In addition to today’s resource, please review

• Ozempic and Mounjaro Aren’t the Same. Here’s How Weight-Loss Drugs Compare. Feb 28, 2024. Scientific American.
  • “A plethora of new weight-loss drugs are now available in the U.S., but they aren’t necessarily the same. Here’s a guide to the latest GLP-1 receptor agonists.”
  • Liraglutide, dulaglutide, semaglutide*, tirzepatide
    • *”Semaglutide is also the first (and so far only) GLP-1 receptor agonist shown to decrease the risk of heart attacks and strokes among people who don’t have diabetes, “so that’s a game changer in the landscape of obesity medicine,” Pedersen says.”
• Sodium-glucose cotransporter-2 (SGLT2) inhibitors. National Kidney Foundation.
  • Approved medicines in the SGLT2 inhibitor class include:
    • Brenzavvy™ (bexaglifloxin)
    • Invokana® (canagliflozin)
    • Farxiga® (dapagliflozin)
    • Jardiance® (empagliflozin)
    • Steglatro® (ertugliflozin)

    All SGLT2 inhibitors work in relatively the same way and are taken orally (by mouth).

  • “Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a class of oral (taken by mouth) prescription medicines that are FDA-approved for use with diet and exercise to lower blood sugar in adults with type 2 diabetes.”
  • “Some SGLT2 inhibitors are also FDA-approved for use in people with chronic kidney disease (CKD) and/or heart failure to lower the risk of heart attack, stroke, and/or heart failure flare-ups, including in people who do not have diabetes. Some SGLT2 inhibitors are FDA approved to help slow the progression of kidney disease.”
  • “Originally, SGLT2 inhibitors were developed as oral antidiabetic (blood sugar lowering) drugs. Later clinical trial data showed significant improvement in kidney health in people with heart failure and/or CKD. This benefit was even higher in people who also had albuminuria.”

Today, I review, link to, and excerpt from The Cribsiders‘ #110: Don’t Sugarcoat It – Pediatric Type 2 Diabetes.*

*Holloway R, Crimmins N, Masur S, Chiu C, Berk J. “#110: Don’t Sugarcoat It – Pediatric Type 2 Diabetes”. The Cribsiders Pediatric Podcast. https:/www.thecribsiders.com/ May 22, 2024.

All that follows is from the above resource.

Summary:

Grab your Metformin and settle in for a sweet conversation as we chat with Dr. Nancy Crimmins, Pediatric Endocrinologist at Cincinnati Children’s Hospital. Dr. Crimmins tells us about when to screen for type 2 diabetes, how to diagnose and our go-to treatment options. She won’t sugarcoat it!

Pediatric Type 2 Diabetes Pearls

1. Type 2 Diabetes Mellitus (T2DM) is characterized by insulin resistance and is often associated with other metabolic syndrome manifestations such as obesity and dyslipidemia.
2. Children often present without symptoms, especially if A1c is <7%.
3. You can diagnose diabetes mellitus with hemoglobin A1c, fasting blood glucose, random blood glucose or oral glucose tolerance testing. To confirm the diagnosis, you need two separate measures/time points.
4. Treatment is a family-centered, multi-disciplinary approach. Meet the family where they’re at and utilize your friendly registered dieticians and exercise specialists, if available!

Pediatric Type 2 Diabetes Notes

Pathophysiology

Diabetes mellitus (DM) describes a group of metabolic diseases that are characterized by chronic hyperglycemia.

Type 1 DM is the result of an autoimmune response that triggers the destruction of insulin producing ß cells in the pancreas and results in an absolute insulin deficiency. It often develops during childhood, manifesting with an acute onset (e.g., diabetic ketoacidosis).

Type 2 DM is characterized by insulin resistance and impaired insulin secretion due to pancreatic-cell dysfunction, resulting in relative insulin deficiency.

Note: Insulin resistance and hyperglycemia are TWO DIFFERENT THINGS! Patients can have insulin resistance without hyperglycemia – this is when they are insulin resistant BUT are still able to produce enough insulin to compensate for the resistance (so they are normoglycemic).

Epidemiology & Risk Factors

Incidence and Trends

The incidence of T2DM among children and adolescents is increasing in many countries. Based on a large representative dataset from the SEARCH for Diabetes in Youth study, there was an increase in T2DM from 9.0 cases per 100,000 in 2002-2003, to 13.8 per 100,000 in 2014-2015.

