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Chronic complications and screening in children and adolescents with type 2 diabetes mellitus

Chronic complications and screening in children and adolescents with type 2 diabetes mellitus
Literature review current through: Jan 2024.
This topic last updated: Oct 10, 2022.

INTRODUCTION — Children and adolescents with type 2 diabetes mellitus (T2DM) often have associated hypertension and dyslipidemia, which contribute to chronic cardiovascular complications. They are also at risk for developing microvascular complications (nephropathy, retinopathy, and neuropathy), which are caused by chronic hyperglycemia [1-3]. Further, they often have nonalcoholic fatty liver disease (NAFLD), which may progress to fibrosis and cirrhosis. Surveillance for and intensive treatment of each of these complications are important components of disease management, in addition to optimizing glycemic control.

Diabetic ketoacidosis and hyperosmolar hyperglycemic state are acute complications that occasionally develop in adolescent patients with T2DM [4-6]; these acute complications are discussed separately. (See "Diabetic ketoacidosis in children: Clinical features and diagnosis", section on 'DKA in type 2 diabetes mellitus' and "Diabetic ketoacidosis in children: Treatment and complications" and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment".)

The comorbidities and complications of T2DM in children and adolescents are presented here and in the table (table 1). The epidemiology, presentation, diagnosis, and management of T2DM in children and adolescents are discussed separately. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents" and "Management of type 2 diabetes mellitus in children and adolescents".)

HYPERTENSION — Primary hypertension is the most common cause of hypertension in adolescents and is especially common in those with obesity [7]. It is an important risk factor for cardiovascular disease and diabetes-associated nephropathy and retinopathy. (See 'Cardiovascular disease' below and 'Other microvascular complications' below.)

Prevalence — Primary hypertension is common in patients with pediatric T2DM. Observational studies of adolescents with T2DM reported hypertension in 17 to 32 percent of patients at presentation [1,8-10]. In the TODAY study, 12 percent of youth with T2DM had hypertension at enrollment, at a mean age of 14 years and mean duration of T2DM of eight months. At the end of the study, the prevalence of hypertension increased to 34 percent after an average follow-up of four years [11]. In long-term follow-up of this cohort, the cumulative incidence of hypertension was 67.5 percent at 15 years after the diagnosis of T2DM [12]. (See "Glycemic control and vascular complications in type 2 diabetes mellitus" and "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Blood pressure control'.)

Screening — In patients with T2DM, blood pressure (BP) should be measured at each routine health care visit [13].

Results are categorized as follows (based on BP measurements obtained on three separate occasions) (table 2) [13,14]:

For children ≥13 years of age:

Normal BP – Systolic and diastolic BP <120/80 mmHg

Elevated BP (previously referred to as prehypertension or "high-normal BP" in some diabetes literature) – Systolic BP 120 to 129 mmHg, with diastolic BP <80 mmHg

Hypertension – Systolic BP >130 mmHg or diastolic BP >80 mmHg

For children <13 years, hypertension is defined as systolic or diastolic BP ≥95th percentile or ≥130/80 mmHg (whichever is lower) (table 2). BP percentiles may be determined from a table for girls (table 3) or for boys (table 4).

If hypertension is detected, the patient should undergo a basic clinical evaluation to confirm that this is primary hypertension rather than due to renal disease or other secondary cause. Ambulatory blood pressure monitoring may be helpful if office-based measurements are equivocal. (See "Evaluation of hypertension in children and adolescents".)

Treatment — Management depends on the degree of BP elevation (table 1):

Elevated BP (prehypertension) – For children with T2DM and BP 120/80 to 129/80 mmHg (or <95th percentile for children <13 years), treatment is nonpharmacologic, consisting of intensive efforts to restrict salt, optimize diet, increase exercise, and promote weight loss. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Nonpharmacologic therapy'.)

If BP remains in this elevated range for six months, it is reasonable to initiate pharmacologic therapy; the decision is based on patient characteristics, including the presence of other cardiovascular risk factors.

Hypertension – For children with T2DM and persistent BP ≥130/80 mmHg (or ≥95th percentile for children <13 years), we suggest initiating pharmacologic treatment as soon as the diagnosis is confirmed, based on expert opinion as reflected in the American Diabetes Association (ADA) guideline, in addition to the nonpharmacologic interventions described above [13].

