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).
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.
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)
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.
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.
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.
According to a a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network and with 675 participants (mean age 12.6 yrs):
Abstract: A new position statement from Europe endorses expert-based recommendations to consider bariatric surgery as a treatment for severe NAFLD in severely obese adolescents. This article discusses the problem of severe paediatric obesity, its relationship with NAFLD, and the knowledge and needs regarding bariatric surgery in adolescents… it is critical that adolescents with NAFLD undergoing bariatric surgery be evaluated and managed in bariatric surgery centres with appropriate paediatric multidisciplinary expertise and a commitment to rigorously phenotype NAFLD histology at baseline and to follow outcomes prospectively as long as possible. These procedures can be particularly challenging in adolescents, who are prone to relocate in adulthood and thus might not return for follow-up. High quality prospective multicentre studies with low attrition rates, such as the Teen Longitudinal Assessment of Bariatric Surgery (USA) and the Adolescent Morbid Obesity Study (Sweden) have begun to provide short to intermediate term (1–2 year) outcomes after adolescent bariatric surgery, but do not include prospectively collected data on histological liver outcomes to support evidence-based recommendations regarding NASH as a specific indication for bariatric surgery. However, given the benefits that are emerging for type 2 diabetes and sleep apnoea, (which are comorbid conditions often associated with NASH), we concur with previously published expert guidelines that conclude that bariatric surgery is not contraindicated in a non-cirrhotic patient with NAFLD who otherwise meets appropriate medical and psychosocial criteria for bariatric surgery.2 The adolescent and family should, however, be counselled that a positive outcome with respect to NAFLD is, as yet, not a foregone conclusion.
Before proceeding with today’s post, those who read yesterday’s post may be interested in Atul Gawande’s take on the NEJM checklist publication -here’s the link (from Atul Gawande’s twitter feed): bit.ly/1d6v31z.
A recent review “Extrahepatic Complications of Nonalcoholic Fatty Liver Disease” (NAFLD)(Hepatology 2014; 59: 1174-97) seems to position the liver as the center of a multitude of problems rather than one of many associated problems.
It is known that NAFLD increases the risk of end-stage liver disease and hepatocellular carcinoma. However, the majority of deaths among individuals with NAFLD are attributed to cardiovascular disease and malignancy. This lengthy review describes in great detail the associations between NAFLD and the risk of developing cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), and colorectal neoplasm. The presence of NAFLD appears to convey an independent increase in risk for these conditions.
“The aggregated evidence provides strong evidence that individuals with NAFLD are at increased “independent” risk of developing CVD. The risk of CVD mortality may be greater in subgroups of subjects with NASH and advanced fibrosis, compared to those with simple steatosis.”
“USS-defined NAFLD is associated with a 2- to 5-fold risk of developing T2DM after adjustment of several lifestyle and metabolic confounders.”
“NAFLD (in particular, biopsy-proven NASH) is associated with a greater prevalence of CKD (20% to 50% of patients). USS-defined NAFLD carries a 1.5- to 2-fold adjusted risk of incident CKD.”
“A true causal relationship between and NASH and colorectal cancer cannot be confirmed.”
Other potential extrahepatic manifestations: hypothyroidism, polycystic ovarian syndrome, obstructive sleep apnea syndrome, and osteoporosis.
Take-Home Message:NAFLD has independent associations for greater risk of CVD, hyperglycemia, and malignancy. Whether these associations are simply an epiphenomenon of more aggressive metabolic syndrome or whether the liver injury primarily causes these additional risks remains unclear.
Could bile acids play a role in reducing metabolic syndrome and in particular fatty liver disease? This question is now being studied (Gastroenterology 2013; 145: 574-82).
This recent study examined whether obeticholic acid (OCA) which is a semisynthetic derivative of the human bile acid chenodeoxycholic acid could aid with insulin resistance and ultimately nonalcoholic fatty liver disease (NAFLD). OCA is an agonist of the farnesoid X receptor which is a nuclear hormone receptor that regulates glucose and lipid metabolism.
The authors performed a phase 2, double-blind, placebo-controlled study to assess the effects of OCA on insulin sensitivity in patients with NAFLD and type 2 diabetes mellitus. Patients received either placebo (n=23), 25 mg OCA (n=20), or 50 mg OCA (n=21) once daily for 6 weeks. Using an insulin clamp, insulin sensitivity was measured before and after the study period. Numerous blood tests were obtained as well.
