ISPAD Clinical Practice Consensus Guidelines 2018: Microvascular and macrovascular complications in children and adolescents

1 |. WHAT IS NEW?

1.1 |. Recommendations

1. Commence screening for microvascular complications at age 11 years (formerly 10 years)

2. Screening for microvascular disease should be performed preconception and during each trimester of pregnancy

3. Screen for lipid abnormalities in the non-fasting state

4. Screen for renal disease by first morning albumin creatinine ratio as the preferred method

1.2 |. Recommendations—Screening for and prevention of complications

1.2.1 |. Prevention

• Intensive education and treatment should be used in children and adolescents to prevent or delay the onset and progression of vascular complications. A

• Achievement of target glycemic control will reduce the risk for onset and progression of diabetes vascular complications. A

• Screening should be performed preconception and each trimester of pregnancy. B

1.2.2 |. Albuminuria

• Screening for albuminuria should start from age 11 years with 2 to 5 years diabetes duration. C

• Annual screening for albuminuria should be undertaken by first morning urine samples for urinary albumin/creatinine ratio (ACR). E

• Because of biological variability, two of three urine samples should be used as evidence of albuminuria. Confounders are exercise, menstrual bleeding, infections, fever, kidney diseases, and marked hyperglycemia. Abnormal screening tests should be repeated, as albuminuria may be transient. E

• Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) agents should be used in adolescents with persistent albuminuria to prevent progression to proteinuria. E

1.2.3 |. Retinopathy

• Screening for diabetic retinopathy should start from age 11 years with 2 to 5 years diabetes duration. B

• Screening for diabetic retinopathy should be performed by an ophthalmologist, optometrist, or a trained experienced observer through dilated pupils via bio-microscopy examination or fundal photography. B

• For those with diabetes duration less than 10 years, mild non-proliferative retinopathy (microaneurysms only) and good glycemic control, biennial screening assessment by biomicrocopic examination or fundal photography can occur. The frequency of retinopathy screening in general should occur biennially for these patients, but should be more frequent if there are high risk features for visual loss (Table 1). E

• Because of potential worsening of retinopathy for patients with longstanding poor glycemic control when control is rapidly improved, ophthalmological monitoring is recommended before initiation of intensive treatment and at three monthly intervals for 6 to 12 months thereafter, particularly if retinopathy is moderate non-proliferative stage or worse at the time of intensification. E

• Laser treatment and intravitreal injections of anti-VEGF agents reduce the rate of visual loss for individuals with vision-threatening stages of retinopathy (severe non-proliferative retinopathy or worse and/or diabetic macular edema). A

TABLE 1.

Screening recommendations and risk factors for vascular complications

	When to commence screening?	Screening methods	Risk factors
Nephropathy	11 years with 2–5 years diabetes duration	Urinary albumin/creatinine ratio	Hyperglycaemia
			High BP
			Lipid abnormalities
			Smoking
Retinopathy	11 years with 2–5 years diabetes duration	Fundal photography or mydriatic ophthalmoscopy	Hyperglycemia
			High BP
			Lipid abnormalities
			Higher BMI
Neuropathy	11 years with 2–5 years diabetes duration	History Physical examination Clinical tests	Hyperglycemia
			Higher BMI
			Age
			Diabetes duration
			Genetics
Macrovascular disease	11 years with 2–5 years diabetes duration	Lipid profile every 2 years, BP annually	Hyperglycemia
			High BP
			Lipid abnormalities
			Higher BMI
			Smoking

1.2.4 |. Other ocular conditions

• A comprehensive initial eye examination should also be considered to detect cataracts, major refractive errors, or other ocular disorders. E

1.2.5 |. Neuropathy

• Screening for peripheral neuropathy should start from age 11 years with 2 to 5 years diabetes duration and annually thereafter. C

• Specific tests to evaluate diabetic neuropathy include assessment of sensation, vibration and reflexes in the feet for peripheral neuropathy, and orthostatic, heart rate variability for cardiac autonomic neuropathy. E

1.2.6 |. Blood pressure

• Blood pressure (BP) should be measured at least annually. E. Hypertension is defined as average systolic BP (SBP) and/or diastolic BP (DBP) that is ≥95th percentile for gender, age, and height on three or more occasions B.

• Confirmation of hypertension may be assisted by 24 hours ambulatory BP measurements. E

• ACEI are recommended for use in children with diabetes and hypertension E (Table 2). They have been effective and safe in children in short-term studies A, but are not safe during pregnancy. B

TABLE 2.

Recommended threshold values for different parameters for intervention and primary prevention of microvascular and CVD in children and adolescents with type 1 diabetes

Threshold value	Type of intervention
BP >90th percentile for age, gender and height	iLfestyle intervention: exercise, less screen time and diet
BP >90th percentile despite lifestyle intervention	ACE inhibitor or other BP lowering agent
	If microalbuminuria is present: ACE inhibitor or ARB
BP >95th percentile for age, gender and height	Lifestyle intervention and ACE inhibitor or other BP lowering agent
	If microalbuminuria is present: ACE inhibitor or ARB
LDL cholesterol >2.6 mmol/L (100 mg/dL)	Dietary and lifestyle intervention
LDL cholesterol >3.4 mmol/L (130 mg/dL)	Statins

1.2.7 |. Lipids

• Screening for dyslipidemia should be performed soon after diagnosis (when diabetes stabilized) in all children with type 1 diabetes from age 11 years E. If normal results are obtained, this should be repeated every 5 years. If there is a family history of hypercholesterolemia, early cardiovascular disease (CVD) or if the family history is unknown, screening should commence as early as age 2 years E.

