Dealing with Dyslipidaemia in Diabetes #(S1/04)

Background 

• Adults with diabetes are at increased risk for atherosclerotic cardiovascular disease (CVD) including heart attack and stroke 

• Mortality from CVD in people with diabetes is significantly increased compared to non-diabetic population

• While CVD events are rare in paediatrics, increased carotid intima-media thickness (cIMT) and endothelial dysfunction have been documented in youth with type 1 diabetes (T1D)

• Dyslipidaemia is a known major and MODIFIABLE risk factor for atherosclerotic CVD (ASCVD)- defined as coronary heart disease)

• Reduction of cholesterol levels reduces coronary disease risk in adults

• In patients with diabetes, control of dyslipidaemia early in life may result in significant decrease in morbidity and mortality due to CVD

DYSLIPIDAEMIA IS VERY COMMON IN YOUTH WITH DIABETES

Screening: ISPAD guidelines

Paediatric Type 1 Diabetes  

• Lipid profile soon after stabilization of glycaemic control for children > 11 years’ old
• As early as 2 years old with positive family history (hypercholesterolemia, CVD) or if family history is unknown
• Fasting screening is ideal but not a necessity for initial screening 
• With elevated non-fasting LDL or triglycerides, rescreening with fasting lipids would be next step
• With normal levels, recheck every 5 years

Paediatric Type 2 Diabetes  

• Risk of complications is increased

• Lipid profile after stabilisation of glycaemic control or 3 months after initial of medication

• Fasting screening is ideal but not a necessity for initial screening 

• With elevated non-fasting LDL or triglycerides, rescreening with fasting lipids would be next step

• With normal levels, recheck annually

Screening: Goal Levels 

• LDL-c <100 mg/dl (<2.6 mmol/L)

• HDL-c >35mg/dl (>0.91 mmol/L) 

• Triglycerides <150 mg/dl (<1.7 mmol/L)

Other important CVD risk factors to consider

• Glycaemic control

• Family history of CVD, dyslipidaemia, hypertension

• Body Mass Index (BMI)- compared to normal of their ages and gender

• Blood pressure compared to normal values of height and gender

• Smoking status

NB. LIPID LEVELS CHANGE DURING AND AFTER PUBERTY. AS A PERSON GETS OLDER, THE LIPID LEVELS TEND TO INCREASE.

Comparison of Change in Lipids to Change in HbA1c (per 1%)

• Glycaemic control may be insufficient to reach lipid goals in some patients with Type 1 Diabetes (T1D)

NB. With every 1% improvement in HbA1c, LDL levels improves by less than 5 mg/dl

• Lipid lowering medications may be required prior to ‘optimizing’ glycaemic control 

Causes of Secondary Dyslipidaemia in Youth

 

Exogenous ·         Alcohol ·         Oral contraceptive ·         Prednisone ·         Anabolic Steroids ·         13-cis Retinoic acid	Storage disease ·         Cystine storage disease ·         Gaucher disease ·         Glycogen storage disease ·         Juvenile Tay-Sachs disease ·         Niemann-Pick disease ·         Tay-Sachs disease
Endocrine & Metabolic ·         Acute intermittent porphyria ·         Type 1 and Type 2 Diabetes ·         Hypopituitarism ·         Hypothyroidism ·         Lipodystrophy ·         Pregnancy	Acute & transient ·         Burns ·         Hepatitis
Renal ·         Chronic renal failure ·         Haemolytic-uremic syndrome ·         Nephrotic syndrome	Others ·         Anorexia nervosa ·         Cancer Survivor ·         Heart transplantation ·         Idiopathic hypercalcemia ·         Kawasaki disease ·         Klinefelter syndrome ·         Progeria (Hutchinson-Gilford syndrome) ·         Rheumatoid arthritis ·         Systematic lupus erythematosis ·          Werner syndrome
Hepatic ·         Benign recurrent intrahepatic cholestasis ·         Congenital biliary atresia ·         Alagille syndrome

 TREATMENT

Non-pharmacologic Interventions

• Diet
• Exercise
• Optimisation of glycaemic control
• Assess thyroid function (TSH, T4)

Dietary/lifestyle recommendations

If fasting lipids abnormal:

• Decrease fat in diet
Limit saturated fat to <7% of calories
Minimize intake of trans fat
Limit total dietary fat to <25-35% of total energy intake
• Involve qualified paediatric dietitian
• Address overweight and obesity
• Increase physical activity as necessary

Pharmacologic therapy 

• Indicated for LDL-c >130 mg/dl (>3.4 mmol/L) in children over age 11 years
• Statins considered first line therapy 
• Baseline liver function (AST, ALT) before initiation 
• Goal for LDL-c lowering to <100 mg/dl (<2.6 mmol/L)
• NB. Before starting medications, counsel youth ‘at risk’ for pregnancy regarding teratogenicity of statins and stop drug immediately if pregnancy suspected. 