Insulin sensitivity improved 28% in the 25mg OCA group and 20.1% in the 50 mg OCA group whereas it decreased 5.5% in the placebo group.
The OCA groups also had significant reductions in gamma-glutamyltransferase, alanine aminotransferase, and dose-related weight loss.
Markers of liver fibrosis decreased in the 25 mg OCA group.
Side effects of OCA were minimal. Constipation was reported in the 50 mg OCA group.
Take-home message: OCA may help patients with NAFLD and a bigger, longer study is in the works (FLINT study: 25 mg OCA for 72 weeks compared with placebo, http://www.clinicaltrials.gov; NCT01265498)
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.
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.”
Two articles in the New England Journal of Medicine point to the role of bariatric surgery in treating type 2 diabetes in obese patients (NEJM 2012; 366: 1567-76 & 1577-85). Type 2 diabetes looms as one of “the most challenging contemporary threats to public health.”
The first study was a randomized nonblinded single-center trial with 150 patients; mean BMI 36 with 34% having a BMI less than 35. Intensive medical therapy was compared to Roux-en-Y gastric bypass or sleeve gastrectomy. Mean patient age was 49 years. 42% of the gastric bypass group, 37% of the sleeve-gastrectomy group, and 12% of the medical treatment group achieved the primary end-point of a glycated hemoglobin level of ≤6% by the 12 month followup; the average starting glycated (HgbA1C) hemoglobin was 9.2%. At the conclusion of the study, the average HgbA1C was 6.4, 6.6, and 7.5 respectively in the three groups.
The second study used a similar trial with 60 obese patients; all had BMI >35 At 2 years, diabetes remission occurred in 75% of their gastric bypass group, 95% of their biliopancreatic-diversion group and in no patients receiving intensive medical therapy patients. HgbA1C had similar rates of improvement as the 1st study: 6.3 in gastric-bypass, 4.9 in biliopancreatic-diversion group, and 7.7 in medical-therapy group.
While surgery has risks (see related material below), its benefits are likely to alter future treatment strategies with surgery being contemplated prior to exhausting all medical treatments.
-JAMA 2012; 307: 56-65. Bariatric surgery and long-term cardiovascular events.
-JAMA 2011 [doi: 10.1001/jama.2011.817]). Large study failed to show that roux-en-Y gastric bypass prolonged life. n=850 VA pts to 41,244 controls. Same group showed no cost savings during initial 3 yrs: Med Care 2010; 48: 989-98.
-NEJM 2011; 365: 1365. Increased frequency of bariatric surgery in adolescents.
Leptin is a cytokine expressed primarily by adipose tissue and helps regulate energy homeostasis in the body. Higher leptin levels are found in obesity and associated with an increase risk of cardiovascular disease, insulin resistance, and type 2 diabetes. In a recent study, physical activity, especially vigorous physical activity, has been shown to be negatively associated with leptin levels (J Pediatr 2012; 160: 598-603).
This study was conducted in school settings in 10 European cities from 9 countries (n=902) with ages 12-18 years. Several fitness tests including handgrip, long jump, and shuttle runs were measured along with serum fasting leptin, insulin, and glucose.
Vigorous activity and fitness test results were associated with lower leptin levels; these findings were maintained when controlling for confounders. It is not known the exact mechanisms whereby physical activity can lower leptin levels as this finding is independent of total body fat. The authors note that previous studies have shown some contradictory results; the authors note that this could be related to drawbacks in how some studies measured physical activity.
This study’s information, when combined with previous studies (see below) on hormonal adaptations with weight loss, suggest a reason why exercise is important to maintain weight loss. Losing weight without exercise could result in increased appetite and make it more difficult to achieve long-term results. In contrast, physical activity may help maintain weight loss by improving hormonal adaptation.
-NEJM 2011; 365: 1597. Persistence of hormonal adaptations with weight loss. Due to persistent changes in hormones like leptin & peptide YY, hard to keep wt off -result is increased appetite.
-NEJM 2009; 360: 859. Obesity-wt loss: composition of diet does not seem to be important. Total calories important.
-NEJM 2007; 356: 237. Leptin receptor deficiency present in 3% of 300 patients with early-onset obesity and hyperphagia.
-Pediatrics 2007; 120: suppl 4: S164-S287.
-NEJM 2007; 357: 370. Obestiy spread in social network.
-Gastroenterology 2007; 132: 2085-2276. Special issue on obesity issues.
-NEJM 2006; 355: 1593. Case review on obesity c DDx and mgt.