• Screening with a fasting lipid profile is ideal but not always practical in youth with diabetes mellitus. Non-fasting lipids screening may be obtained and if triglycerides or Low density lipoprotein (LDL) levels are elevated, a fasting lipid profile would then be indicated. E

• High LDL cholesterol is defined as >2.6 mmol/L (100 mg/dL) E. If this is present then interventions to improve metabolic control, dietary changes and increased exercise should be instituted.

• If the above interventions do not lower LDL cholesterol <3.4 mmol/L (130 mg/dL), statins should be commenced in children from age 11 years E (Table 2).

1.2.8 |. Lifestyle

• Prevention or cessation of smoking will reduce progression of albuminuria and CVD B.

1.2.9 |. Macrovascular disease

• Screening of BP and lipids is recommended, as above. The benefit of routine screening for other markers of macrovascular complications outside the research setting is unclear E.

1.2.10 |. Type 2 diabetes

• Complications screening should commence at diagnosis. Attention to risk factors should be escalated because of the increased risk of complications and mortality B. (See also the ISPAD Guidelines chapter on type 2 Diabetes.)

2 |. INTRODUCTION

The long-term vascular complications of diabetes include nephropathy, retinopathy, neuropathy, and macrovascular disease. The outcomes are:

• renal failure and hypertension due to diabetic nephropathy

• visual impairment and blindness due to diabetic retinopathy

• pain, paresthesia, muscle weakness due to peripheral neuropathy

• postural hypotension, gastroparesis, diarrhea, bladder paresis and impotence, due to autonomic neuropathy

• cardiac disease, peripheral vascular disease, and stroke due to macrovascular disease

Clinically evident diabetes-related vascular complications are rare in childhood and adolescence. However, early functional and structural abnormalities may be present a few years after the onset of the disease.

Childhood and adolescence is a period during which intensive education and treatment may prevent or delay the onset and progression of complications.¹

There has been a declining incidence of complications reported in many areas with specialized clinics.^2,3 This has occurred over a period of time during which there have been major changes and intensification of diabetes management, identification of putative risk factors, and the advent of regular screening for complications. There is no evidence that this is a worldwide occurrence: in areas where health care is not optimal, a greater risk of complications will remain.⁴ Nevertheless vascular complications still remain a key contributor to mortality in young people with an onset of diabetes during childhood.⁵

2.1 |. Interventional studies of intensive glycemic control

The diabetes control and complications trial (DCCT) was a multicenter, randomized controlled clinical trial involving 1441 patients with type 1 diabetes conducted in North America from 1983 to 1993⁶. Study participants included 195 pubertal adolescents (aged 13–17 years). Patients were randomized to either intensive or conventional treatment. The DCCT provided unequivocal evidence that intensive diabetes treatment and improved glycemic control conferred a significant risk reduction for microvascular complications compared with conventional treatment⁶.

After completion of the DCCT (a median in the whole group of 6.5 years) and hence the end of randomization, the Epidemiology of Diabetes Interventions and Complications (EDIC) study continued to follow patients. The EDIC study demonstrated that this positive effect continued after the end of the intervention: that is, that there was a memory effect of improved glycemic control, now called a legacy effect.^7–9 During this phase a positive effect of the intensive therapy for reduction in macrovascular disease was also identified with a 50% reduction in cardiovascular events over 17 years.^10,11

In the adolescent cohort, the intensive treatment compared with conventional treatment (for a median of 7.4 years), reduced the risk and progression of diabetic retinopathy by 53%, clinical neuropathy by 60%, and microalbuminuria by 54%. The difference in HbA1c was 8.1% vs 9.8%. The benefits of intensive therapy persisted in the former adolescent cohort for 4 years during the EDIC study: with a 74% risk reduction for vision-threatening retinopathy, 48% less microalbuminuria, and 85% less albuminuria.⁹

2.2 |. Other risk factors for the development of complications

Longer duration of diabetes, older age, and puberty are risk factors for complications. A higher prevalence of microvascular complications has been reported for adolescent girls compared with boys.^12,13 The prepubertal years of diabetes duration have a significantly lesser impact especially further from the onset of gonadarche¹⁴; however, the risk of vascular complications is greater for those living with diabetes during puberty, compared to young people who develop diabetes after puberty.¹⁵ For the same diabetes duration, age and puberty increase the risk for retinopathy and elevated albumin excretion rate (AER).¹⁶ Longitudinal studies have also reported that younger age of type 1 diabetes onset, particularly before puberty, is associated with a longer time free of complications such as nephropathy and retinopathy.¹⁴ However, in the long term this initial advantage disappears.¹²

High rates of cardiovascular risk factors have been found in children and adolescents with type 1 diabetes from Norway and in SEARCH, a population-based study from the United States.^17,18

Smoking is associated with an increased risk of developing persistent albuminuria.¹⁹ The evidence for the effect of smoking on retinopathy is less clear. Type 1 diabetes and smoking interact to produce excess cardiovascular morbidity and mortality.²⁰

High blood pressure (BP) and alterations in the circadian BP rhythm have been associated with the risk of developing nephropathy and retinopathy in youth with type 1 diabetes.^21–23 Hypertension has a greater impact on cardiovascular disease (CVD) in diabetic patients than in non-diabetic individuals.²⁴ BP control (<130/80 mm Hg in adults) is effective in decreasing cardiovascular morbidity and mortality in diabetes.²⁵

Dyslipidemia was associated with microalbuminuria and retinopathy development in the DCCT/EDIC and other studies.^26–28 This included higher total LDL cholesterol and higher non-High density lipoprotein (HDL) cholesterol levels for microalbuminuria, as well as larger LDL particle size and apolipoprotein B in men.

