Outcomes of Youth-Onset Type 2 Diabetes

While pediatric gastroenterologists typically are not coordinating the management pediatric patients with Type 2 Diabetes Mellitus (T2DM), we certainly see many with T2DM and often are involved in some aspects of their care (eg. fatty liver disease).

A recent study (TODAY study group. NEJM 2021; 385: 416-426. Long-Term Complications in Youth-Onset Type 2 Diabetes) details the heavy burden due to T2DM.

This “TODAY2” study annually followed 500 participants from the TODAY trial (2011). The age of the participants was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years.

Key definitions:

  • Hypertension: At 95% or greater for age (at least SBP 130 or DBP 80) on 3 consecutive visits and/or needing medical therapy
  • Dyslipidemia: Consecutive LDL values of at least 130, consecutive triglycerides of at least 150, or values requiring medical therapy
  • Albuminuria: ratio of urine albumin to creatinine of at least 30
  • Diabetic Nerve Disease: based on scores of Michigan Neuropathy Screening Instrument -consecutive values of at least 2 or more (scores range from 0 to 8)
  • Diabetic Eye Disease: based on a grade of at least 20 according to criteria of Early Treatment Diabetic Retinopathy Study criteria (grades range from 10 to 85)

Key findings:

  • The cumulative incidence of hypertension: 67.5%
  • The incidence of dyslipidemia: 51.6%
  • The incidence of diabetic kidney disease:54.8%
  • The incidence of nerve disease: 32.4%.
  • The prevalence of retinal disease: 13.7% (2010 to 2011) and 51.0% (2017 to 2018)

The authors note that the high incidence of complications is “most likely related to extreme metabolic phenotype (which includes severe insulin resistance and rapid worsening of beta-cell function) and to challenging socioeconomic circumstances.”

Study strengths: 15 years of prospective, extensive data and population representative of U.S.

My take: “Taken together, these data illustrate the serious personal and public health consequences of youth-onset” T2DM by age 26 years!! Unless medical therapies improve further, these consequences argue for careful consideration of bariatric surgery.

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Comparing Gastric Bypass Outcomes in Adolescents and Adults

Studies have shown that adults with obesity who were obese as adolescents have worse medical outcomes than persons who became obese in adulthood (Nat Rev Endocrinol 2018; 14: 183-8; NEJM 2011; 365; 1876-85). Thus, the question is whether earlier intervention would improve outcomes.

A recent study (TH Inge et al. NEJM 2019; 380: 2136-45, editorial TD Adams, pgs 2175-7) compares the 5-year outcomes of adolescents (n=161) and adults (n=396) who underwent Roux-en-Y gastric bypass (RYGB). The two prospectively enrolled cohorts were participants in two related but independent studies.

Key findings:

  • There was similar weight loss in both groups at the 5-year mark: -26% in adolescents and -29% in adults
  • Adolescents had greater remission in both type 2 diabetes (86% vs 53%) and in hypertension (68% and 41%).
  • Three adolescents (1.9%) and seven adults (1.8%) died in the 5-years after surgery.  Two of the adolescents deaths were consistent with overdose.
  • Reoperations were significantly higher in adolescents than adults (19 vs 10 reoperations per 500 person years). The authors comment that the reason for this finding is unclear, possibly related to recall bias or closer monitoring of the adolescents.
  • Nutrient deficiencies were common in adolescents at followup. After 2 years, 48% of adolescents had low ferritin compared with 29% of adults (98% of participants had normal ferritin prior to RYGB. The authors note that  this is likely related to adherence to vitamin/mineral supplementation (which is needed lifelong).

Limitations: observational study design

The associated commentary::

  • “Almost 6% of adolescents in the U.S. are severely obese and  bariatric surgery is now the only successful long-term management…Negative health outcomes of bariatric surgery reported in adolescents mirror those reported in adults — including, for example, potential for self-harm (including suicide) and increased risk of alcohol or drug abuse.”
  • “Adolescent patients may not have fully developed the capacity for decision making, especially about a procedure that will have lifetime consequences.”