Treatment: LDL-cholesterol Lowering

Statins

• HMG-CoA reductase inhibitors
• Competitively inhibit HMG-CoA reductase to inhibit endogenous synthesis of cholesterol resulting in lower LDL-c levels
• Other effects: plague stabilisation, anti-inflammation, anti-thrombosis 
• Decreased CVD events and mortality in adults with diabetes 
• Oral medication taken once per day
• Not approved for patients <10 years old (no safety data)
• Teratogenic- counselling recommended for females, consider urine pregnancy testing prior to initiation
• Re-check lipids in 3 months 

Other labs:

• Creatine kinase (CK) if concern for muscle ache, weakness, inflammation or rhabdomyolysis 
• Liver function tests if symptoms of hepatotoxicity (jaundice, abdominal pain, dark-coloured urine)
• Safety of simvastatin, lovastatin, pravastatin established in short term trials in youth over 10 years old
• Safety of atorvastatin conformed in AdDIT trial in adolescents with T1D treated for 2-4 years

Other pharmacologic options beyond statins (not included in the ISPAD guidelines)

Ezetimibe 

• Inhibits cholesterol absorption in small intestine 
• Additive benefit for LDL lowering seen in adults
• Approved in US for patients with familial hypercholesterolemia 
• Available for adult use in combination with statin
• May consider when statin not tolerated
• Once per day, oral medication

Bile acid sequestrants (aka Resins) 

• Mechanism- resins binding bile acid in GI track, preventing reabsorption and recirculation of bile acids leading to lowering of circulating LDL-cholesterol
• side effects include nausea, abdominal pain
• Previously considered first line in paediatric patients
• Less well tolerated and less effective compared to statins

Niacin

• Generally, not recommended in paediatrics due to adverse effects
• Inhibits VLDL-c production by liver
• Lowers LDL-c, increases HDL-c
• Adverse effects: flushing, impaired glucose tolerance, myopathy, liver failure

Treatment of Hypertriglyceridemia

Target < 150 mg/dl (1.7 mmol/L)

TG 150-400 mg/dl (1.7-4.5 mmol/L):

• Recheck fasting if obtained non-fasting

• Diet changes- reducing simple carbohydrates; increase intake of omega-3 fatty acids

• Improve glycaemic control

Fasting TG > 400 mg/dl or non-fasting TG > 1000 mg/dl (11.3 mmol/L):

• Increased risk for acute pancreatitis 

In addition to above:

• Initiate use of fibrates to reduce risk for pancreatitis 
• Assess for symptoms, lab findings consistent with pancreatitis  

High risk for pancreatitis:

• May be an urgent for management and monitoring 

• Assess for pancreatitis and consider hospitalisation with acute intervention if indicated 

• Diet to include strict fat restrictions to <5-10% of total calories or < 20-40 grams fat/day

• Fibrates ineffective at TG levels > 1000 mg/dl; initiate when < 1000 mg/dl

• Plasmapheresis may be considered in severe cases 

• IV fluids

HDL-c 

• No medication recommendations for treatment of low HDL

• Factors that lead to increase in HDL include exercise 

• Some data to suggest HDL sub-fractions are not normal in T1D and high HDL may not always be beneficial 

• Further research is needed

Lifestyle intervention as was recommended by the American Diabetes Association 2020

1. Intensify lifestyle therapy and optimize glycaemic control for patients with elevated triglyceride levels (≥150 mg/dL [1.7 mmol/L]) and/or low HDL cholesterol (<40 mg/dL [1.0 mmol/L] for men, <50 mg/dL [1.3 mmol/L] for women).

2. Glycaemic control may also beneficially modify plasma lipid levels, particularly in patients with very high triglycerides and poor glycaemic control.

3. Reduction of saturated fat and trans fat; increase of dietary n-3 fatty acids, viscous fiber, and plant stanols/sterols intake; and increased physical activity should be recommended to improve the lipid profile and reduce the risk of developing atherosclerotic cardiovascular disease in patients with diabetes.

4. Obtain a lipid profile at initiation of statins or other lipid lowering therapy, 4–12 weeks after initiation or a change in dose, and annually thereafter as it may help to monitor the response to therapy and inform medication adherence.

5. For patients with diabetes aged 40–75 years without atherosclerotic cardiovascular disease, use moderate-intensity statin therapy in addition to lifestyle therapy.

6. For patients with diabetes aged 20–39 years with additional atherosclerotic cardiovascular disease risk factors, itmay be reasonable to initiate statin therapy in addition to lifestyle therapy.

7. In patients with diabetes at higher risk, especially those with multiple atherosclerotic cardiovascular disease risk factors or aged 50–70 years, it is reasonable to use high-intensity statin therapy.

8. In adults with diabetes and 10-year atherosclerotic cardiovascular disease risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL cholesterol levels by 50% or more.

Future Directions

Screening 

• Data emerging that may support screening apolipoprotein B, Lp(a)

Treatment

• New drugs approved for use in adults with little or no paediatric data

May offer intervention options in future

• Icosapent ethyl- found effective in adults with high risk for CVD (REDUCE-IT)

• PCSK9 inhibitors 

• Bempedoic acid – ATP-citrate lyase inhibitor – cleared for use in US and EU in 2020

Summary

• Dyslipidaemia is an important risk factor for CVD

• Screening for dyslipidaemia in patients with diabetes should begin in childhood

• Fasting lipid levels are idea but always practical; non-fasting lipids should be considered to avoid delays in screening

• Improvement in diet and exercise are important non pharmacologic components of treatment 

• Pharmacologic treatment should be considered be considered in patients over 11 years old with LDL > 130 mg/dl (3.4 mmol/L) to lower the future risk for CVD

• Pharmacologic treatment is indicated for hypertriglyceridemia to lower the risk for acute pancreatitis

• Further data needed to determine the value of screening apoB, Lp(a) and utility of treatment with newer therapies in paediatric patients with diabetes 

Curtsey of R. Paul Wadwa, MD