Pediatric type 2 diabetes (T2D) has become a global public health concern driven by childhood obesity (1–4). Multiple biosocial drivers contribute to the intertwining of both diseases (1, 5). Over the past three decades, T2D has increased steadily in children (6), with a 7.1% annual increase in incidence rates (3) and a 95% increase in prevalence in the USA over almost two decades (7). Recent global data suggest incidence rates of up to 31-94 per 100,000 per year and prevalence of up to 160-5,300 per 100,000 in high-risk populations, such as Indigenous and African youth (8). While initially described as a disease of Indigenous children, current data reveal a surge in T2D across different ethnic groups (9, 10). There are currently no population-based screening programs for T2D in children; the disease remains uncommon in children, with most cases of new-onset diabetes being type 1 diabetes. This pattern is coupled with the 30% reproducibility of one of the primary screening tests in children–the oral glucose tolerance test (11). The use of glycated hemoglobin A1c (HbA1c) has been purposed for monitoring glycemic control in these children rather than establishing the diagnosis alone (12, 13). The more reproducible test, fasting glucose, is not very practical in children for obvious reasons and does miss those who become hyperglycemic after a carbohydrate challenge.

As up to 50% of children with T2D are asymptomatic at presentation and are mostly diagnosed when screened because they have obesity, the current prevalence and incidence rates for T2D likely underestimate the true scale of the disease in children (9, 14).

T2D presents as an aggressive disease with multiple comorbidities, and patients have a progressive failure of β-cell function and progress to insulin dependence within 3-5 years post-diagnosis. This rapid deterioration of β-cell function is more rapid in children when compared to adults with T2D (15–19).

Several conditions are associated with T2D including obesity, dyslipidemia, hypertension, obstructive sleep apnea, polycystic ovary syndrome, and non-alcoholic fatty liver disease (20–24). Microvascular complications manifest as nephropathy, neuropathy, and retinopathy and present much earlier than those in children with type 1 diabetes (25).

T2D impacts the children’s longevity and quality of life, and the premature mortality seen in this population is a significant concern (26).

While initial approaches to treatment involved using lifestyle to manage diabetes, it has become clear that this approach needs supplementation with pharmacotherapy to establish and maintain glycemic control (27). So far, pharmacotherapies used to treat T2D include metformin, insulin, sodium-glucose cotransporter-2 (SGLT-2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists (28–31). This review focuses on the use of Metformin in the management of T2D patients.

Metformin is the most widely prescribed pharmacotherapeutic agent to treat T2D globally (32–35). Metformin is a biguanide derived from a guanidine, galegine, from the French lilac or goat’s rue (Galega officinalis), which was used for centuries to treat diabetes (36). Metformin hydrochloride (HCl) is hydrophilic and has a molecular weight of 165.63 kDa (37). The molecular formula of Metformin HCl, the compound used in clinical preparations, is C₄H₁₁N₅ • HCl (37). Metformin is hydrophilic and has a molecular weight of 129.16 kDa (38). The molecular formula of Metformin is C₄H₁₁N₅ (38). For the remainder of the paper, the use of Metformin assumes the use of Metformin HCl.

Advances in chemistry and new drug manufacturing methods pioneered almost a century ago led to the synthesis of Metformin in 1922 as dimethylbiguanide (39). However, it did not come into broad use to treat diabetes initially. One of the most critical biomedical discoveries of the 20^th century–insulin in 1921, overshadowed the use of other medications to treat diabetes (40). In 1957, Metformin was studied by Dr. Jean Sterne, who investigated its antihyperglycemic properties and called it Glucophage (glucose eater), a name that still resonates today as a brand name for metformin (41). Although the higher potency of other biguanides, such as phenformin, led to their prioritization in clinical trials (42), the development of lactic acidosis led to early discontinuation of the trials and the interest in Metformin was reignited (43, 44). While less potent than other guanidines, Metformin did possess a better safety profile (45). Furthermore, the U.K. Prospective Diabetes Study further supported the use of Metformin in T2D, with improved glycemic outcomes and decreased morbidity and mortality (46). These discoveries elevated Metformin to become the first-line therapy for adults with T2D (46, 47).

