In contrast with the large number of medications available for adults, until 2019 there were just two agents approved to treat high blood glucose in pediatric type 2 diabetes, only one of which was based on evidence from a randomized controlled trial.
Veteran clinical trial investigator William Tamborlane (Yale School of Medicine, New Haven, Connecticut, USA) explains that there are just not that many children with type 2 diabetes available to recruit, and most of these live in the USA or Mexico.
“And at least in the US, the large majority of patients are disadvantaged inner-city minority people – so African American, Hispanic, low income – and they’re a very challenging population to recruit,” he says.
The end result is that pediatricians are currently poorly served when it comes to having a choice of medications to help their young patients achieve glucose control. While many can and do opt for off-label options, Phil Zeitler (Children’s Hospital Colorado, Aurora, USA) says: “I know from colleagues that, in many states, they are unable to prescribe any medication that is not FDA-approved using Medicaid insurance.
Before 2019, only metformin had been formally tested in a randomized trial involving pediatric patients. The agent is cheap and effective, with a very well-established safety profile, having been in continuous clinical use for over 50 years.
The ISPAD guidelines advise starting at a dose of 500 to 1000 mg daily and increasing in increments of 500–1000 mg over 3–4 weeks according to tolerability of gastrointestinal side effects, to a maximum dose of 1000 mg twice daily, 850 mg three times a day, or 2000 mg once daily if an extended-release product is available.
But despite its long-established efficacy, metformin may not always meet the needs of this challenging adolescent population. The TODAY trial showed that although some participants achieved durable glucose control on metformin over 60 months of use, more than half did not.
All insulins are approved for use in children with type 2 diabetes, but not directly on the basis of trial data, rather on the extrapolation of safety and efficacy from their use in children and adults with type 1 diabetes, and adults with type 2 diabetes.
Insulin is currently used in two situations in children with type 2 diabetes. First, when a child’s glucose levels are so high (decompensation, or glucotoxicity) that they require immediate and rapid correction. This may often be the case at diagnosis, and clinicians will aim to bring glucose levels back under control and then transition to metformin. The second scenario is when glucose control is no longer possible with other medications and lifestyle changes, making insulin the default option, starting with basal insulin and then adding a prandial insulin as required.
Insulin is of course extremely effective, with an established safety profile and long clinical experience. But it has many drawbacks when considering use in adolescents with type 2 diabetes, including the potential for weight gain, the need for one or more daily injections, and the challenges of dose titrations. On top of that, dependent on the healthcare system, are cost and access issues.
Liraglutide and exenatide
Glucagon-like peptide (GLP)-1 receptor agonists are the newest additions to the pediatric type 2 diabetes armamentarium, with liraglutide gaining approval in 2019 based on the positive results of the Ellipse trial. Extended-release exenatide received FDA approval in April 2021, but has not been approved in Europe at the time of writing.
The recency of these approvals means the medications have not yet entered most guidelines; however, experts suggest starting them in children who cannot achieve glycemic control with metformin and lifestyle changes alone, reserving insulin as the final option.
Liraglutide requires a single daily injection, which can be viewed as a negative or a positive according to the comparator (ie, metformin or insulin), whereas exenatide is given by weekly injection. In common with the class as a whole, these medications are associated with gastrointestinal side effects that usually resolve with continued use.
In adults, GLP-1 receptor agonists are also known to promote weight loss. This was not seen in Ellipse, but Tamborlane, who was the lead investigator, believes this to be because the liraglutide dose was titrated according to glucose levels, so most participants never achieved the maximum study dose of 1.8 mg/day. Indeed, a subsequent trial demonstrated significant weight loss versus placebo in obese adolescents given liraglutide 3.0 mg/day, the dose indicated for weight loss in adults.
Also in adults, most medications in this class, including liraglutide but not exenatide, have demonstrated significant cardioprotective effects, which may be a consideration in young people who will live most of their lives with the detrimental effects of type 2 diabetes.
A note on safety data
Bill Tamborlane is resigned to the regulatory authorities’ insistence on formally testing the efficacy of type 2 diabetes medications in children and adolescents, rather than simply extrapolating from adult data, but is adamant that these trials are an unreliable source of safety data.
“Safety should be extrapolated from adult studies, because that’s where millions of people are taking the drug,” says Tamborlane.
What other medications may become available in the future?
Other GLP-1 receptor agonists
There are a number of other options in this class. Notable among these medications are dulaglutide, currently undergoing a phase 3 trial in children and adolescents, which would provide a weekly injectable option with demonstrated cardioprotective ability, and oral semaglutide, which would remove the need for injections altogether.
Related article: Round-up of the GLP-1 receptor agonist CV outcome trials
Use of dipeptidyl peptidase (DPP)-4 inhibitors is well established in adults with type 2 diabetes. They are effective for glycemic control and have a benign general adverse event profile, but this includes a neutral cardiovascular safety profile, contrasting with the cardioprotection offered by the other new glucose-lowering medication classes, and they have no effect on bodyweight.
Linagliptin is currently undergoing testing in children and adolescents, in a trial also testing the sodium-glucose cotransporter (SGLT)2 inhibitor empagliflozin.
Related article: Round-up of the DPP-4 inhibitor CV outcome trials
Medications in the SGLT2 inhibitor class, which control blood glucose by increasing its excretion via the kidneys, also offer cardioprotection in adult populations, particularly against heart failure, as well as renal protection.
Rare but notable side effects include an increased risk for genital infections, Fournier gangrene, a disputed association with amputations, and an increased risk for euglycemic diabetic ketoacidosis.
Canagliflozin and empagliflozin are undergoing phase 3 study in children and adolescents at the time of writing, and a study of dapagliflozin in children and young adults has just published. This revealed significant improvements in glycemic control with the SGLT2 inhibitor versus placebo, but only in the per-protocol population of participants who took at least 80% of their doses.
Related article: Round-up of the SGLT2 inhibitor CV outcome trials
The beginnings of multimorbidity…
Phil Zeitler points out that type 2 diabetes has many associated complications and comorbidities of the type you would not normally be alert for in children and adolescents.
He stresses the need for the monitoring for and, where needed, treatment of hypertension, dyslipidemia, sleep apnea, and kidney disease. For the latter, Zeitler says, physicians should be checking for the development of hyperfiltration, which is the forerunner of a rapid decline in glomerular filtration rate and loss of kidney function.
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