Family history of vascular complications or cardiovascular risk factors increases the risk for nephropathy.^29,30 Higher body mass index (BMI) is a risk factor for microalbuminuria,³¹ retinopathy³², neuropathy,³³ and CVD.³⁴

Lifestyle issues also contribute to complications risk; sedentary men with diabetes have higher mortality than active individuals.³⁵

Celiac disease is also an independent risk factor for retinopathy, early elevation of AER nephropathy in patients with type 1 diabetes.^36,37

2.3 |. Diabetic nephropathy

Diabetic nephropathy is a major cause of morbidity and mortality amongst young adults with type 1 diabetes. In the absence of diabetic nephropathy, mortality in patients with type 1 diabetes is similar to that in the general population, whereas it is significantly higher in patients with abnormal urinary AER.^38,39

The changes occurring in the kidney in patients with type 1 diabetes are generally classified into five stages, reflecting specific and progressive alterations in renal morphology and function. The earliest stage is characterized by glomerular hypertrophy, hyperfiltration, and hyperperfusion. This is followed by a stage of subclinical morphological changes and increases in albumin excretion rates (AER) within the normal range.⁴⁰ Further increases in albumin excretion, with an AER between 30 and 300 mg/24 h or 20 and 200 μg/min in a 24-hour or timed urine collection, indicate the development of albuminuria (formerly “microalbuminuria”) (stage 3), which may further progress to overt proteinuria (formerly termed “macroalbuminuria)” (AER >200 μg/min or >300 mg/24 h) (stage 4) and, without any treatment, to end-stage renal disease (ESRD) (stage 5).⁴¹

Although advanced stages of nephropathy, such as overt proteinura or ESRD, are rare in children and adolescents with type 1 diabetes, early structural and functional renal alterations develop soon after diagnosis of diabetes, and often progress during puberty. Biopsy studies have shown that renal lesions, such as basement membrane thickening and mesangial expansion, can be detected in young normoalbuminuric subjects and these changes are predictive of subsequent albuminuria.⁴²

Albuminuria with AER <200 μg/min has been for long time considered as the earliest clinical manifestation of nephropathy and a key risk factor for progression to proteinuria. However, 40% to 50% of cases of albuminuria can be transient or intermittent and thus not necessarily progress toward more advanced stages of nephropathy. However, as highlighted by recent studies, even if albuminuria regresses into the normal range, patients’ experiences intermittent microalbuminuria have an increased cardiorenal risk.^12,43

Extensive evidence indicates that increases in albumin excretion, even within the normal range, predict CVD risk in adults with type 1 diabetes as well as in non-diabetic populations.⁴⁴ In young people with childhood-onset type 1 diabetes, early increases in albumin excretion rates can occur during the first years after diagnosis and can predict future risk of albuminuria and proteinuria.⁴⁵ In an incident cohort, after 6 years duration, early elevation of AER (>7.5 μg/min) was examined as an even earlier marker of renal dysfunction. Comparing children before and after 11 years, elevated AER was present in 5% compared to 25%; and comparing children before and after puberty, it was present in 5% compared to 26%.¹⁶ There has been no secular reduction in AER or albuminuria in the same cohort that has shown a reduction in retinopathy: 24% to 22% in the short duration cohort (2-<5 years duration)⁴⁶; 45% to 30% in the cohorts with median duration 8.6 years.³ Similar results have been found in Bangladesh.⁴⁷ The recent results from the screening phase of the adolescent type 1 diabetes cardiorenal intervention trial (AdDIT) showed that adolescents aged 10 to 16 years, with increased urinary albumin excretion levels (upper tertile of the normal range) had higher glomerular filtration rate (GFR) and increased CVD risk, as indicated by higher lipid levels, arterial stiffness, increased aortic intima media thickness, and signs of impaired cardiac autonomic function.^48–50

2.3.1. | Screening for albuminuria

One of the first markers of diabetic nephropathy is albuminuria,⁵¹ which is defined as any of those below:

• Albumin/creatinine ratio (ACR) 2.5 to 25 mg/mmol or 30 to 300 mg/g (spot urine) in males and 3.5 to 25 mg/mmol or 42 to 300 mg/g in females (because of lower creatinine excretion)

Values above the upper limit of the albuminuria range denote proteinuria.

Assessing ACR in a spot urinary sample is the easiest method to carry out in an office setting and it generally provides accurate information. First-voided urine in the morning is preferable because of the known diurnal variation in albumin excretion and postural effects. A random sample can be used but being aware that this is associated with an increased risk of false positive results, and therefore in case of an abnormal result, screening should be repeated with first morning urine collections. Timed overnight or 24 hour collections are more burdensome and add little to prediction or accuracy.^52,53

Confounding factors to be considered when screening for albuminuria are: strenuous exercise, infections, kidney disease (ie, IgA or other types of nephritis), marked hyperglycemia, fever, menstrual bleeding. All these factors can lead to increased ACR/AER.

