Case Study: Type 1 Diabetes, Familial Hypercholesterolemia, and Elevated Lipoprotein(a)

Introduction

Familial hypercholesterolemia (FH) and type 1 diabetes (T1D) are characterized by significant morbidity and premature mortality. Lipoprotein(a) [Lp(a)], an independent cardiovascular disease (CVD) risk factor, is considered a risk enhancer. Because FH, T1D and elevated levels of Lp(a) are all common, some individuals may have more than one of these conditions. In youth with T1D (Y-T1D) early identification of all risk factors is critical if we are to implement timely intervention with the goal of improving outcomes. This requires early screening, an understanding of lipid and lipoprotein metabolism in T1D and timely intervention. We present a case study to illustrate the importance of CVD risk factor screening and discuss the role of hypercholesterolemia, including Lp(a), in individuals with T1D.

Case Presentation

A 9-year-old, previously healthy and developmentally normal female presented with a 1-2-week history of polyuria, polydipsia, and weight loss of 10 pounds. She was found to have new onset T1D, with positive glutamic acid decarboxylase and insulinoma-associated protein 2 antibodies. After initial diagnosis and implementation of standard treatment of T1D, she underwent global CVD risk factor assessment. Her initial results are shown in Table 1.

Family History

There is no information available regarding the biologic father.  The maternal grandfather has a history of diabetes and hypercholesterolemia; the maternal grandmother has lupus erythematosus. The mother has a history of mild hypercholesterolemia, but was advised against use of lipid-lowering medication. It was suggested that she continue routine cholesterol testing every five years.

Genetic Testing

An FH phenotype was suspected and genetic testing was performed according to recent guidelines.(2) The patient’s testing revealed a pathogenic variant in LDLR (c.1027G>A (p.Gly343Ser)). Cascade screening was recommended of all 1st and 2nd degree biologic relatives. In addition to the mother, the child’s 18-year-old sister was found to have hypercholesterolemia.  Genetic testing results are shown in Table 2.

 

Discussion

Lipid profiles of Y-T1D in good glycemic control are similar to nondiabetic youth, whereas youth with suboptimal glycemic control have elevated TC, LDL-C, and non-HDL-C.(3) They also have significantly elevated apolipoprotein B (apoB) levels and small, dense LDL particles compared to nondiabetic youth, regardless of glycemic control.(4, 5, 6) As a consequence, atherogenic cholesterol plays a significant role in the pathogenesis of CVD in Y-T1D. As illustrated in our case study, Y-T1D may also have dyslipidemia as a result of acquired and genetic factors unrelated to diabetes. When available, lipid profiles obtained prior to the onset of diabetes and an accurate, informative family history may be helpful in determining the etiology of hypercholesterolemia in Y-T1D. 

Both FH and T1D are associated with very high risk of CVD-related events and premature mortality.  Recently, the role of elevated Lp(a), present in 20% of the population, has also been highlighted.(7) As a result, individuals with all three should be classified as having a very high lifetime risk. All three conditions are commonly found in the general population (approximate prevalence rates FH 1:220; T1D 1:500; elevated Lp(a) 1:5). Global risk factor assessment and early intervention are key to improving outcomes in individuals with one or more of these conditions. Systematic screening of secondary causes of dyslipidemia is also recommended.

The increased mortality associated with FH is well known. Less appreciated is the premature mortality associated with T1D. Youth, who develop diabetes at an early age, have the greatest excess risk for CVD. (8, 9) The risk of coronary heart disease (CHD) and acute myocardial infarction is increased 30-times in individuals diagnosed with T1D under 10 years-of-age. (10) Despite improved glycemic control, mortality rates are 3- to 18-times higher than expected, CVD (CHD, cerebrovascular accidents [CVA] and peripheral arterial disease) accounting for 2/3 of deaths. Life expectancy is reduced by up to 13 years. (11) Although Y-T1D generally do not experience CVD-related symptoms, most 
have evidence of early atherosclerosis which is greatly accelerated in diabetes. Modifiable CVD risk factors, present in up to 60% at diagnosis in all ages, increase with age.(12, 13, 14) Approximately 14– 45% of youth with T1D have ≥2 CVD risk factors.(12, 13, 15)

Y-T1D may have evidence of subclinical CVD within the first decade of diagnosis. (16, 17, 18) Since youth have a longer duration of disease, it is not surprising that the magnitude of lifetime risk from premature CVD in T1D remains at least 10-times higher than in the general population. The lack of signs and symptoms related to atherosclerosis in this population supports the importance of routine screening of risk factors for early detection.

 

Despite excellent glycemic control, diabetes is associated with an increased risk for CVD-related death.(19, 20) Since glycemic control and insulin resistance have not consistently shown direct associations with mortality in T1D, chronic complications resulting from poor glycemic control are likely contributing factors. There is considerable evidence, however, that controlling risk factors is helpful in preventing or slowing CVD in diabetes.(20) In addition to poor glycemic control and hypercholesterolemia, recent guidelines have highlighted evidence supporting Lp(a) role in atherosclerosis and thrombosis.(7) The combined proatherogenic and prothrombotic properties of Lp(a) have particular relevance to individuals with T1D.(6) Although the causative role Lp(a) plays in CVD is well-established, it is less well known and underutilized in assessing risk in clinical practice.  Other barriers to Lp(a) screening include additional cost of testing, lack of test standardization, the absence of a commercially available Lp(a) lowering drug and lack of outcome studies.(7) 

Screening and Management Guidelines

Recent guidelines addressing Lp(a) screening and treatment predominately focus on the adult population but several include pediatric recommendations, (21) with the most comprehensive pediatric guidance coming from the National Lipid Association (NLA) which recommends selective screening of Lp(a) in youth (<20 years of age).(7) Although not specifically targeting those with diabetes these guidelines highlight the role of Lp(a) as an independent risk factor for premature CVD and recommend screening of adults with varying screening criteria.

