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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From Chesapeake and Ohio Canal National Historic Park (near Washington D.C.)

Possible Quality Metric for Fatty Liver Disease: Dyslipidemia

With nonalcoholic fatty liver disease (NAFLD), it is well-documented that adverse cardiovascular events influence mortality more than any other factor.  Dyslipidemia plays an important role in these outcomes.

A recent study (KE Harlow et al. J Pediatr 2018; article in press. DOI: https://doi.org/10.1016/j.jpeds.2018.02.038) indicates that “clinically actionable dyslipidemia” is present in more than half of pediatric patients with NAFLD.

This multicenter, longitudinal cohort study included children (n=585) with NAFLD enrolled in the National Institute of Diabetes and Digestive and Kidney Diseases Nonalcoholic Steatohepatitis Clinical Research Network.

Key findings:

  • The prevalence of children warranting intervention for low-density lipoprotein cholesterol at baseline was 14%. After 1 year of recommended dietary changes, 51% achieved goal low-density lipoprotein cholesterol, 27% qualified for enhanced dietary and lifestyle modifications, and 22% met criteria for pharmacologic intervention
  • Elevated triglycerides were more prevalent, with 51% meeting criteria for intervention at baseline. At 1 year, 25% achieved goal triglycerides with diet and lifestyle changes, 38% met criteria for advanced dietary modifications, and 37% qualified for antihyperlipidemic medications.

My take: Assessing/managing dyslipidemia is an important component of NAFLD care.

Link to abstract: Clinically Actionable Hypercholesterolemia and Hypertriglyceridemia in Children with Nonalcoholic Fatty Liver Disease

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Cholesterol controversy

Recent guidelines (Pediatrics 2012; 130: 353-56) have recommended universal screening for hypercholesterolemia between ages 9-11 along with additional targeted screening.  These recommendations have been met with a number of criticisms (Pediatrics 2012; 130: 349-52).

In the first referenced commentary, the experts who issued the guidelines commissioned by the National Heart Lung and Blood Institute (NHBLI) claim that the criticism “misrepresent the evidence regarding screening and the specificity and rigor of the guideline development.”  In the second commentary, the guidelines are considered overly aggressive and not adequately founded on evidence-based medicine.  In addition, they cite two JAMA commentaries that also question the wisdom of the guidelines (JAMA 2012; 307: 257-58, & 259-60).

NHBLI recommendations:

▪  Universal screening of all 9-11 year-olds with a nonfasting lipid panel.

▪  Targeted screening of 2-8 year-olds and 12-16 year-olds with 2 fasting lipid profiles.  The targeted group are for those with diabetes, hypertension, BMI >95%, smoke cigarettes, have a parent with cholesterol >240 (or known dyslipidemia), 1st or 2nd degree relative (includes parents, aunts, uncles, and grandparents) with stroke or coronary artery disease <55 years for men or <65 for women.  According to the critical commentary, 30-40% of children will meet family history criteria and many more will meet other criteria.

▪  If LDL ≥130 mg/dL, then a “CHILD-1” diet is recommended.

▪  Individuals with abnormal screening are to have fasting lipid panels every 6-12 months indefinitely even if their values become acceptable.

Criticisms and responses by guideline authors in italics

▪  While the critics concede that cumulative exposure to high LDL and hypertension increase the risk of cardiovascular disease (CVD), they indicate that with the exception of a small number of individuals (rare homozygous familial hypercholesterolemia) that there is not proof that intervention in childhood is necessary.  The chain of evidence cited by the panel has “notably the absence of even observational evidence or modeling to estimate the clinical event benefits of screening for and intervening on these risk factors in children.”  Atherosclerosis is a lifelong process…Heterozygous familial hypercholesterolemia affects 1:500 and 51% of untreated men develop CV disease events by age 50 years… Accidental death studies (ages 15-30 years) have shown that a 30 mg/dL increase in non-HDL was equivalent to 2 years of vascular aging.  Bogalusa Heart Study showed that number of risk factors correlated with increased atherosclerosis at autopsy after accidental death.  Carotid intima media thickness in adulthood correlates with LDL levels obtained between 12-18 years of age.

▪  No quantification of potential harms such as neuroses, family conflict, CVD anxiety or from medication.  Among children with familial cardiovascular disease, interview studies have shown positive future health perceptions and effective coping.  ‘A study of universal CV risk screening in schools, accompanied by environmental change, showed improvements in healthy lifestyle behaviors and CV risk profiles.’  Risk of statin therapy, (only 0.8% of adolescents would be eligible per authors) has shown no adverse effects in children and adolescents.

The majority of the panel members…disclosed an extensive assortment of financial relationships with companies making lipid-lowering drugs and lipid-testing instruments.  Evidence regarding the efficacy and safety of these medications would not be available without academic partnership with industry.  Potential conflicts of interest were declared and vetted.

▪  Cost/cost-effectiveness. The present policy proposes an intervention applied to a healthy and asymptomatic population, with an enormous impact on costs and the potential to transform well children into patients with a chronic disease label. “Any intervention with nonzero benefit may be recommended, regardless of how much it costs and how much better health might be achieved by investing those resources elsewhere.”  There have been several studies exploring the cost-effectiveness of screening and management strategies for familial hypercholesterolemia (FH). In the Netherlands, a genetic screening program showed that new cases of FH gained 3.3 years of life at an average lifetime cost of US$8700 per year gained.  More complex cost-effectiveness modeling of treatment of children and adolescents has not yet been performed.

So who is right in this debate?

Previous related blog entry:

Cardiovascular disease for the entire family