The treatment goal is to maintain BP <130/80 mmHg (or <90th percentile in children <13 years) [13].

When a decision is made to initiate pharmacologic therapy, angiotensin-converting enzyme (ACE) inhibitors are generally recommended for initial treatment because they reduce the risk of progressive renal disease. Angiotensin II receptor blockers (ARBs) may be used if the patient cannot tolerate ACE inhibitors or if targeted BP goals are not reached [13,15]. ACE inhibitors and ARBs are teratogenic; female patients should receive appropriate reproductive counseling. These drugs should be avoided in those who are not using reliable contraception and should be discontinued immediately if a pregnancy occurs. Alternative agents should be considered for females at risk for an unplanned pregnancy. Pregnancy prevention is especially important because females with T2DM who have menstrual abnormalities may have improved fertility after beginning metformin therapy. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Management approach'.)

Therapy is initiated at the lowest recommended dose and increased until the BP goal (<130/80 mmHg for children ≥13 years and <90th percentile for children <13 years) is reached. Serum creatinine and potassium should be checked monthly during the first two to three months because ACE inhibitors and ARBs can reduce renal function and cause hyperkalemia.

If ACE inhibitors or ARBs are contraindicated (eg, pregnancy) or not well tolerated, therapeutic alternatives include thiazide diuretics, calcium-channel inhibitors, and/or a beta blocker. Beta blockers can impair hypoglycemia awareness and may not be the best choice in patients who are at risk for hypoglycemia (ie, patients receiving exogenous insulin or oral insulin secretagogues). (See "Treatment of hypertension in patients with diabetes mellitus".)

DYSLIPIDEMIA — Dyslipidemia is an important risk factor for cardiovascular disease in patients with T2DM as well as in the general population. In adults with T2DM, clinical trials of statin therapy, which lowers low-density lipoprotein cholesterol (LDL-C) concentration, reduced the risk of cardiovascular disease. (See "Prevalence of and risk factors for coronary heart disease in patients with diabetes mellitus", section on 'Dyslipidemia' and "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Similar data demonstrating the beneficial effect of statin therapy in childhood T2DM are lacking. However, because dyslipidemia is associated with pediatric T2DM, it is generally accepted that children and adolescents with T2DM are at increased risk for progressive atherosclerosis and cardiovascular disease.

Prevalence — Patients with T2DM often have increased serum triglycerides (TG), low high-density lipoprotein cholesterol (HDL-C), and, occasionally, high LDL-C. These lipid abnormalities are correlated with insulin resistance and obesity.

Although dyslipidemia is not as common in pediatric patients as in adult patients with T2DM, a substantial proportion of young patients with T2DM have abnormal serum lipids. In the TODAY study, at baseline, 4.5 percent of participants had elevated LDL-C levels ≥130 mg/dL or were receiving lipid-lowering therapy; after 36 months of follow-up, the prevalence of elevated LDL-C or lipid-lowering therapy rose to 10.7 percent [16]. Elevations in TG were present in 21 percent at baseline and rose to 23 percent after three years. In long-term follow-up of this cohort, the cumulative incidence of dyslipidemia was 52 percent at 15 years after the diagnosis of T2DM [12]. In further observational follow-up, participants who did not maintain durable glycemic control (hemoglobin A1c ≥8 percent) tended to have progressive lipid abnormalities despite insulin treatment [17].

Screening — The following screening procedures have been recommended by the American Diabetes Association (ADA) (table 5) [13]:

Lipid testing should be performed at diagnosis of diabetes (but after glycemic control is well established) and annually thereafter. The profile should include measurements of LDL-C, HDL-C, and TG. If the sample was nonfasting (random) and results are indeterminate, confirm with a fasting lipid panel.

Optimal goals for fasting lipid levels in adolescents with diabetes are:

LDL-C <100 mg/dL (2.6 mmol/L)

HDL-C >35 mg/dL (0.9 mmol/L)

TG <150 mg/dL (1.7 mmol/L)

Of note, the LDL-C goal for children with diabetes is lower than the goal of <130 mg/dL (3.36 mmol/L) recommended for the general pediatric population. (See "Overview of the management of the child or adolescent at risk for atherosclerosis".)

