Table 5.

Medications for use in T2D

Medication (Brand Name)	Approval and potential adverse effects	Dosing	ETD between groups (treatment vs. placebo) if available and percent HbA1c lowering within the treatment group	Impact on metabolic parameters
Biguanides (glucophage, Metformin®)	Approved in youth	Oral once, twice or three times daily	HbA1c ↓ of 0.8% at 16 weeks [89], 0.8% at 24 weeks and 0.46% at 52 weeks, respectively [90]	Weight: an initial anorexic effect that may promote limited weight loss
	Can cause transient abdominal pain, diarrhea, nausea, all attenuated by the extended-release formulation	Starting dose 500 mg		Lipids: TC, LDL-C, TG ↓, HDL-C ↑
	Avoid in DKA, if eGFR <30 mL/min, cardiac or respiratory insufficiency, or receiving radiographic contrast materials	Can increase to 2,000 mg		BP: SBP ↓
Glucagon-like peptide-1 [GLP-1] receptor agonists GLP-1 RA can have side effects including nausea, vomiting, diarrhea, and infrequently dizziness, headache, and dyspepsia Discontinue if pancreatitis suspected. GLP-1 RA should not be used in combination with a DPP-4 inhibitor In patients with MEN, these medications have a risk of C-cell hyperplasia and thyroid carcinoma Adult trials show reduction in cardiovascular, renal events, and mortality [91–93]. There are no data in children
liraglutide (Victoza®)	FDA approved in youth aged 10 years and older	SC once daily	ETD: 1.06% and 1.3% at 26 and 52 weeks	Weight/BP: no difference compared to placebo at week 26
	Higher dose Liraglutide, Saxenda® 3 mg is approved for weight loss in youth aged >12 years with obesity	Start with 0.6 mg	HbA1c ↓ of 0.64% and 0.5% at 26 and 52 weeks [94]	Lipids: VLDL and TG ↓ at week 26, but no difference observed at week 52 [94]
		Can increase to maximum tolerated dose (1.2 or 1.8 mg) daily [95].
Exenatide (Bydureon®)	FDA approved in youth aged 10 years and older	SC once weekly	ETD: 0.85% at 24 weeks	Weight/BP: no difference compared to placebo [95]
		Single dose (2 mg), no titration available	HbA1c ↓ of 0.36% at 24 weeks [95]	Lipids: no data
Dulaglutide (Trulicity®)	FDA approved in youth aged 10 years and older	SC once weekly	ETD: 1.5% at 26 weeks	Weight/BP: no difference compared to placebo [96]
		Start with 0.75 mg, increase to 1.5 mg as tolerated	HbA1c ↓ of 0.9% and 0.6% at 26 and 52 weeks [96]	Lipids: TC, LDL-C and TG ↓ in the dulaglutide groups
Sodium-glucose co-transporter 2 (SGLT-2) inhibitors SGLT-2 inhibitors can increase risk for ketosis and euglycemic DKA though rates of these side effects were low in pediatric T2D studies to date. As a result, caution is recommended in youth who may have ever presented with ketoacidosis or DKA. Adult trials show weight loss and reduction in cardiovascular disease and renal protection [97, 98]. There are no data in children
empagliflozin (Jardiance®)	FDA approved in youth 10 years and older	Oral once daily	ETD: 0.84% at 26 weeks	Weight/BP: no difference compared to placebo [76]
	Metformin-Empagliflozin combination approved age 10 years and older	Starting dose is 10 mg	HbA1c ↓ of 0.17% and 0.04% at 26 and 52 weeks, respectively [76]	Lipids: no data
		Can increase to 25 mg/day
dapagliflozin Farxiga® (US) and Forxiga® (EU)	FDA approved for youth 10 years and older	Oral once daily	ETD: 0.75% at 24 weeks [99]; 1.03% at 26 weeks [100]	BMI/weight/BP: no difference compared to placebo [99, 100]
	Approved by the EMA in children	Starting dose is 5 mg	HbA1c ↓ of 0.25% at 24 weeks [99]	Lipids: no data
	10 years or older	Can increase to 10 mg/day	HbA1c ↓ of 0.62 at 26 weeks [100]