The burden of T2DM varies widely by ethnic and racial groups. In the United States in 2014-2015, the incidence of T2DM in each group was:

• Non-Hispanic White youth – 4.5 per 100,000
• Asian/Pacific Islander youth – 11.9 per 100,000
• Hispanic youth – 20.9 per 100,000
• Native American youth – 32.8 per 100,000
• Non-Hispanic Black youth – 37.8 per 100,000

Risk Factors

• The most important risk factor is obesity and excess adipose tissue, which increases peripheral resistance to insulin-mediated glucose uptake.
• Genetic Susceptibility – Strong evidence suggests a polygenic trait that becomes compounded by environmental risk factors;  T2DM is much more likely to develop in children who have a parent or grandparent with T2DM.
• Puberty & Age – Many patients develop DM at the onset of or during puberty due to increased physiologic insulin resistance.
• Sex – Females are 1.2 to 1.7 times more likely than males to progress from prediabetes and develop T2DM during adolescence. The reason for this is most likely multifactorial, including rates of PCOS.
• Prenatal exposures – Maternal undernutrition (leading to infants that are small for gestational age) or gestational diabetes may cause metabolic/hormonal changes in the child that promotes obesity and insulin resistance later in life.

Presenting Symptoms

The presentation in pediatric T2DM can be variable. 40% of patients are asymptomatic at time of presentation – most often if they have an A1c less than 7%. 60% of patients present with minimal symptoms including polyuria, polydipsia and nocturia. Occasionally, T2DM in children and adolescents can present as diabetic ketoacidosis (DKA, 5-12% of patients), and very rarely hyperosmolar hyperglycemic syndrome (HHS, 2%).

Patients may present with symptoms associated with insulin resistance, including acanthosis nigricans* (thickening of the skin around the neck and axillae), obesity or increased skin tags.

*Acanthosis Nigrans from StatPearls. Mark F. Brady, Prashanth Rawla. Last Update: August 11, 2023.

Diagnosis

Screening

The American Diabetes Association (ADA) guidelines suggest starting to screen at age 10 (prior to puberty).

Puberty naturally increases insulin resistance and redistribution of fat due to hormones. While the exact mechanism of puberty’s role in diabetes is not completely understood, the TODAY trial showed 40% of pediatric cases occur between 10-14 years of age, and the remaining 60% occur between 15-19 years of age. Insulin sensitivity was shown to decrease by ~30% in puberty, related to increased activity of growth hormone.

Screen earlier than 10 years old in certain populations, including 1) those with an affected first-degree relative, 2) those who are at-risk minorities, 3) those who are of low socioeconomic status, or 4) patients with concomitant conditions that share genetic risk for T2DM, such as PCOS.

Hyperglycemia secondary to medications including steroids or atypical antipsychotic medications are classified differently than insulin resistance.

Expert pearl: Often, in the case of medication-induced hyperglycemia, providers will not prematurely stop the offending medication, but instead will treat the hyperglycemia with medications like Metformin. This situation, however, does not meet criteria for T2DM (see diagnostic criteria below).

Typically, providers will screen with a hemoglobin A1c or fasting blood glucose.

Diagnostic Criteria

Diagnosing Diabetes

• The patient cannot be on medication that causes hyperglycemia (steroids, atypical antipsychotics, etc.).
• How to diagnose diabetes per the American Diabetes Association:
  • Pre-Diabetes:
    • HbA1c 5.7-6.4%
    • Fasting serum glucose 100-125 mg/dL
    • OGTT 140-200 mg/dL at the 2 hour mark
    • Dr. Crimmins’s pearl: It is very important to discuss pre-diabetes early with families to increase likelihood of potential lifestyle changes!
  • Diabetes
    • HbA1c >6.5%
    • Fasting serum glucose >126 mg/dL
    • OGTT >200 mg/dL at the 2 hour mark
    • Random serum glucose >200 mg/dL (suggestive, but gets tricky if sick or stressed).
  • Must have two different time points or two different clear cut measures for an official diagnosis.

Differentiating Type 1 vs. Type 2 DM

Once you have the diagnosis of diabetes (from the above criteria), you can determine whether it’s T1DM or T2DM (which can be difficult in kids!).

Utilize islet cell antibody studies to differentiate:

• There are four main antibodies that most institutions test: Insulin (IAA), Glutamic acid decarboxylase (GAA or GAD), Protein tyrosine phosphatase (IA2 or ICA512), and Zinc transporter (ZnT8).
• In theory for type 2 diabetes, all antibody studies should be negative. That said, in a clinically significant number of patients, T2DM patients will be GAD+. The clinical significance of this is unknown.
• Additionally, you can have Type 1.5 DM which is typically a patient with 1 or more antibodies positive but also who have signs of insulin resistance (fasting insulin and C-peptide levels high, which indicate insulin resistance).

Pro-tip: If your institution does not offer islet cell antibodies as a lab, or the family’s insurance does not approve the test, the Juvenile Diabetes Research Foundation (JDRF) offers reasonably priced antibody testing within the community that you can refer patients to.