Treatment — If the above goals for lipid levels are not met, the recommended approach to treatment is (table 5) [13]:

First, initiate nonpharmacologic therapy, consisting of optimizing glycemic control, diet, exercise, and weight reduction. The dietary change typically includes limiting total fat to 25 to 30 percent of calories, saturated fat <7 percent of total calories and dietary cholesterol intake <200 mg/day and avoiding trans fats. Patients with elevated TG should also attempt to decrease simple sugar intake and increase dietary omega-3 fatty acid intake. Dietary management also may include increased fiber intake, although adherence to the above dietary measures can be difficult. (See "Dyslipidemia in children and adolescents: Management", section on 'Heart-healthy lifestyle' and "Lipid management with diet or dietary supplements".)

Follow-up fasting lipid profiles should be obtained at three months and again at six months after the start of nonpharmacologic therapy.

After six months of nonpharmacologic intervention:

If lipids are within the target range above, continue nonpharmacologic intervention and repeat the lipid profile annually.

If LDL-C is >100 to 130 mg/dL (2.59 to 3.36 mmol/L), intensify nonpharmacologic intervention.

If LDL-C is >130 mg/dL (≥3.36 mmol/L), and the child is >10 years old, we suggest initiating pharmacotherapy, based on expert opinion reflected in a guideline from the ADA [13]. The first-line choice for therapy is a statin (3-hydroxy-3-methyl-glutaryl-coenzyme A [HMG-CoA] reductase inhibitor). The goal of pharmacologic therapy is an LDL <100 mg/dL. Start with the lowest recommended dose and then increase the dose if needed depending on the LDL-C measurements and side effects. Side effects of statin therapy include hepatic and renal dysfunction and muscle injury. Adolescent females should be counseled about the possibility of drug teratogenicity and appropriate contraceptive methods while receiving statin therapy, and these drugs should be discontinued immediately if pregnancy is discovered. (See "Dyslipidemia in children and adolescents: Management", section on 'Statin therapy'.)

If fasting TG is ≥150 to 400 mg/dL (1.7 to 4.5 mmol/L), optimize glycemic control and support lifestyle management for weight reduction [18]. In the rare patient with fasting TG ≥400 mg/dL (4.5 mmol/L), treat with fibric acid in addition to optimizing diabetes management. Severe hypertriglyceridemia is associated with an increased risk of pancreatitis [15,18]. (See "Dyslipidemia in children and adolescents: Management", section on 'Hypertriglyceridemia'.)

CARDIOVASCULAR DISEASE — Several lines of evidence indicate that youth with T2DM are at high risk for clinically important cardiovascular disease earlier in adult life than generally expected, including the following findings from the TODAY study:

Youth with T2DM have a high prevalence of several cardiovascular risk factors, including the diabetes itself, hypertension, dyslipidemia, obesity, and inflammatory biomarkers. More than 40 percent of participants in the TODAY study had high-risk concentrations of high-sensitivity C-reactive protein (hsCRP) or other inflammatory markers [16,17]. (See "Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood".)

Youth with T2DM have a variety of subclinical cardiovascular abnormalities, including increased left ventricular wall thickness (22 to 47 percent of patients) [1], increased arterial stiffness compared with obese and nonobese controls, and increased carotid intima media thickness (indicating premature aging of the cardiovascular system) [19-21]. In the TODAY study, 16 percent of youth with T2DM had adverse left ventricular geometry on echocardiography performed at a mean age of 18 years and a mean duration of T2DM of 4.5 years [22]. The cardiac changes were positively related to obesity and hypertension, but there was no association with the treatment used to manage the diabetes.

Adults with early onset of T2DM (diagnosed between 15 and 30 years of age) have double the cardiovascular mortality compared with those with T1DM of similar age and duration [23].

To reduce this risk for macrovascular disease, aggressive treatment and control of hypertension and hyperlipidemia are recommended for youth with T2DM, based on indirect evidence for this strategy from clinical trials in adults with T2DM [13,15]. In addition, because smoking is also a major risk factor for macrovascular disease, smoking cessation should be strongly encouraged and supported. Improving glycemic control improves cardiovascular outcomes in type 1 diabetes but has not been established for type 2 disease. (See 'Hypertension' above and 'Dyslipidemia' above.)