Albuminuria is confirmed by finding 2 or all of three samples abnormal over a 3- to 6-month period. Persistent albuminuria has been shown to predict the progression to end stage renal failure ^51,54 and is associated with an increased risk of macrovascular disease.⁴⁴

Regular follow-up is important to identify rapid or slow progression to albuminuria, as well as cases of regression to normoalbuminuria. Regular longitudinal follow-up of albumin excretion is also important to identify patients with progressive small increases of urinary albumin excretion within the normal range, which might be a prelude to the development of albuminuria.

2.4 |. Antihypertensive treatment for prevention of nephropathy

Effective antihypertensive therapy in patients with nephropathy prolongs the time to end-stage renal disease.^55,56 A recent prospective study has shown further improvement in prognosis with preservation of renal function in those diagnosed with nephropathy after 2000, associated with better control of BP, greater use of Renin angiotensin system (RAS) inhibition, better control of lipids and glycemia control and less smoking.⁵⁷ Hypertension in children is defined as BP equal to or above the 95th percentile for age, sex, and height, whereas in adolescents (age ≥13 years) it is defined as SBP ≥130 and/or diastolic BP (DBP) ≥80 mm Hg.

Elevated BP (previously known as “prehypertension”) is defined as BP ≥90th percentile for age, sex, and height, or from the age of 13 years as BP between 120 and 129/80 mm Hg. Similar to overt hypertension, elevated BP is associated with adult hypertension and potentially amenable to treatment.^58,59

Children and adolescents found to have elevated BP or hypertension should have elevated BP confirmed on three separate days. Confirmation of hypertension may be assisted by 24 hours ambulatory BP measurements (ABPM). Normative ABPM values are available and should be used for the interpretation of the results.⁶⁰

In children and adolescents with elevated BP, initial treatment includes lifestyle interventions, including DASH diet and moderate to vigorous physical activity at least 3 to 5 days per week (30–60 minutes per session).^58,61,62 If target BP is not reached within 3 to 6 months of initiating lifestyle intervention, pharmacologic treatment should be considered.

When hypertension is confirmed in children and adolescents with type 1 diabetes, in addition to lifestyle modification, pharmacologic treatment of hypertension should be considered.⁶³ Pharmacologic treatment of hypertension in children and adolescents should be initiated with an angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), long-acting calcium channel blocker, or a thiazide diuretic. Angiotensin converting enzyme inhibitors (ACEI) are recommended for use in children and adolescents with hypertension and albuminuria but an angiotensin receptor blocker can be used if the ACE inhibitor is not tolerated (eg, due to cough).⁶³ They have been effective and safe in children in short-term studies.^64–66

Reproductive counseling and implementation of effective birth control is required when treatment is implemented, due to the potential teratogenic effects of both drug classes. The goal of treatment is BP consistently <90th percentile for age, sex, and height.

In adults, ACEI and angiotensin II receptor blockers (ARBs) reduce progression from microalbuminuria to macroalbuminuria and increase the regression rate to normoalbuminuria.^67,68 A systematic review and meta-analysis showed that in subjects with diabetes, only ACEI can prevent the doubling of serum creatinine compared to placebo.⁶⁹ In addition, in placebo-controlled studies, only ACEI (at the maximum tolerable dose) significantly reduced the risk of all-cause mortality.⁷⁰

A recent meta-analysis including trials comparing RAS blockers vs other antihypertensive agents in people with diabetes (and largely without albuminuria or proteinuria) did not show any superior effect of RAS blocker for the prevention of renal and cardiovascular outcomes, and suggest that any class of antihypertensive agents can be used in people with diabetes especially in those without renal impairment.⁷¹

Despite the above evidence mainly in adults, there are still some concerns regarding the use of ACEI in protecting long-term renal function in young people without hypertension. In meta-analysis of individual patient data, the beneficial effects were more modest in those with the lowest levels of microalbuminuria.⁷² Young people with albuminuria would potentially be taking ACEI for decades. Side effects include cough, hyperkalemia, headache, and impotence^73,74. A key safety issue related to the use of ACEI, as well as to ARBs, is the potential risk of congenital malformation when used during pregnancy. A recent systematic review has highlighted that fetal exposure to ACEI or ARBs has serious neonatal and long-term complications and recommend to improve the awareness of these potential deleterious effects.⁷⁵ Therefore, when starting treatment with these drugs in adolescent girls, they need to be aware of this risk and birth control measure need to be recommended.

Recent data from AdDIT, where 443 adolescents were randomized to treatment with an ACE inhibitor (Quinapril, 5 mg), a statin (Atorvastatin, 10 mg), a combination of both or placebo using a two-by-two factorial design, indicate that treatment with ACE inhibitors over 2 to 4 years in adolescents with type 1 diabetes deemed to be at risk of complication based on their ACR in the upper tertile of the normal range is safe, with only few reported side effects, mainly hypotension (requiring drug reduction). Treatment with ACE inhibitors in this group did not have any significant effect on the primary outcome measure (change in area under the curve of log₁₀ACR), but was associated with a 43% decrease in the secondary outcome cumulative incidence of microalbuminuria during the 2 to 4 year treatment period, although that did not reach statistical significance.⁶⁶

2.5 |. Diabetic retinopathy

Non-proliferative retinopathy is characterized by microaneurysms, retinal hemorrhages both pre- and intraretinal, cotton wool spots related to ischemia and microinfarction, hard exudates due to protein and lipid leakage, intraretinal microvascular abnormalities (IRMAs), and venular dilatation and tortuosity. Mild and moderate stages of non-proliferative retinopathy are not vision-threatening and do not invariably progress to more severe stages of retinopathy.⁷⁶

Severe non-proliferative retinopathy (previously known as preproliferative) is characterized by vascular obstruction, increase in number of retinal hemorrhages and microaneurysms, IRMAs, marked venous abnormalities, and ischemia and infarctions of the retinal nerve fibers causing cotton wool spots.

