in the transition to adulthood.
The severity of these data is underscored by comparison with the risk of microvascular complications reported in type 1 diabetes and adult-onset type 2 diabetes. Microvascular complications, including diabetic kidney disease, affect approximately 25% of young people with type 1 diabetes duration of more than 10 years.17
The Pittsburgh Epidemiology of Complications of Early-Onset Diabetes in Girls Study reported a 32% cumulative risk for diabetic kidney disease with a duration of type 1 diabetes of 25 years.18
With respect to type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) showed a 25% prevalence for moderately increased albuminuria after 10 years, with an increase in incidence of 2% each year thereafter, thus correlating with an estimated cumulative risk of diabetic kidney disease of 55% at 25 years after the initial diagnosis.19
In the Diabetes Prevention Program (DPP) and the DPP Outcomes Study, the incidence of the composite microvascular outcome (kidney, nerve, and retinal diseases) was between 12.3% and 14.3%. .4% among adult participants with type 2 diabetes.20
The reason for the high incidence of complications in young-onset type 2 diabetes is unknown, but is most likely related to the extreme metabolic phenotype (including severe insulin resistance and rapid worsening of cell function). beta21-23) and to challenging socioeconomic circumstances.24 In this cohort, the accumulation of complications was closely associated with hyperglycemia, insulin resistance, hypertension, and dyslipidemia.
Unfortunately, youth-onset type 2 diabetes is characterized by a suboptimal response to currently approved medications, 10,25,26 which is compounded by major challenges in adherence and management due to age and characteristic socioeconomic factors.27
The only medications approved by the Food and Drug Administration (FDA) for young-onset type 2 diabetes are metformin and insulin, with the recent addition of a glucagon-like peptide-1 (GLP-1) receptor agonist. ).28
Sodium-glucose cotransporter 2 (SGLT2) inhibitors , which prevent the progression of cardiovascular and kidney disease in patients with adult-onset type 2 diabetes, are not yet approved by the FDA for adult-onset type 2 diabetes. young people, and it is unknown whether SGLT2 inhibitors and GLP-1 receptor agonists will have cardioprotective and renoprotective effects in patients with youth-onset type 2 diabetes.
Metabolic bariatric surgery , an emerging intervention for youth with type 2 diabetes, results in durable improvement and weight loss in glycemic control in the majority of patients.29,30
Data from a collaboration between the TODAY study group and the longitudinal Adolescent Evaluation of Bariatric Surgery Study (Teen-LABS) showed a greater effect of bariatric surgery than medical treatment on glycemic and non-glycemic outcomes.29 Teen- LABS showed greater regression and earlier attenuation of kidney disease in youth with type 2 diabetes than in adults with type 2 diabetes.31,32
Given the associations of hyperglycemia, hypertension, and dyslipidemia with a high risk of developing complications, studies are needed that explore early aggressive management of glycemia and risk factors for youth-onset type 2 diabetes. However, until such data are available, primary and secondary prevention strategies based on extrapolation of data from studies in adults should be considered, including the use of medications not yet approved for youth.
Additionally, there is a need to understand the health care needs and health care use patterns of young adults with youth-onset type 2 diabetes, so health systems in countries with large populations of people with type 2 diabetes beginning in youth are prepared for the anticipated needs.
Strengths of this study include a large sample of participants with youth-onset type 2 diabetes with up to 15 years of prospective, comprehensive, and rigorous phenotyping. The diverse cohort is representative of the general population with youth-onset type 2 diabetes in the United States.2,27 Additionally, assessment of complications was predefined and adjudicated.
However, incomplete follow-up of a quarter of the original cohort may have led to underrepresentation of event accumulation and clustering, although findings were consistent in sensitivity analyses.
Furthermore, nicotine use is recognized as an important cardiovascular risk factor; Information on participants’ history of nicotine use was collected but was identified as unreliable during analysis.
Participants were willing to participate in an intensive clinical trial and received intensive management at no cost as part of the study until 2014; therefore, the incidence of complications could have been even higher in the absence of these interventions.
Finally, the lack of longitudinal data on microvascular complications in adolescents without diabetes but with a similar degree of obesity precludes comparison of event rates between youth with and without type 2 diabetes. Furthermore, more specific complications of diabetes, such as ocular, it is widely recognized that they do not occur in populations without diabetes.33
These data show a high burden of diabetes-specific complications in youth-onset type 2 diabetes, with an early and severe effect on people with this disease, as well as substantial implications for public health.