Indirect evidence from adults with T2DM and cardiovascular disease suggests that liraglutide or sodium-glucose co-transporter 2 (SGLT2) inhibitors may have benefits for cardiovascular outcomes [24]. These agents are generally reserved for patients who fail to meet glycemic targets despite diet, exercise, and metformin. (See "Management of type 2 diabetes mellitus in children and adolescents", section on 'Intensification of therapy' and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Contraindications to or intolerance of metformin'.)

Guidelines recommend against routine screening for heart disease using electrocardiography, echocardiography, or stress testing in asymptomatic youth with T2DM [13].

MICROVASCULAR COMPLICATIONS — Microvascular complications of T2DM are common among youth and tend to progress more rapidly than in adults. In long-term follow-up of the TODAY study cohort (mean age 26.4±2.8 years and mean time since diagnosis of diabetes 13.3±1.8 years), 60 percent of the participants experienced at least one microvascular complication and 28 percent experienced at least two [12]. Risk factors for the development of these complications included hyperglycemia, hypertension, dyslipidemia, and minority race or ethnic group.

Nephropathy (albuminuria) — Diabetes-associated nephropathy is a progressive disorder of the microvasculature of the kidney. The earliest sign of diabetic nephropathy is moderately increased albuminuria (formerly known as microalbuminuria). In youth with diabetes, moderately increased albuminuria predicts progression to overt proteinuria, which can be accompanied by systemic hypertension and impaired glomerular filtration [25]. Some patients with overt proteinuria will progress to end-stage kidney disease. Hypertension, chronic hyperglycemia, and smoking are important risk factors for diabetes-associated nephropathy. As a result, intensive monitoring and management for each of these risk factors are essential to reduce the risk for nephropathy. Screening for and treatment of diabetes-associated nephropathy are modeled on the strategies used for adults with T2DM. (See "Moderately increased albuminuria (microalbuminuria) in type 1 diabetes mellitus" and "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus" and "Diabetic kidney disease: Pathogenesis and epidemiology".)

Prevalence — Moderately increased albuminuria is common among adolescents with T2DM, occurring in 6 to 22 percent at presentation, and the prevalence increases rapidly during the first few years of disease [1,11,12,26]. In the TODAY study, increased albuminuria was present in 6.3 percent at baseline and increased to 13.4 percent at five years [27]. Poorer glycemic control (higher hemoglobin A1c) was associated with the risk of albuminuria. In long-term follow-up of this cohort, the cumulative incidence of diabetic kidney disease (moderate or severely increased albuminuria) was 55 percent at 15 years after the diagnosis of T2DM [12]. The incidence and progression of nephropathy in youth with T2DM is greater than in type 1 diabetes, after adjustment for age, disease duration, glycemia, and obesity [28].

Screening — All patients with T2DM should be screened annually for albuminuria [13,15]. Screening is most conveniently performed by measuring the urine albumin-to-creatinine ratio (UACR) in a random urine sample. Initial testing should be performed at diagnosis of diabetes, ideally after initial attempts to optimize glycemic control and blood pressure (BP), and repeated at least annually. The estimated glomerular filtration rate (eGFR) should also be calculated annually, based on serum creatinine, age, and height (calculator 1).

Results for UACR are categorized as follows:

Moderately increased albuminuria – UACR 30 to 300 mg/g (3.4 to 34 mg/mmol)

Severely increased albuminuria – UACR ≥300 mg/g (34 mg/mmol)

Patients with positive results (UACR >30 mg/g) should have repeat screening on at least two occasions during the subsequent three to six months. False-positive results can be caused by urinary tract infections, menstrual bleeding, febrile illness, upright posture, or exercise. Therefore, a first-morning void should be obtained if a random urine sample reveals elevated urinary albumin excretion. (See "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus", section on 'Detection'.)

Treatment — Initiate pharmacotherapy for patients with persistently elevated UACR (ie, at least two of three samples) (table 1) [13,15]:

Moderately increased albuminuria (UACR 30 to 300 mg/day), if BP is elevated. If BP is not elevated, we do not initiate pharmacotherapy but follow the BP and UACR closely and initiate treatment if BP becomes elevated, UACR steadily increases, or UACR remains persistently elevated during follow-up despite efforts to improve glycemic control.

Severely increased albuminuria (UACR ≥300 mg/day), regardless of BP. These patients should also be evaluated for other causes of kidney disease.