Proliferative diabetic retinopathy (PDR) is characterized by neovascularisation in the retina and/or vitreous posterior surface. The vessels may rupture or bleed into the vitreoretinal space which is vision-threatening and/or.

Diabetic macular edema/maculopathy is characterized by decreased vascular competence and microaneurysm formation which produce exudation and swelling in the central retina.

Adolescents have a higher risk of progression to vision threatening stages of retinopathy (severe non-proliferative retinopathy or worse and/or diabetic macular edema) compared to adults with diabetes.⁷⁷ The progression may be rapid, especially in those with poor glycemic control.⁷⁸ Hence, adolescence is the time when efforts should be directed to screening for early signs of diabetic retinopathy and modifiable risk factors. Regression of retinopathy can also occur with improved glycemic control.^79,80 Regular screening for diabetic retinopathy has reduced the proportion of blind patients due to diabetes.^81,82

In the United Kingdom, a national screening program was introduced from 2002 with the initial age of screening starting at 12 years because there were no reports of vision-threatening retinopathy before this age.⁸³ Recently, reported results of 2125 adolescents screened at age 12 to 13 years found referral retinopathy rates of less than 20%, but of these, three individuals with short duration (<5 years) required fast track referral for moderate to severe retinopathy. At subsequent 5-year follow-up, progression to vision-threatening retinopathy had occurred in 9% of adolescents diagnosed before age 5 years and in 3% diagnosed at age 5 to 7 years.

Recent reports have found low rates of referral for retinopathy screening in well-controlled diabetes pediatric clinics.^84,85 In the T1D Exchange Registry in the United States, less than 1% of 12 235 patients reported treatment for retinopathy⁸⁶ at a mean age of 12 years and duration 5 years, although this is likely to under-report the actual prevalence since the data were based self-reported retinopathy and only cases requiring treatment.

Conversely, insurance claims data show markedly higher rates reported by optometrists or ophthalmologists in a large US managed-care network: 20% of 2240 youth had developed diabetic retinopathy at a median duration of 3.2 years with an incident rate of 52.3 per 1000 person-years; estimated to be 25% at 5 years duration. Severe retinopathy or macular oedema was present in 2% and the youngest patient with PDR was age 6 years. Lower rates of screening uptake were found in those with lower family income and this group had higher rates of retinopathy, suggesting that the actual rate may be even higher.^87,88

Initial worsening of diabetic retinopathy can occur with the initiation of improvement in glycemic control as occurred in the DCCT but such worsening did not result in clinically significant visual loss and over time, intensive therapy continued to be superior to standard therapy. This initial worsening of diabetic retinopathy with improvement of glycemic control also occurred in patients with growth failure due to severe under-insulinization.^89,90 However, within 1.5 to 3 years, the advantage of intensive treatment is evident.⁸⁹ Pregnancy is a recognized risk for acceleration and progression of retinopathy^91,92; hence, screening for retinopathy should be undertaken preconception, every trimester and 1 year postpartum.

2.5.1 |. Assessment of retinopathy

The most sensitive detection methods for retinopathy screening are a clinical bio-microscopic fundus slit examination through dilated pupils by an ophthalmologist or optometrist and mydriatic seven-field stereoscopic retinal photography. The latter is optimal for research but not often available in the clinical setting. Other methods are mydriatic and non-mydriatic two-field fundal photography, direct ophthalmoscopy, indirect ophthalmoscopy, fundus fluorescein angiography, and optical coherence tomography (OCT). Fundal photography provides a validated result that can be useful for monitoring clinical quality and in research, but photographs may be not be gradable in which case ophthalmoscopy needs to be performed; mydriasis can reduce the technical failure rate.⁹³ Fluorescein angiography reveals functional vascular abnormalities (vascular permeability) as well as structural abnormalities in the blood vessels whereas OCT reveals only structural abnormalities, specifically macular oedema and other structural abnormalities including loss of the various layers of the neural retina.

The landmark study of diabetic retinopathy carried out in Wisconsin starting in 1980 to 1982, examined prevalence of retinopathy using seven-field stereoscopic retinal photography in people diagnosed with diabetes less than 30 years of age and on insulin within 1 year of diagnosis.⁹⁴ With longer diabetes duration there was an increase in retinopathy, so that after 15 years 98% had background retinopathy and after 35 years duration 62% had proliferative retinopathy. This study helped establish the existence of screening for diabetic retinopathy and the search and treatment of risk factors. Subsequent changes in diabetes management have been associated with a reduction in proliferative retinopathy demonstrated by comparison with a later diagnosed study group. After 20 years diabetes duration the later onset group of type 1 patients examined in 2007 to 2011, had less proliferative retinopathy than the earlier onset group examined 1980 to 1996:18% vs 43%.⁸⁰