Other medications studied in children
sitagliptin (Januvia®)	Upper respiratory infections, nasopharyngitis	Oral once daily	ETD: 0.19% at 20 weeks (nonsignificant)	Weight/BP: No difference compared to placebo [101]
		Dose is 100 mg/day	HbA1c: ↓0.01% lowering at 20 weeks [101]	Lipids: no data
		Combination available with metformin
alogliptin (Nesina®, Vipidia®)	Upper respiratory infections, nasopharyngitis	Oral once daily	Results in youth pending	Weight/lipids/BP: no data
		Dose is 25 mg/day
saxagliptin (Onglyza®)	Upper respiratory infections, nasopharyngitis	Oral once daily	ETD: 0.44% at 26 weeks (nonsignificant)	Weight/BP: no difference compared to placebo [100]
		Dose is 5 mg/day	HbA1c: ↑ 0.6% at 26 weeks [100]	Lipids: no data
linagliptin (Tradjenta®)	Upper respiratory infections, nasopharyngitis	Oral once daily	ETD: 0.34% at 26 weeks (nonsignificant)	Weight/BP: no difference compared to placebo [76]
		Dose is 5 mg/day	HbA1c: ↓0.33% at 26 weeks and 0.8% at 52 weeks [76]	Lipids: no data
Thiazolidinedione (pioglitazone, Actos®) rosiglitzone, Avandia®)	Pioglitazone is the preferred TZD due to overall fewer cardiovascular side effects in adults compared to rosiglitazone [102, 103]	Oral once daily	Associated with the lowest therapeutic failure when rosiglitazone was combined with metformin (38.6%) vs. metformin alone (51.7%) vs. metformin plus lifestyle (46.6%) [86]	Weight: ↑ [86]
	Risk of weight gain if used in combination with insulin	Starting dose 15 mg, can increase to 30 mg/day		Lipids/BP: no significant change
	In the TODAY study no significant side effects reported with rosiglitazone therapy [86]	A 45 mg/day dose is available but limited additional benefit and increased side effects
	Liver toxicity has not been seen with newer TZDs; instead, may be beneficial in MASLD [104]	Can be useful in youth given their severe insulin resistance and normal cardiac function particularly when metformin is not tolerated
α-Glucosidase inhibitoracarbos (acarbose, Precose® miglitol, Glyset®)	Reduce postprandial glucose rise Particularly successful when carbohydrates are substantial part of diet [105]	Oral up to three times a day with meals	No data	Weight/BP/Lipids: No data
	Can lead to flatulence, diarrhea, abdominal cramps	Acarbose 25–100 mg with each meal
		Miglitol 100 mg three times a day
Sulfonylurea and Meglitinides (glimepiride: Amaryl®) approved for children in Japan [106].	Mild or severe hypoglycemia	Oral once daily	Glimepiride showed no HbA1c lowering with a greater degree of weight gain and hypoglycemia [107]	Weight: ↑ in Glimepiride vs. metformin group
	Weight gain	Starting dose: 1 mg taken once daily with breakfast or the first main meal of the day		Lipids: No difference in Glimepiride compared to metformin [107]
	May accelerate β-cell function loss [108, 109]	Can increase to 8 mg per day		BP: no data
	Glimepiride, a new sulfonylurea, stimulates insulin release before meals and has additional pancreatic effects including decreased liver glucose production and enhanced peripheral tissue insulin sensitivity [102]

BP, blood pressure; DPP-4, dipeptidyl peptidase-4; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; EMA, European Medicines Agency; ETD, estimated treatment difference compared to placebo; FDA, Food and Drug Administration; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; MEN, multiple endocrine neoplasia; TG, triglycerides; SBP, systolic blood pressure; SC, subcutaneous; TC, total cholesterol; TZD, thiazolidinedione; VLDL, very low-density lipoprotein.