Metformin HCl was licensed in the United Kingdom in 1958 and in 1972 in Canada (48). The U.S. Food and Drug Administration (FDA) only approved the use of Metformin for T2D treatment in adults in December of 1994 and in children ≥10 years old with T2D in December of 2000 (49). Extended-release metformin formulations were subsequently approved (50), and the first extended-release liquid formulation followed more recently (51, 52). The availability of liquid formulations offers an alternative to Metformin tablets that may be large or hard to swallow for pediatric patients, leading to decreased adherence. Additionally, when evaluating the taste of liquid Metformin formulations, they were preferred compared to crushed Metformin tablets (53). Therefore, liquid Metformin may improve adherence to treatment in the pediatric population. However, the liquid form may not be readily available in all parts of the world.

Metformin is taken orally. The typical doses to treat diabetes for immediate-release preparations are 500-2,000 mg/day. The leading site of metformin absorption is the small intestine in the duodenum and jejunum via the action of plasma membrane monoamine transporter (PMAT) in intestinal cells, with a minor contribution of the colon (54, 55).

Taken orally, Metformin has a bioavailability of up to 60%, and it is absorbed within 6 hours (56). After absorption, Metformin does not bind to plasma proteins and is distributed to the liver (57–59). The non-absorbed Metformin accumulates at the distal small intestine, and it is then eliminated in the feces (60).

Metformin has a mean elimination plasma half-life of around 5 hours. Its onset of action is at around 1.5 hours, and the total duration of action is 16-20 hours (61). The therapeutic concentration of Metformin has been debated, and there are limitations in the literature about the levels and their methods of measurement at clinically relevant doses. However, a widely accepted circulating level at therapeutic doses (20 mg/kg/day) is 10-40 μmol/L (62, 63). Metformin is excreted unchanged via renal tubular excretion as the major route for elimination (64).

The extended-release formulation is based on the combination of Metformin with polymer delivery systems that allow the tablet to absorb water and expand to 150% of its original size within 15 minutes of ingestion, anchoring it in the stomach (65, 66). The pill slowly releases Metformin into the small intestine over 8-9 hours. When the Metformin is released, the tablet’s excipients disintegrate and are excreted in the feces at around 15 hours post-ingestion. The main advantage of extended-release Metformin is the potential for improved adherence to treatment in children and reduced gastrointestinal side effects. This metformin formulation is administered once daily, and the typical dose of these preparations is 1000-2000 mg/day, with a half-life of 6.5 hours and actions on plasma glucose for 24 hours (65, 67) (68).

Metformin exerts its glucose-lowering effect through various mechanisms in different organs ( Figure 1 ).

The liver is one of the important target organs of metformin actions. Metformin reduces hepatic glucose output by inhibiting gluconeogenesis (69, 70). While Metformin inhibits complex 1 of the respiratory chain in the mitochondria leading to an increase in adenosine monophosphate (AMP) and activation of AMP-activated protein kinase (AMPK), which in turn inhibits hepatic gluconeogenesis, the concentration of Metformin needed to achieve such effects in humans is supra-therapeutic (71, 72).

Additionally, Metformin inhibits hepatic gluconeogenesis by AMPK-independent mechanisms (73). These mechanisms include inhibiting gene transcription (73) and activity of enzymes in the gluconeogenic pathway (74), in addition to decreasing substrates available for gluconeogenesis such as lactate and glycerol (75, 76). Metformin also inhibits hepatic lipogenesis and increases fatty acid oxidation (77, 78).

Metformin’s additional actions include increasing glucose uptake and fatty acid oxidation in skeletal muscle and adipose tissue (78–82). It also reduces adipogenesis and activates brown adipose tissue leading to enhanced thermogenesis (83).

More recently, the effect of Metformin on the gut has been recognized (84). Metformin decreases the absorption of glucose from the intestine. It increases glucose transport from the blood into the lumen of the intestine (85–87), in addition to increasing glucose utilization by intestinal cells (88). Metformin also promotes the secretion of Glucagon-Like Peptide-1 (GLP-1) from the upper intestine, augmenting glucose-dependent insulin secretion (89, 90). Furthermore, Metformin influences the gut microbiome by promoting the growth of beneficial species that degrade mucin and generate short-chain fatty acids (91, 92). Animal studies have shown that mice given a metformin-modulated gut microbiome have improved glucose tolerance (92).