When an incident cohort of children was examined for retinopathy after 6 years duration, the relative effects of age and puberty could be compared. Seven-field stereoscopic fundal photography was performed with early retinopathy defined as one microaneurysm or hemorrhage, which was present in 24%. Comparing children before and after 11 years, retinopathy was present in 8% vs 25%; and comparing children before and after puberty, it was present in 12% vs 29%. The incident cohort was diagnosed in 1990 to 1992 and examined in 1996 to 1998 when their median HbA1c was 8.7%.¹⁶

More recent data using the same methods in mid-adolescence (median age 16.4 years) with median diabetes duration of 8.6 years demonstrated that retinopathy declined from 53% (in 1990–1994) to 23% (in 2000–2004) and then to 12% (in 2005–2009).³ In a younger group aged 11 to 17 years (median age 14.5 years, duration 2–5 years), the prevalence of mild background retinopathy declined from 16% in 1990 to 1994 to 7% in 2003 to 2006.⁴⁶ Furthermore, those with shorter duration had considerably less retinopathy, and retinopathy was present in only 6% of the youngest group (aged 11–13 years) over the whole time of observation.

2.5.2 |. Specific treatment for retinopathy

Once sight-threatening retinopathy has been detected, treatment options include laser photocoagulation and/or anti-VEGF therapy.^76,95 Panretinal laser photocoagulation (PRP), commonly known as “laser therapy,” consists of multiple discrete outer retinal burns throughout the mid and far peripheral area but sparing the central macula. It has been proven to reduce the progression of visual loss by more than 50% in patients with PDR.^96,97 However, photocoagulation is not indicated for eyes with mild or moderate non-proliferative retinopathy.⁹⁸ Side effects of treatment are decreased night and peripheral vision and subtle changes in color perception. Complications of laser therapy are vitreous and choroidal hemorrhages or visual sequelae of misplaced burns.

For PDR, intravitreal injection of anti-VEGF (ranibizumab, aflibercept, bevacizumab) is now increasingly used and show better 12-month results for visual acuity than PRP.⁹⁹ This treatment is not destructive but does require repeated visits and injections for efficacy (eg, monthly injections for the first 5 months with up to nine injections in the first year); and carries the rare risk of ocular infection.¹⁰⁰

For diabetic macular edema involving vision loss, anti-VEGF (ranibizumab, aflibercept, bevacizumab) is now considered standard of care and has shown superior outcomes over 5 years compared to laser treatment.^101,102 Intravitreal use of steroids (dexamethasone and fluocinolone) was tested in phase 3 trials and approved by the Food and Drugs Administration (FDA) in the United States. However, because of the inferior visual acuity results and the potential adverse effects of cataract and glaucoma development, intravitreal steroid is rarely used as first-line of therapy for diabetic macular edema.

Surgical treatment such as vitrectomy may be indicated for persistent vitreous hemorrhage, tractional retinal detachment, or extensive fibrosis.⁹⁵

2.6 |. Diabetic cataracts

Cataracts have been reported in type 1 diabetes close to or even preceding the diagnosis.^85,103,104 A recent review found the prevalence to be 0.7% to 3.4% from 16 studies published since 1993.¹⁰⁵ Hence, comprehensive initial eye examination should also be considered to detect cataracts, especially if there is any visual disturbance. Examination for cataracts should be performed otherwise at time of screening for diabetic retinopathy. Surgical removal may be required (49 of the reported 66 cases).¹⁰⁵

2.7 |. Diabetic neuropathy

Diabetes can affect the somatic and autonomic nervous system. In youth, prevalence rates of peripheral neuropathy vary from <10% to as high as 27%,^3,106,107 and may be increasing,¹⁰⁸ although some of this variability may relate to different methods of screening in addition to recognized risk factors. Clinical symptoms of autonomic neuropathy are uncommon in the pediatric population, however, subclinical findings have been reported.^109,110 The most important associations of diabetic neuropathy are with glycemic control¹¹¹ and diabetes duration. ^112–114

2.7.1 |. Generalized neuropathy

The most common type of all diabetic neuropathies is the Diabetic Sensorimotor Polyneuropathy. The generic terms “diabetic neuropathy” and “peripheral neuropathy” are commonly used referring to this type of neuropathy. It is a polyneuropathy caused by a diffuse damage to all peripheral nerve fibers, motor, sensory, and autonomic. Such damage occurs insidiously and progressively and is characterized at first by sensory loss and later by mild loss of motor function, in a “stocking and glove” distribution. Small fiber dysfunction precedes large-fiber damage in diabetic sensorimotor polyneuropathy.¹¹⁵ Patients usually complain of numbness, prickling, burning and/or paresthesia of hands and/or feet, which can progress to persistent pain.¹¹³

2.7.2 |. Assessment of peripheral neuropathy

Physical examination should include clinical tests to evaluate: small-fiber function: temperature or pinprick sensation; large-fiber function: perception of vibration and soft touch sensation (usually 10 g mono-filaments), and evaluation of ankle and knee tendon reflexes.^113,116

Peripheral nerve lab tests include: quantitative vibration, thermal discrimination thresholds, and nerve conduction. These are mostly used in research settings or for more severe cases. Age- and gender-specific normal ranges need to be applied when interpreting results.

Focal neuropathies are less common and include mononeuropathies such as carpal tunnel syndrome, palsy of the peroneal nerve, palsy of the third cranial nerve, and proximal nerve conditions (eg, diabetic amyotrophy). Symptoms and diagnostic evaluation are related to the affected nerve.

