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


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