Metformin downregulates inflammation by inhibiting the NFϰB pathway and decreasing the secretion of inflammatory cytokines (93, 94). It also affects the proportion of white blood cells by reducing the ratio of neutrophils to lymphocytes (93) and inhibits the differentiation of monocytes to macrophages (95).

Lifestyle interventions encompassing healthy eating and physical activity recommendations need to be provided to children with T2D in a culturally and developmentally appropriate manner (96). While the exact endpoints of lifestyle interventions may not be easily achievable and are not solely focused on glycemic control, a suggested target is at least a 7% weight loss, presumed to improve metabolic markers such as HbA1c and C-peptide levels (97), and may help reduce the risk of microvascular complications (98). However, the aggressive nature of T2D and the high treatment failure rates have put a particular urgency on efforts to identify adjunct therapies to lifestyle interventions that may improve outcomes.

Currently, Metformin is the first pharmacotherapeutic choice for children with T2D with metabolic stability, including being asymptomatic and with an HbA1c <8.5% and blood glucose levels <250 mg/dL (<13.9 mmol/L) (96) ( Tables 1 , 2 ). In the presence of symptomatic hyperglycemia with polyuria, polydipsia, and weight loss, with biochemical deterioration and HbA1c >8.5% and blood glucose >250 mg/dL (≥14.0 mmol/L) and no acidosis, both Metformin and basal insulin are initiated (96). In general, Metformin treatment reduces HbA1c by 1-2% (99, 102).

A minority of patients with T2D present in diabetic ketoacidosis (DKA) at diagnosis (103). In these patients, conventional DKA management with insulin is initiated to reverse the acidosis; then Metformin is started in addition to subcutaneous insulin therapy for a few weeks and then a decision is made as to whether insulin can be weaned or stopped with continued Metformin treatment (96).

Because of its gastrointestinal side effects, Metformin should be started at a low dose with gradual titration, depending on tolerance. The typical metformin regimen involves a starting dose of 250-500 mg/day, with the weekly escalation of the dose up to a maximum of 1,000 mg twice daily or 850 mg three times per day (96, 104, 105). Extended-release formulations can be prescribed to reduce gastrointestinal side effects, or Metformin can be taken with meals.

Even though Metformin has been approved for use in pediatric T2D for decades, prospective studies in this population are limited, and trials of new medications have used them as add-ons to Metformin with or without insulin.

A randomized controlled trial of 16 weeks compared Metformin to a placebo in youth aged 10-16 with T2D. Metformin lowered HbA1c and fasting plasma glucose when compared to placebo (99).

Another study from Japan included youth with T2D and found that Metformin decreased HbA1c by 0.81% at 24 weeks and 0.46% at 52 weeks (101). While gastrointestinal side effects were widespread in almost all patients, no serious adverse events necessitated Metformin’s discontinuation over the 52-week study period (101).

Compared to glimepiride, a sulfonylurea, Metformin achieved similar reductions in HbA1c in those aged 8-17 years with T2D. While the incidence of hypoglycemia was similar in both groups, Metformin led to less weight gain compared to glimepiride (100).

Significant insights into the role of Metformin in pediatric T2D management were gleaned from the seminal TODAY study, a randomized controlled clinical trial that included 699 children with T2D. The trial compared Metformin with or without lifestyle interventions and Metformin plus rosiglitazone. The primary outcome was the need to use insulin due to failure in achieving glycemic control, defined as an HbA1c <8% for at least six months (106).

At a median of two months of metformin therapy during the run-in period, Metformin led to 91% of participants achieving an HbA1c <8%, with 78% achieving an HbA1c level less than 7% and 46% having an HbA1c level less than 6% (107). The benefits of Metformin waned over time, with only 49.3% for Metformin alone and 53.4% for the Metformin plus lifestyle intervention achieving durable glycemic control after four years (27).