2.7.3 |. Autonomic neuropathy

Autonomic neuropathy can affect many systems—the cardiovascular (CV), urogenital (UG) and gastro-intestinal (GI). Generally, the damage occurs gradually and progressively. While overt autonomic neuropathy is rare in childhood and adolescence, subclinical signs of autonomic dysfunction are common, and can be found even soon after diabetes diagnosis and may be accelerated by puberty.¹¹⁰ Symptoms and investigation are related to the affected system.

Autonomic neuropathy can cause postural hypotension, vomiting, diarrhea, bladder paresis, impotence, sweating abnormalities, impaired light reflex, impotence, and retrograde ejaculation. Abnormal heart rate responses and prolonged beginning of Q wave to end of T wave on the electrocardiogram (QT) intervals have been associated with increased risk of sudden death.¹¹⁷ Risk factors for autonomic neuropathy in young people include longer diabetes duration, poor glycemic control, higher BMI,¹¹⁸ and presence of aldose reductase gene (AKR1B1) polymorphisms, specifically the Z-2/Z-2 genotype.¹¹⁹

Cardiovascular autonomic neuropathy (CAN): the most common cardiac symptom is postural hypotension and alteration of heart rate. Progression of loss of heart rate (HR) variability may increase risk of severe hypoglycemia, as it is associated with impaired awareness of hypoglycemia.¹²⁰

Cardiac autonomic nerve tests include: heart rate response to deep breathing, standing from a lying position, Valsalva Maneuver, heart rate variation at rest, QT interval and postural changes in BP.¹¹⁰ Studies with young adults showed that resting heart rate, presence of somatic diabetic neuropathy, and retinopathy were independent factors associated with cardiac autonomic neuropathy.¹²¹ Abnormal heart rate responses and prolonged QT intervals have been associated with increased risk of sudden death.¹¹⁷

Gastrointestinal:

GI symptoms include those related to “diabetic gastroparesis” (retarded gastric emptying, nausea, postprandial vomiting, eructation), as well as those caused by lower intestinal compromise (abdominal pain, diarrhea, and fecal incontinence).¹²²

Urogenital system:

UG manifestations are usually related to bladder paresis (hesitation, increase in interval time between urination, inadequate emptying of bladder and urinary retention) and, more rarely, in adolescent males, erectile dysfunction.¹²³

Other symptoms of AN include sweating abnormalities, generally presented as a reduction of sweating in a “stocking and glove” manner, that can progress to global anhydrosis, and alterations of pupillary adaptation response to light and dark.¹¹⁰

Clinical symptoms of autonomic neuropathy are uncommon in the pediatric population. However, subclinical findings have been reported including significant cardiac autonomic neuropathy detected with heart rate variability studies in youth with type 1 diabetes.¹⁰⁹

2.8 |. Macrovascular disease

The mortality and morbidity of CVD are markedly increased in individuals with diabetes compared to the general population.¹²⁴

Hypertension has a greater impact on CVD in patients with diabetes than in individuals without this condition.²⁴ BP control (<140/80 mm Hg in adults) reduces cardiovascular morbidity and mortality in diabetes.¹²⁵

A family history of early CVD (before 55 years of age), lipid disturbances, type 2 diabetes, hypertension^26,126,127 and smoking place the individual with diabetes at higher risk.

Atherosclerosis starts in childhood and adolescence as shown by intima-media thickness of the carotids and aorta^128–130 and silent coronary atherosclerosis measured by intravascular ultrasound in young adults with childhood onset diabetes.¹³¹ Silent coronary atherosclerosis and cardiovascular events are strongly associated with poor glycemic control.^131,132

Cholesterol plays an important role in the initiation and progression of atherosclerosis. Well-controlled type 1 diabetes is not associated with gross blood lipid disturbances, but more advanced lipoprotein subclass examinations reveal atherogenic profiles.²⁸ Poor glycemic control was associated with a potentially more atherogenic lipoprotein profile.¹³³

Changes in lipids associated with increased cardiovascular risk are also associated with central obesity in type 1 diabetes (as well as type 2 diabetes).¹³⁴ Individuals with type 1 diabetes are at risk for hypercholesterolemia; the prevalence approached 50% of young adults in one study ¹³⁵. The prevalence of elevated non-HDL cholesterol was 25% in a study of individuals less than 21 years of age with type 1 diabetes.¹³⁶

Adolescents with type 1 diabetes have higher levels of apolipoprotein B (apoB) compared to similar age non-diabetics.¹³⁷ Studies in adults and adolescents with type 1 diabetes suggest a possible complementary role for measurement of apoB in addition to screening LDL-c. However, data are insufficient at this time to warrant the addition of apoB screening to current lipid screening guidelines for youth with diabetes.