My take: This study and commentary point out some clear health benefits for adolescents who undergo RYGB. Given the lifelong need for monitoring and adherence with medical treatment as well as some of the negative health outcomes, it is also clear how challenging it is to proceed with RYGB in teenage years.

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Breakfast: a marker for heart-healthy habits

Summary of study (Circulation 2013; 128: 337-343) from Epocrates (emphasis in blue by blog):

Study Question:
Is eating breakfast or not associated with risk for coronary heart disease (CHD) among men residing in the United States?
Data for this analysis were from the Health Professionals Follow-up Study, an ongoing prospective study of male health professionals. Approximately 97% of participants were of white European descent. Eating habits, including breakfast eating, were assessed in 1992 in 26,902 American men, ages 45-82 years, who were free of cardiovascular disease and cancer. Participants were followed through mailed biennial questionnaires that ascertained medical history, lifestyle, and health-related behaviors. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for CHD, adjusted for demographic, diet, lifestyle, and other CHD risk factors.
Participants who did not report eating breakfast were younger than those who did, and were more likely to be smokers, to work full-time, to be unmarried, to be less physically active, and to drink more alcohol. Men who reported that they ate late at night were more likely to smoke, to sleep <7 hours a night, or to have baseline hypertension compared with men who did not eat late at night. The late-night eating abstainers were more likely to be married and to work full-time, and ate on average one time less per day than the late-night eaters. The mean diet quality of the participants was high among participants, regardless of their breakfast or late-night eating status. During 16 years of follow-up, 1,527 incident CHD cases were diagnosed. Men who skipped breakfast had a 27% higher risk of CHD compared with men who did not (relative risk, 1.27; 95% confidence interval, 1.06-1.53). Compared with men who did not eat late at night, those who ate late at night had a 55% higher CHD risk (relative risk, 1.55; 95% confidence interval, 1.05-2.29). These associations were mediated by body mass index, hypertension, hypercholesterolemia, and diabetes mellitus. No association was observed between eating frequency (times per day) and risk of CHD.
The investigators concluded that eating breakfast was associated with significantly lower CHD risk in this cohort of male health professionals.
These data suggest that time of meals is associated with other lifestyle behaviors. Adjustment for body mass index, hypercholesterolemia, hypertension, and diabetes [resulted in the relationship between breakfast (and late-night meals) and CHD no longer being significant.] Physicians may use this information to assist in the identification of those who may be at risk and need to improve lifestyle habits. However, it is unlikely that eating breakfast by itself would confer significant protection against heart disease.

Full text available at http://circ.ahajournals.org/content/128/4/337

Related blog post:

Skipping breakfast –boomerang effect for obesity | gutsandgrowth

TODAY is worrisome for a lot of tomorrows

The TODAY study (NEJM 2012; 366: 2247-56 and editorial 2315-16) =Treatment Options for Type 2 Diabetes in Adolescents and Youth.

While the study has a catchy acronym, the findings are disturbing.  Eligible patients (n=699) were 10 to 17 years old were followed on average over 3.86 years; they were divided into three groups:

  • Metformin 1000mg BID –48% achieved primary outcome (glycated hemoglobin <8% for at least 6 months).
  • Metformin with lifestyle changes –53% achieved primary outcome.  The lifestyle counseling that patients received in the study likely exceeded the typical counseling that most patients receive in clinical practice.
  • Metformin with rosiglitazone (4mg BID) –61% achieved primary outcome.  While this group had the best glycemic response, this group also had the greatest increase in BMI.