Comprehensive guidelines for lipid screening and management of Y-T1D 
are limited, hampered by the lack of intervention and outcome studies. (1, 8, 9, 12, 22) Despite the paucity of evidence in youth, the American Heart Association (8, 9, 12) and the American Diabetes Association (23) categorizes youth with T1D in the highest tier for CVD risk and recommends both lifestyle and pharmacologic treatment for those with elevated LDL-C levels. The ADA guidelines for lipid screening and management in adults and in youth are summarized in Table 3.

Lipid Lowering in Youth with T1D

While levels of LDL-C levels can be achieved by improving glycemic control and reducing BMI in those who are overweight and obese with adoption of a heart-healthy lifestyle, such goals are hard to achieve and sustain.(24, 25)  Furthermore, although improved glycemic control is associated with a more favorable lipid profile; improved glycemic control alone does not appear to normalize lipids in youth with T1D and dyslipidemia. (13) Therefore other strategies, including use of lipid-lowering medications, may be beneficial in lowering the burden of atherogenic lipids and lipoproteins.

In adults with diabetes, results from randomized clinical trials (RCT) have convincingly demonstrated that reduction of LDL-C with lipid-lowering medications reduces the risk of major CVD events.(26, 27, 28) Although similar outcome trials are not available for Y-T1D, it seems plausible that similar management strategies, implemented at an earlier age, have the potential for significantly reducing the burden of CVD in this population. Drug therapy for hypercholesterolemia should include recommendations for lifestyle interventions, such as weight management, optimal dietary strategies, 30-60 minutes a day of moderate-to-vigorous physical activity, smoking avoidance/cessation, and glycemic control.

Statins are recommended as 1st-line therapy for cholesterol lowering in adults and youth diabetes (Table 3). No differences have been noted in efficacy of LDL-C reduction and frequency of reported adverse effects in those with and without diabetes. While neither long-term safety nor CV outcome efficacy of statin therapy has been established for Y-T1D, youth with FH treated with pravastatin for up to 20 years have revealed no major safety concerns, while all showed improved outcome and the lack of CVD-related events.(29)

Limited lipid lowering interventional trials in Y-T1D are available. In a short-term trial, statin use improved the lipid profiles of 10-16 year-old youth with T1D, whose urine albumin-to-creatinine ratio values were in the upper tertile. While no adverse side effects were noted, treatment resulted in no significant effects on carotid intima – media thickness, other cardiovascular markers, the glomerular filtration rate, or progression of retinopathy.(30)

Short-term studies of metformin’s ability to reduce body weight, LDL-C and progression of intima media thickness suggests that it may have a role in helping prevent CVD in Y-T1D, independent of its ability to improve glycemic control and insulin resistance.(31, 32)

Despite overwhelming evidence of benefit, the use of statins, particularly in youth, should be undertaken with caution and continued vigilance. Fortunately, few side effects have been reported in youth, with or without diabetes, treated with statins. However, studies of statin use in Y-T1D remain limited and of short duration.

While statins remain the 1st-line therapy in diabetes, add-on treatments may be beneficial in helping achieve better outcomes. Such add-on therapies include ezetimibe (33) and emerging therapies such as PCSK9 inhibitors. The role of fibrates as an add-on to statins for CVD risk reduction is not established, although they may be helpful in preventing hypertriglyceridemia (HTG)-related acute pancreatitis in those with high TG.(34) A decision to use additional lipid-lowering medications, such as PCSK9 inhibitors to further lower atherogenic lipoproteins in Y-T1D requires clinical judgment. Although not currently FDA approved for use in this population, the ODYSSEY KIDS clinical trial is currently testing the safety and efficacy of PCSK9 inhibition in children with heterozygous familial hypercholesterolemia. Those who may benefit from such therapy include youth with FH, those with persistent LDL-C levels > goal despite good compliance and maximally tolerated statin therapy and those with high CVD risk who are unable to tolerate statins.(35)

Conclusion

The present case illustrated the benefit of screening all youth, including those with diabetes and of cascade screening when significant hypercholesterolemia or elevated Lp(a) are found. Current recommendations for lipid and lipoprotein screening and management of Y-T1D need to be re-examined with the goal of providing clear, concise recommendations that can be easily implemented in clinical practice. Early screening and appropriate intervention are likely to reduce modifiable risk factors during early childhood and have the potential of reducing future CVD events. While additional clinical trials are needed to determine the safety and efficacy of aggressive screening and treatment of risk factors in Y-T1D, evidence of early onset, accelerated atherosclerosis resulting in early CVD and increased mortality in this vulnerable population suggests such measures are warranted.

Disclosure statement: Mr. Hamilton has no financial disclosures to report. Dr. Wilson has received honoraria from Alexion. Dr. McNeal has received honoraria from Amarin. 

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