Angiotensin-converting enzyme (ACE) inhibitors are usually the first-line choice. Angiotensin II receptor blockers (ARBs) may be used if the ACE inhibitor is not tolerated (eg, due to persistent cough). The dose is adjusted to target normal BP, rather than albuminuria. Because ACE inhibitors and ARBs are teratogenic, female patients should be counseled to avoid pregnancy and these drugs should be discontinued immediately if a pregnancy is discovered. The above thresholds for initiating pharmacotherapy are based on expert opinion, as reflected in guidelines [13,15]. Evidence that these drugs can reverse the albuminuria and delay or prevent the progression of renal disease is primarily from studies in adults with T2DM or children with T1DM, as discussed separately. (See "Moderately increased albuminuria (microalbuminuria) in type 2 diabetes mellitus", section on 'ACE inhibitors and ARBs'.)

In addition to pharmacotherapy with antihypertensive agents, management of albuminuria should include optimization of glycemic control, avoiding smoking, and weight management. Patients with worsening UACR or decrease in eGFR should be referred to a nephrology specialist for further evaluation and management. (See "Chronic kidney disease in children: Clinical manifestations and evaluation".)

Other microvascular complications — In addition to diabetic nephropathy, other microvascular complications of diabetes include retinopathy and neuropathy (peripheral and autonomic) (table 1). Youth with T2DM have a higher risk for these vascular complications compared with those with type 1 diabetes, after adjustment for age, disease duration, glycemic control, and obesity [28]. Improved glycemic control and control of hypertension delay the onset and progression of microvascular disease, based on randomized trials in adults, and accumulating data in adolescents suggest that similar approaches are appropriate for this age group. The pathologic processes that cause vascular disease in either type 2 or type 1 diabetes are thought to be the same and are discussed in detail separately. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)

Retinopathy — Diabetes-associated retinopathy is a progressive disorder that affects the microvasculature of the retina. Most patients develop the mildest form of retinopathy (nonproliferative diabetic retinopathy [NPDR]) as duration of diabetes increases. NPDR can progress to an intermediate stage (pre-proliferative) and to proliferative retinopathy, which carries a high risk of visual loss when untreated. In the absence of adequate data in children with T2DM, pending the results of the follow-up retinopathy outcomes in the TODAY study, screening for and treatment of diabetic retinopathy are modeled on the strategies used in adults with T2DM. (See "Diabetic retinopathy: Classification and clinical features".)

Prevalence – In the TODAY study, NPDR was identified by retinal photography in 13.7 percent of participants after they had had T2DM for two to eight years. The NPDR was very mild in 12.4 percent of the cohort and mild in 1.4 percent [29]. Presence of retinopathy was related to higher hemoglobin A1c, older age, and longer duration of diabetes. Surprisingly, those youth with the highest body mass index had the lowest risk of retinopathy. After seven additional years of follow-up, 51 percent had developed retinopathy, which was moderate or severe in 9 percent [12]. In a separate study, 9 percent of young adults with T2DM had retinopathy after eight years mean diabetes duration, compared with 6 percent in an age-adjusted population with type 1 diabetes [28]. Retinopathy progresses more rapidly in individuals with youth-onset T2DM compared with adult-onset T2DM [30].

Screening – Children with T2DM should undergo dilated eye examination or retinal imaging to evaluate for retinopathy at the time of diagnosis [13,15]. The timing of subsequent examinations is determined by the presence and severity of retinopathy at the initial examination. If the examination is normal, screening is performed annually. Less frequent examinations (eg, every two years) may be appropriate for those with a normal examination and good glycemic control [13]. (See "Diabetic retinopathy: Screening".)

Screening allows detection of retinopathy in the nonproliferative stage. At this stage, improving glycemic control can reverse nonproliferative changes and prevent progression. In more severe cases of retinal disease, laser therapy or intravitreous injections can prevent further progression of disease and visual loss [31]. (See "Diabetic retinopathy: Prevention and treatment".)

Neuropathy — Diabetes-associated neuropathy is a progressive disorder that affects both the autonomic nervous system (eg, heart rate, postural BP control, pupillary adaption to darkness, and gastroparesis) and peripheral nerves (eg, nerve conduction, vibratory threshold, and sensory perception). (See "Screening for diabetic polyneuropathy".)