Importantly, an HbA1c of <6.3% at randomization was associated with durable glycemic control (108). In participants with deteriorating glycemic control, a decline in β-cell function rather than reduced insulin sensitivity was noted (18, 109). Data from the Pediatric Diabetes Consortium T2D Registry confirmed this association of lower HbA1c at diagnosis with maintained glycemic control ≥2 years post-diagnosis (110).

Importantly, in youth with recent-onset T2D or impaired glucose tolerance, neither insulin glargine followed by metformin nor metformin alone preserved β-cell function (111). However, discontinuation of therapy resulted in worsening glycemic control, reflected by HbA1c, fasting and 2-hour post prandial glucose, as well as a decline in β-cell function after a 9-month washout period (112).

Future research efforts must concentrate on understanding Metformin’s glycemic effects and potential benefits in preventing or decreasing diabetes-related complications and cardiovascular events.

There is limited evidence that suggests that Metformin is safe and effective in improving weight or BMI as well as other metabolic markers of obesity in children younger than 10 years of age.

A randomized trial evaluating the use of Metformin to treat obesity in prepubertal children recruited 80 participants, who were randomized to either Metformin or placebo (169). At 6-months, the Metformin arm had a lower BMI z-score, as well as an improved quantitative insulin sensitivity check index (QUICKI) and a higher leptin-to-adiponectin ratio compared to the placebo arm, with no serious adverse events or cases of lactic acidosis (169). Similar results were reported by another study that included 18 prepubertal children, with improvement in weight and BMI SDS as well as the fat mass after 24 months of therapy (170). However, due to the small sample size, the study was underpowered to detect a statistically significant difference (170). In obese pre-adolescents with hyperinsulinemia, metformin reduced BMI, BMI SDS, weight, HOMA-IR, fasting insulin, and fasting glucose (122). Yet, there was no significant change in first-phase insulin secretion or insulin sensitivity by clamp studies (122).

Metformin may also have a positive effect on the body composition and metabolic profile of children with a history of being small for gestational age (SGA), given their risk of obesity and insulin resistance (127). A small pilot study that recruited 23 children 6-9 years of age with a history of SGA and catch-up growth with increased visceral fat were randomized to Metformin (n=6) and placebo (n=17) (127). After 24 months, the Metformin arm participants had lower weight and BMI SDS as well as lower total and abdominal fat compared to the control arm (127). Additionally, HOMA-IR improved in the Metformin group (127). There is a need for adequately powered randomized clinical trials to address the role of metformin in managing obesity in this age group.

Metformin has a favorable safety profile. The most common metformin-related side effects are gastrointestinal including diarrhea, abdominal pain, bloating, nausea, and loss of appetite. These side effects occurred in around 50% of participants in the TODAY study (27). Gastrointestinal side effects are typically temporary and tend to improve with time (27, 129, 131). These symptoms can be mitigated by gradual dose escalation, ingestion of Metformin alongside meals, or the administration of extended-release preparations.

Metformin has been linked with vitamin B12 deficiency, most likely due to its effect on the gastrointestinal tract (171–173). The most plausible mechanism is the alteration in the calcium-dependent binding of the intrinsic factor and vitamin B12 complex with the receptors in the terminal ileum (174, 175). However, small short-term studies that included pediatric patients on Metformin for various indications did not demonstrate an association between metformin and vitamin B12 deficiency (176, 177).

Serious adverse events related to Metformin, namely hypoglycemia and lactic acidosis, are rare. Metformin’s risk of hypoglycemia is very low, when used as monotherapy and when patients consume carbohydrates regularly (105). Hypoglycemia in metformin therapy typically occurs when insulin or other hypoglycemic medications are also used.

Lactic acidosis is a concerning side effect associated with Metformin in adults and occurs in the presence of hypoperfusion or hypoxemia (178). The risk of lactic acidosis with Metformin is negligible in children and adolescents on Metformin in obesity (129, 131). In the TODAY study, there was only one case of lactic acidosis that was deemed unrelated to metformin use (27). Additionally, there were no clinically significant cases of lactic acidosis reported in two other trials that included youth with T2D on metformin (99, 101). Therefore, Metformin does not seem to cause lactic acidosis in pediatric T2D patients. However, it can certainly occur with a concurrent illness or dehydration that may drive lactic acid build-up.