Treatment

Goals of therapy include:

• Achieving and maintaining glycemic control.
• Improving insulin sensitivity.
• Identifying and treating comorbidities such as hypertension, dyslipidemia and steatotic liver disease, when necessary.
• Preventing microvascular and macrovascular complications.

What A1c should providers target? 

Dr. Crimmins states an A1c of less than 7% has been shown to reduce rates of complications, but the lower the better!

When and how do you treat T2DM?

A1c	Treatment
<7%	Lifestyle Modifications
7-9.5/10%	Metformin +/- Second Oral Agent or Basal Insulin
>9.5/10% or If patient presents in DKA or with urine ketones	Basal-Bolus Insulin

 

Lifestyle modifications are first line, especially if you have a patient who is in the pre-diabetic A1c range or has an A1c <7%. These include weight loss, dietary counseling as outlined by the Academy of Nutrition and Dietetics, physical activity (ideally moderate to vigorous for 1 hour daily) and restricting screen time to less than 2 hours daily.  Utilize your institution’s teams of Registered Dieticians, Exercise Physiologists and Mental Health Specialists, if available!

Pro-Tip #1: Spend time getting to know your patient’s family and their dietary preferences, patterns of physical activity/screen time, cultural background, time and financial constraints and educational levels.

Pro-Tip #2: Lifestyle goals should include input from the child and family, and be measurable and achievable (SMART goals). Examples of potential “lifestyle prescriptions” include decreasing portion sizes, substituting a fruit or vegetable for a carbohydrate-rich/processed food, decreasing high-calorie beverages and decreasing frequency of eating out.

Pro-Tip #3: Remember to screen for high-risk behaviors including smoking, vaping and alcohol use. These behaviors increase risk for vascular complications, and cessation is ideal. Also screen for sexual activity; any patient who has T2DM and becomes pregnant is at high risk of complications, so be sure to discuss contraceptive options in this population.

Oral & IM pharmacologic agents are first line in patients with A1c’s in the 7-9.5% range. 

#1 – Metformin, unless kids have kidney disease.

Dr. Crimmins’ Pearl: Utilize extended release formations because it increases compliance to take pills once a day (versus twice)!

#2 – GLP-1 agonists and SGLT2-inhibitors are also approved in certain age ranges:

1. Semaglutide (IM, weekly) = approved 12+ for weight loss, and 18+ for T2DM (it was easier to do weight loss trials in younger children due to prevalence of diabetes vs. obesity).
2. Dulaglutide (IM, weekly) and Liraglutide (IM, daily) = approved 10+ for T2DM
3. Dual-incretin therapy (Tirzepatide, IM, weekly) = 18+ age, superior to GLP-agonists alone in both Diabetes & weight loss, however expensive to get and insurances may not allow as preferred therapy (may have to fail another medication first).
4. Empagliflozin (PO, daily) = approved for 10+.

#3 – Basal insulin can also be added in this A1c range if hyperglycemia is refractory to oral/IM agents.

If A1c is >9.5/10%, or the patient presents with DKA or ketonemia, treat with basal-bolus insulin. 

Use a basal-bolus regimen, as opposed to carb ratios in type 1 diabetes, because you don’t have to be so exact since there’s enough insulin resistance (lower risk of hypoglycemia).

Screening for Complications

Diabetes is much more aggressive in kids than adults, so time to complications is much shorter.

The TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study was a large, multi-center, multi-year, randomized clinical trial that aimed to compare the efficacy of treatment regimens to achieve glycemic control in children and adolescents with T2DM. Secondary outcomes included metabolic outcomes and adverse events, providing much of the data for what we know about pediatric T2DM.

1. Hypertension – measure at each visit; if detected, perform basic clinical evaluation to confirm this is primary HTN rather than due to kidney disease or other cause.
2. Dyslipidemia – test at diagnosis (but after glycemic control is well established) and annually thereafter.
3. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) – annual serum AST & ALT screening.
4. Albuminuria – test at diagnosis, after initial attempts to optimize glycemic control and blood pressure, and annually thereafter; measure the urine albumin-to-creatinine ratio in a random urine sample.
5. Retinopathy screening – test at diagnosis and annually thereafter (if initial screening is normal).
6. Neuropathy screening – test at diagnosis and annually thereafter (use a 10-g monofilament at specific sites on the foot, testing of vibration sensation using a tuning fork, and ankle reflex tests).

Future Innovation

Currently, a triple-hormone-receptor agonist, Retatrutide, is in phase 2 trials for obesity treatment and is showing promising results. See this NEJM Article for more information.