Prevalence – In an observational study, nearly 18 percent of young adults with T2DM had peripheral neuropathy after a mean diabetes duration of eight years, compared with 9 percent of those in an age-adjusted population with type 1 diabetes [28]. No significant differences in cardiovascular autonomic neuropathy were seen. In long-term follow-up of the TODAY study cohort, the cumulative incidence of neuropathy was 32 percent at 15 years after the diagnosis of T2DM [12]. Up to 20 percent of adult patients have evidence of nerve damage at the time of diabetes diagnosis. Similar to other microvascular complications, the risk of diabetic neuropathy in adults increases with poor glycemic control and duration of disease. Improved glycemic control improves nerve function in adults with diabetes. (See "Management of diabetic neuropathy".)

Screening – Children with T2DM should undergo annual screening for neuropathy, beginning at diagnosis [13]. Screening consists of a foot examination and testing for pressure sensation using a 10-g monofilament examination at specific sites on the foot, testing of vibration sensation using a tuning fork, and ankle reflex tests (figure 1) [18]. If the screening examination is abnormal, we refer to a neurologist for further evaluation, in addition to intensive efforts to improve glycemic control and assess and manage other cardiovascular risk factors such as BP and dyslipidemia. (See "Screening for diabetic polyneuropathy", section on 'Approach to screening' and "Evaluation of the diabetic foot", section on 'Assessment for loss of protective sensation'.)

NONALCOHOLIC FATTY LIVER DISEASE — Obesity and T2DM are associated with a clinical spectrum of liver abnormalities collectively known as nonalcoholic fatty liver disease (NAFLD). NAFLD is the most common liver disease in children and is particularly common in children with T2DM and/or obesity. NAFLD describes a spectrum of liver abnormalities, ranging from hepatic steatosis (increased liver fat without inflammation) to nonalcoholic steatohepatitis (NASH; increased liver fat with inflammation), which may progress to fibrosis or cirrhosis. For patients with simple steatosis or mild steatohepatitis, the likelihood and risk factors for progression to more severe liver disease are unknown.

Prevalence — Mild elevations of serum alanine aminotransferase (ALT) are common in youth with T2DM [1]. In most cases, this is attributable to NAFLD because of the established associations of obesity and insulin resistance with both T2DM and NAFLD. In the TODAY study, 6.5 percent of youth had mild ALT elevations (1.5 to 2.5 times the upper limits of normal [ULN]) shortly after their diagnosis with T2DM [32]. During the study (follow-up 2 to 6.5 years), 16 percent of participants experienced ALT elevations >1.5 times the ULN and one-third of these were >2.5 times ULN; these rates did not vary by treatment group (metformin alone, metformin plus lifestyle modification, or metformin plus rosiglitazone) [33]. Metformin therapy was temporarily discontinued when levels were >2.5 times the ULN and resumed if and when the levels normalized or fell to 1.5 to 2.5 times the ULN.

Screening — Routine surveillance for NAFLD in children and adolescents with T2DM should include abdominal examination for hepatomegaly and annual monitoring of serum aminotransferase concentrations [13]. Patients who have persistent aminotransferase elevations (eg, ALT >80 units/L or >2.5 times the ULN) should be further evaluated for other causes of hepatic dysfunction by history and laboratory testing. An approach to screening and evaluation is detailed in a separate topic review. (See "Metabolic dysfunction-associated steatotic liver disease in children and adolescents", section on 'Laboratory evaluation'.)

Treatment — The only established treatment for NAFLD is weight reduction. Since virtually all adolescents with T2DM have obesity, the initial intervention for those with any ALT elevation should be intensive efforts to support weight control and optimize glycemic control. Patients should be advised to avoid or limit alcohol consumption since this may exacerbate NAFLD. Bariatric surgery may cause further elevations in serum ALT during the early phase of rapid weight loss. These abnormalities are typically transient, and NAFLD usually improves by the time that weight loss plateaus [34]. However, acute hepatic decompensation also has been reported during rapid weight loss, so monitoring is warranted [35] (See "Metabolic dysfunction-associated steatotic liver disease in children and adolescents", section on 'Management'.)