Other findings:

Comorbid conditions were common:

  • Hypertension: at baseline in 81 (11.6%) and new cases during study 155 (22.2%)
  • Dyslipidemia (LDL): at baseline in 23 (3.3%) and new cases during study 49 (7%)
  • Triglyceridemia: at baseline in 127 (18.2%) and new cases during study 70 (10%)
  • Microalbuminurina: at baseline in 44 (6.3%) and new cases during study 72 (10.3%)

Frequent adverse events noted with medications (Table 2 in study): gastrointestinal symptoms noted in about half of all study participants in each group, rash noted in about 40%, and elevated LFTs in about 40%.

Take home messages (borrowed from editorial):

“Most youth with type 2 diabetes will require multiple oral agents or insulin therapy within a few years after diagnosis”

“Fifty years ago, children did not avoid obesity by making healthy choices; they simply lived in an environment that provided fewer calories and included more physical activity.”

“Public-policy approaches–sufficient economic incentives to produce and purchase healthy foods and to build safe environments that require physical movement…will be necessary to stem the epidemic of type 2 diabetes and its associated morbidity.”

Related posts:

Treating diabetes with surgery

Cardiovascular disease for the entire family

Staggering cost of obesity

Lower leptin with physical activity

Cardiovascular disease for the entire family

This month’s Journal of Pediatrics features an article for the entire family (J Pediatr 2012; 160: 590-7 [editorial pg 539]).  The authors demonstrate that children screened for cholesterol can serve as an index case for the entire family.  During a 26-year prospective followup of 852 pediatric patients (5-19 years old at enrollment) from Cincinnati, the authors assessed relationships of childhood risk factors with parental cardiovascular disease (CVD), type 2 diabetes (T2DM), and high blood pressure (HBP).

  • Pediatric HBP and low HDL cholesterol were predictive of parental CVD ≤age 50
  • Pediatric HBP and high triglycerides were predictive of parental CVD ≤age 60
  • Pediatric high triglycerides and high LDL cholesterol were predictive of parental CVD ≤age 66

The related editorial reviews large studies regarding lipid assessments, including the Bogalusa study with more than 3000 children and the Muscatine study with more than 14,000 children.  In addition, the editorial reviews the recommendations from an expert pediatric panel which suggested screening all children for dyslipidemia between 9 and 11 years. Interestingly, the editorial reviews the fact that screening for cholesterol has not been shown to harm children.  “The evidence is not sufficient to demonstrate any adverse affects.”

Although no harm has been proven, the expert recommendations do not have prospective data demonstrating benefit either.  While it is known that atherosclerotic lesions, including fatty streaks and calcifications, can develop in childhood, it is not known that current treatment strategies will improve long-term outcomes.  This study, however, provides an additional rationale for screening; namely, by identifying children with dyslipidemia, primary care providers can identify parents with cardiovascular disease who are more likely to benefit from urgent intervention.

Additional references:

  • http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=prof (cholesterol risk calculator)
  • Pediatrics 2011; 128 (suppl 5): S213-56.  Expert panel guidelines for cardiovascular health and risk reduction in children and adolescents.
  • -NEJM 2011; 365: 2078.  Use of statins to lower LDL to 60-70 range halted progression of coronary artery disease.
  • -Pediatrics 2007; 120: e189, e215.  US Preventive Services Task Force:  “the evidence is insufficient to recommend for or against routine screening for lipid disorders” up to age 20.  Consider pediatric drug Rx:
    1. After dietary failure
    2. LDL >190
    3. LDL >160 & FHx of CVD before age 55
    4. triglycerides >250-500 persistently
  • Pediatric Nutrition Handbook AAP Lipid types:type I -increased trig  (rare)
    type IIa -increased chol & LDL
    (most common)
       Homozygous: chol >500
         xanthomas before 10 yrs, vascular dz before age 20
       Heterozygotes with lower chol
    type IIb -elevated trig & chol/LDL
    (3rd most common)
    type III -abnormal LDL density (rare)
    type IV -elevated trig (2nd most common)
         may be increased with diabetes, obesity, inadequate fasting; may need to study parents to establish dx
    type V -increased trig/VLDL (rare)
         exclude nephrotic synd, hypothyroid, diabetes