In a cohort of adolescents with type 1 diabetes, those achieving 4 to 6 of the goals of Screening Guidelines had better surrogate markers of macrovascular disease than those achieving less, and have comparable results to non-diabetic controls.¹³⁸

2.8.1 |. Management of dyslipidemia

In adults with diabetes, statins are effective in the primary and secondary prevention of major cardiovascular events including vascular mortality, stroke and limb and coronary revascularization.^139,140 The Heart Protection Study was a 5 year interventional study of 5963 patients with diabetes, 10% of whom had type 1 diabetes. This benefit was independent of glycemic control and cholesterol levels.¹⁴⁰

Short-term trials have shown that simvastatin, lovastatin, and pravastatin are effective and safe in children and adolescents, mainly in the context of familial hypercholesterolemia.^141–143 No significant side effects were observed in terms of growth, pubertal Tanner grading, testicular volume, menarche, endocrine function parameters, or liver or muscle enzymes.^143,144 The AdDIT trial confirmed the safety of statin (atorvastatin) in adolescents with type 1 diabetes treated for a 2 to 4 year period.⁶⁶

High LDL cholesterol is defined as >2.6 mmol/L (100 mg/dL).¹⁴⁵ If this is present then interventions to improve metabolic control, dietary changes and increased exercise should be instituted. If the above interventions do not lower LDL cholesterol to <3.4 mmol/L/130 mg/dL, statins should be considered in children aged >10 years, with an ideal target <2.6 mmol/L (100 mg/dL).

Lipids screening with a fasting lipid profile is not required. Data from the NHANES III study suggest that non-fasting lipids screening has good prognostic value¹⁴⁶ but data in pediatric patients with diabetes are lacking. If triglycerides or LDL levels are elevated, a fasting lipid profile is then indicated.¹⁴⁷ Fasting lipids are also indicated for patients under treatment for dyslipidemia.

2.8.2 |. Functional changes in cardiac and peripheral vascular function

Diabetes is also associated with changes in cardiac and peripheral vascular function. In adults diabetes is associated with increased cardiovascular risk and altered cardiovascular function independent of hypertension or other coronary artery disease.¹⁴⁸ Diastolic dysfunction is characterized by reduced early diastolic relaxation, changes ventricular filling patterns,^149,150 increases in left ventricular filling pressure during exercise,¹⁵¹ and decreases resting and exercising end-diastolic volume (EDV).¹⁵² At a more advanced stage, these changes are collectively defined as diabetic cardiomyopathy, which may be a precursor to diastolic heart failure.¹⁵³ Abnormalities in diastolic filling will affect stroke volume and thus cardiac output.

Previous studies in diabetic adults have shown that aerobic capacity and left ventricular stroke volume during exercise are associated with diastolic dysfunction in adults.^152,154 Adults with asymptomatic type 1 diabetes have reduced exercise capacity and lower stroke volume at peak exercise compared with non-diabetic peers, limitations that are strongly associated with diastolic dysfunction ^154,155 and reduced EDV during exercise.^152,154 Current evidence suggests that healthy adolescents with diabetes may also have lower aerobic capacity^156,157 and lower exercise stroke volume.¹⁵⁶ In a recent study, 52 adolescents with type 1 diabetic (mean duration of diabetes was 6 years) were assessed at rest and during submaximal exercise (at a fixed heart rate) by cardiac magnetic resonance imaging (MRI).¹⁵⁸ These data confirmed that not only was there reduced diastolic filling at rest but this was exacerbated with exercise reducing stroke volume further. Moreover, peak heart rate (the only other mechanism to increase cardiac output) was lower in adolescents with diabetes suggesting they will have impaired cardiac output which may limit their aerobic capacity. Diastolic filling was associated with HbA1c but not diabetes duration suggesting this could be reversed with improved control. Indeed, there are data from adult elite athletes with diabetes; those with better control have better cardiovascular performance compared to those with poorer control.

Similar to adults, peripheral vascular function is also impaired in children and adolescents with type 1 diabetes. Endothelial dysfunction is an early event in the development of atherosclerosis and it occurs early in type 1 diabetes.^159,160 It appears to be intimately involved in the pathogenesis of microvascular and macrovascular complications of diabetes.^160,161 Studies looking at flow mediated vasodilatation and glyceryl trinitrate have elegantly demonstrated impaired vasodilatation in children and adolescents.^162–165 Associations with both hyperglycemia and hypoglycemia and reduced endothelial function have been made as well as an improvement of endothelial function with folate.^163,166,167 However, folate supplementation was only successful when folate was deficient, with no effect of folate on vascular function in folate replete children.¹⁶⁸ Increased physical activity may also be beneficial although this data remains conflicting. Impaired vasodilation of muscle capillary beds also results in increased systolic and diastolic BP during exercise. This has been demonstrated in maximal and submaximal exercise paradigms.¹⁵⁸

Prevention of the later vascular complications of diabetes would be assisted by the identification of early abnormalities such as those observed in the heart and peripheral vasculature. While better glycemic control has been associated with better cardiac and peripheral vascular function other strategies improving of these early changes will potentially reduce the risk of later microvascular and macrovascular complications.

2.9 |. Type 2 and complications

Type 2 diabetes in youth is associated with greater risk for microalbuminuria and hypertension than type 1 diabetes.^47,107,108 Neuropathy may also be increased.^107,169 Mortality data of those diagnosed at age 15 to 30 years suggest that mortality is higher in type 2 diabetes than type 1 diabetes, for the same level of glycemic control.¹⁶⁹ Hence, complications screening and attention to risk factors should be more aggressive for youth with type 2 diabetes. In comparison to older people diagnosed with type 2 diabetes youth with this condition have greater risk of proliferative retinopathy for the same degree of glycemic control.¹⁷⁰

3 |. CONCLUSIONS

Complications become less common when diabetes management is optimized. Other modifying factors are BP, weight, smoking and lipids, which are more significant/important in type 2 diabetes and insulin resistance. Screening for complications is important during adolescence and also to prepare for lifelong screening.