Metformin is the first-line treatment for T2DM in adolescents with or without NAFLD. Metformin probably does not have either beneficial or adverse effects on NAFLD [36]. However, metformin is generally contraindicated in other liver diseases because it increases the risk for lactic acidosis. Therefore, we do not use metformin for patients with markedly elevated ALT levels (eg, >2.5 times the ULN). Similarly, if ALT rises above this threshold during metformin therapy, we hold metformin for at least two weeks and repeat measurement of ALT to determine if this might be an adverse drug effect. We resume metformin only if ALT decreases and remains ≤2.5 times the ULN, similar to the protocol used in the TODAY study [33]. (See "Management of type 2 diabetes mellitus in children and adolescents".)

For patients who are unable to tolerate metformin, or those with severe or progressive NAFLD, alternative approaches to treat the diabetes and NAFLD include liraglutide and bariatric surgery. Liraglutide is a second-line agent for T2DM in adolescents and also appears to have modest beneficial effects on NAFLD, based on studies in adults. Metabolic weight loss surgery is an effective intervention for adolescent and adult patients with obesity and T2DM and should be considered in those with progressive NAFLD or other comorbidities [37]. (See "Management of nonalcoholic fatty liver disease in adults", section on 'Patients with NASH and diabetes' and "Surgical management of severe obesity in adolescents".)

OTHER COMORBIDITIES AND COMPLICATIONS

Psychological — Youth with T2DM have an increased risk for depression and binge eating compared with nondiabetic youth. In the baseline data from the TODAY study, 26 percent of participants endorsed clinical or subclinical symptoms of binge eating on a standardized eating disorder questionnaire and 15 percent reported depressive symptoms [38]. In follow-up of the same cohort, stressful life events predicted impaired psychosocial functioning and lower adherence to prescribed medications [39].

Because both binge eating and depression interfere with weight loss efforts in youth with obesity and are associated with poorer glycemic control in those with T2DM [13,40,41], identifying and treating these issues may be an important step in management of T2DM. Therefore, periodic surveillance for depression and eating disorders is recommended for all youth with T2DM, with referral to mental health clinicians if needed [13,15].

Menstrual irregularity — Menstrual irregularity with polycystic ovary syndrome (PCOS) is a common comorbidity of obesity and T2DM. In the TODAY study, menstrual irregularity occurred in 21 percent of females who were at least one year postmenarche and were not receiving hormonal contraceptives [42]. The menstrual irregularities were associated with abnormalities in sex steroid levels, supporting a likely diagnosis of PCOS in many of these patients.

Management of PCOS often includes hormonal contraceptives for patients with or without T2DM [18]. Metformin treatment for T2DM often improves menstrual regularity, which increases the risk for unplanned pregnancy. (See "Diagnostic evaluation of polycystic ovary syndrome in adolescents" and "Treatment of polycystic ovary syndrome in adolescents".)

Other obesity-related comorbidities — In addition to PCOS, youth with T2DM are at risk for other comorbidities of obesity including obstructive sleep apnea and orthopedic complications. The clinician should be vigilant for suggestive symptoms and signs of each of these disorders and evaluate more specifically as needed. (See "Overview of the health consequences of obesity in children and adolescents".)

Pregnancy complications — Young women with T2DM experience a high rate of adverse pregnancy outcomes. In the TODAY study, adolescents who became pregnant had high rates of premature birth (15 percent) and major congenital malformations (21 percent) [43]. Similar adverse pregnancy outcomes are also seen in adult women with T2DM; the congenital malformations appear to be associated with the degree of hyperglycemia in the periconception period. (See "Pregestational (preexisting) diabetes: Preconception counseling, evaluation, and management".)

These findings underscore the crucial importance of reproductive counseling for adolescents with T2DM, using a tool such as Ready-Girls [44], so that they are aware of these risks and have access to appropriate contraception if desired.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Lipid disorders and atherosclerosis in children" and "Society guideline links: Diabetes mellitus in children".)

SUMMARY AND RECOMMENDATIONS

Overview – Chronic complications are common among youth with type 2 diabetes mellitus (T2DM) and tend to progress more rapidly than in adults, with documented cumulative incidence over 15 years of more than 50 percent for diabetic kidney disease, retinopathy, hypertension, and dyslipidemia and 30 percent for neuropathy. Surveillance and management for complications are outlined in the table (table 1). (See 'Nephropathy (albuminuria)' above and 'Retinopathy' above and 'Hypertension' above and 'Dyslipidemia' above and 'Neuropathy' above.)

Hypertension – Primary hypertension (formerly called "essential" hypertension) is present in 17 to 32 percent of adolescent patients with T2DM at presentation. Both T2DM and hypertension increase the risk for macro- and microvascular disease. (See 'Hypertension' above.)