Contraindications to Metformin include significant cardiac impairment resulting in hypoperfusion and hypoxia (179). Additionally, significant liver impairment is another contraindication (37).

Metformin can be used safely in youth with elevated liver enzymes in the context of NAFLD, provided liver function is preserved (165–167). Until recently, Metformin was also contraindicated for renal impairment. However, the FDA has updated its labelling to indicate that Metformin can be used safely in mild and some cases of moderate renal impairment (180). Metformin is contraindicated when eGFR is less than 30 ml/min/1.73 m² and is not recommended when eGFR is between 30 and 45 ml/min/1.73 m² (37, 180). Metformin should be stopped in cases of acute illness if there is a risk of dehydration, poor fluid intake, and hypoxemia, such as sepsis (179). Additionally, Metformin should be withheld before surgery and restarted once oral intake has resumed (37, 179). Metformin should also be discontinued before administration of radiographic contrast and for 48 hours afterwards until renal function is re-evaluated (37, 179).

Since T2D is a severe and aggressive metabolic disorder in children, prevention efforts have targeted the upstream events in its development, including pre-diabetes (181) ( Table 2 ).

The current worldwide pooled prevalence of pre-diabetes is 8.84% (182). Up to 8% of children and adolescents with pre-diabetes progress to T2D, with increased body mass index (BMI)-based measures being essential predictors of progression (183–185). While adult studies have shown that Metformin can help prevent the progression to T2D (186–188), most pediatric studies have focused on markers of insulin sensitivity rather than T2D development as an outcome.

The effect of Metformin on markers of glycemic control or insulin resistance, including fasting plasma glucose, HbA1c, fasting insulin, and HOMA-IR, has been variable. Trials that treated youth with obesity and clinical or biochemical signs of insulin resistance with Metformin provided mixed results. Some studies demonstrated a reduction in fasting plasma glucose and insulin levels with an improvement in insulin sensitivity; yet, there were no differences in insulin levels or HOMA-IR in other studies (115, 116, 189–191). In a small, randomized controlled trial that included children and youth with impaired glucose tolerance regardless of weight, Metformin treatment for three months reduced HbA1c and HOMA-IR (192). However, Metformin may not have a clear beneficial effect on β-cell preservation during puberty in children and adolescents with obesity and normoglycemia. A randomized controlled study that followed 44 normoglycemic children and adolescents with obesity from early puberty to puberty completion demonstrated that, although Metformin improved anthropometric parameters such as BMI z-score, waist circumference and percent body fat, it did not have a beneficial effect on insulin sensitivity or β-cell function compared to placebo (193).

The Metformin in Obese Children and Adolescents (MOCA) trial included children and adolescents with obesity and impaired glucose tolerance or hyperinsulinemia that were randomized to Metformin versus placebo. There was minimal improvement in fasting glucose levels at three months, and that trend was not persistent at six months (119). Similarly, in another randomized controlled trial that included children and adolescents with obesity and insulin resistance based on HOMA-IR, there was no significant difference in HbA1c or HOMA-IR when comparing Metformin to placebo over 18 months of therapy (133). Moreover, an open label 18-month extension of this study found that there was a progressive increase in both BMI and HOMA-IR in participants who continued Metformin (134).

In summary, while Metformin helps reduce the progression to T2D in adults and may positively influence markers of glycemic control and insulin sensitivity in children and adolescents, current evidence on the role of Metformin in preventing progression from pre-diabetes to T2D in youth is lacking. Adequately powered trials with long-term follow-up focusing on T2D prevention as a primary outcome in youth are required.

Metformin is considered first-line therapy in newly diagnosed pediatric patients with T2D, with or without insulin. It is generally considered a well-tolerated and safe medication. Even though Metformin has been approved for use in children for almost three decades, long-term prospective studies in this population are lacking. They are needed to better understand Metformin’s role in reducing T2D complications and preventing progression from pre-diabetes to diabetes. In addition to improving glycemic control and insulin sensitivity, Metformin may support BMI reduction which is important in improving insulin sensitivity.

MCS is the guarantor. The paper topics, layout, writing, editing, and final approval was done by both authors. All authors contributed to the article and approved the submitted version.