Blood pressure (BP) should be measured at all routine health care visits for pediatric patients with T2DM. The results are categorized as follows, based on BP measurements taken on three separate occasions (table 2) (see 'Screening' above):

-For adolescents ≥13 years, elevated BP (prehypertension) is defined as systolic BP 120 to 129 mmHg, with diastolic BP <80 mmHg. Hypertension is defined as systolic or diastolic BP ≥130/80.

-For children <13 years, elevated BP and hypertension are based on BP percentiles, as outlined in the table (table 2).

If elevated BP is present, nonpharmacologic therapy (salt restriction, healthful diet, exercise, and weight reduction) should be used initially. If BP remains in this elevated range for six months, it is reasonable to initiate pharmacologic therapy; the decision is based on patient characteristics, including the presence of other cardiovascular risk factors. (See 'Treatment' above.)

If hypertension is diagnosed in a patient with diabetes, we suggest initiating pharmacologic therapy (Grade 2C). The preferred antihypertensive agent is an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blockers (ARB) if the ACE inhibitor is not tolerated. These drugs are teratogenic, should be avoided in females of childbearing age who are not using reliable contraception, and should be discontinued immediately if a pregnancy occurs. (See 'Treatment' above and "Nonemergent treatment of hypertension in children and adolescents".)

Dyslipidemia – Patients with T2DM are at increased risk for dyslipidemia, a major risk factor for cardiovascular disease. In our practice, we use the American Diabetes Association (ADA) guidelines for screening and treatment of dyslipidemia in pediatric patients with T2DM (table 5). (See 'Dyslipidemia' above.)

In all pediatric patients with T2DM, a lipid profile should be obtained at diagnosis (after blood glucose control has been well established) and repeated annually.

Nonpharmacologic therapy (diet, exercise, improved glycemic control, and weight reduction) should be used for initial management of dyslipidemia. We suggest pharmacologic therapy for children over 10 years of age who fail nonpharmacologic therapy and have elevated low-density lipoprotein cholesterol (LDL-C; ≥130 mg/dL [≥3.36 mmol/L]) (Grade 2C). Our preferred pharmacologic agent is a statin.

Microvascular complications – In both adults and children with T2DM, the risk of microvascular complications increases with poor glycemic control and duration of the disease. Early detection allows for intervention that may reverse vascular disease or delay further progression. (See 'Other microvascular complications' above.)

For pediatric patients with T2DM, guidelines recommend the following screening procedures:

Nephropathy – Annual screening for albuminuria by measuring the urine albumin-to-creatinine ratio (UACR). The results inform treatment decisions:

-For patients with moderately increased albuminuria (UACR ≥30 to 300 mg/day) and elevated BP, we suggest initiating pharmacotherapy (ACE inhibitor or ARB) (Grade 2C). If BP is not elevated, we do not initiate pharmacotherapy but follow the BP and UACR closely and initiate treatment if BP becomes elevated, UACR steadily increases, or UACR remains persistently elevated during follow-up despite efforts to improve glycemic control.

-For patients with severely increased albuminuria (UACR ≥300 mg/day) and elevated BP, we recommend initiating pharmacotherapy (ACE inhibitor or ARB) (Grade 1B) and suggest such therapy even if BP is normal (Grade 2C).

(See 'Nephropathy (albuminuria)' above.)

Retinopathy – Dilated eye examination and/or retinal imaging to screen for diabetic retinopathy. If the initial examination is normal, it should be repeated every one to two years, depending on glycemic control. (See 'Retinopathy' above.)

Neuropathy – Annual screening for diabetic neuropathy. Annual screening typically is performed with a careful examination of the sensory nerves. (See 'Neuropathy' above.)

Nonalcoholic fatty liver disease (NAFLD) – NAFLD is common among children with T2DM and is usually the cause of elevated aminotransferase levels. The only established treatment is weight reduction. Metformin and other antihyperglycemic drugs used for treatment of T2DM also may cause aminotransferase elevations, but it is reasonable to proceed with metformin therapy as long as serum aminotransferase levels are closely monitored and ≤2.5 times the upper limits of normal (ULN). (See 'Nonalcoholic fatty liver disease' above.)

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Topic 5826 Version 32.0

References

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