Loader

Please wait...

Canadian Pharmacists Association
Canadian Pharmacists Association
Share
Facebook Share
Twitter Share
LinkedIn Share
Google Plus Share
Email Share

Chapter 24: Dyslipidemia

Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

Dyslipidemia in Diabetes
  • People with diabetes have a 2- to 4-fold higher risk of vascular disease, compared to individuals without diabetes.
  • Cardiovascular disease (CVD) is the primary cause of death among people with type 1 and 2 diabetes.
  • The most common lipid pattern in people with type 2 diabetes consists of hypertriglyceridemia (hyper-TG), low high-density lipoprotein cholesterol (HDL-C), and relatively normal plasma concentrations of low-density lipoprotein cholesterol (LDL-C)
  • Glycation and oxidation are believed to increase the atherogenicity of LDL-C, even in those with type 1 diabetes with a normal lipid profile.

TABLE 1

Risk Assessment of Individuals with Diabetes
Screening
  • The burden of dyslipidemia is high in people with diabetes. A national cross-sectional chart audit study of 2473 Canadians with type 2 diabetes revealed that 55% of individuals with a diabetes diagnosis of ≤2 years’ duration also had dyslipidemia. This proportion rose to 66% in those with diabetes for ≥15 years.
  • A fasting (8-hour fast) lipid profile (TC, HDL-C, TG, and calculated LDL-C) or nonfasting lipid profile (apo B, non-HDL-C calculation) should be measured at the time of diagnosis of diabetes. If lipid-lowering treatment is not initiated, repeat testing is recommended yearly. More frequent testing (every 3–6 months) should be performed after treatment for dyslipidemia is initiated [Grade D, Consensus].
Lifestyle Modification
  • Lifestyle interventions remain a key component of CVD prevention strategies and of diabetes management in general.
  • Fundamental considerations to improve glycemic control, overall lipid profile and reduction of CVD risk include (but are not limited to):
    • Achievement of ideal weight and aerobic activity level
    • Adoption of an energy-restricted, compositionally well-balanced diet that is low in cholesterol
    • Saturated and trans fatty acids and refined carbohydrates
    • Inclusion of viscous fibres, plant sterols, nuts and soy proteins
    • Use of alcohol in moderation
    • Smoking cessation
LDL-C
  • For patients with indications for lipid-lowering therapy, treatment should be initiated with a statin [Grade A, Level 1], to achieve LDL-C ≤2.0 mmol/L [Grade C, Level 3].
    • Studies and meta-analyses have shown that LDL-C lowering with statins and the beneficial effects of lowering LDL-C apply equally well to people with and without diabetes in terms of primary and secondary prevention of vascular disease.
    • In the small group of lower-risk individuals with type 2 diabetes, the absolute benefit from statin therapy is predicted to be smaller than those at higher global risk for CVD.
      • The global CVD risk of these individuals will increase with age. Therefore, repeated monitoring of the CVD risk status of patients with diabetes is recommended.
  • The Heart Protection Study (HPS), compared simvastatin 40 mg daily to placebo, results showed a 27% reduction in cardiovascular events and 25% reduction in stroke, relative to placebo
    • These results emphasized the benefits of statin treatment irrespective of the pre-existing serum LDL-C level.
  • The Collaborative Atorvastatin Diabetes Study (CARDS) assessed the effectiveness of atorvastatin 10 mg daily in reducing the risk of a first CV event in people with type 2 diabetes without known vascular disease.
    • Treatment resulted in a mean LDL-C of 2.0 mmol/L, and was associated with a reduced risk for both CV events and stroke
  • The Treating to New Targets (TNT) trial conducted in individuals with stable coronary artery disease (CAD), saw that those subjects with diabetes treated with intensive therapy (atorvastatin 80 mg daily) reduced the rate of all CVD and cerebrovascular events compared to atorvastatin 10 mg daily.
  • The Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis found that for every 1.0 mmol/L reduction in LDL-C there was an approximate 20% reduction in CVD events, regardless of baseline LDL-C.
  • Study of Heart and Renal Protection (SHARP) trial showed that patients with diabetes and renal dysfunction or those requiring dialysis who have had LDL-C reductions with simvastatin plus ezetimibe were associated with reductions in the incidence of major atherosclerotic events vs. placebo.
  • To reduce the CVD morbidity and mortality associated with prediabetes and metabolic syndrome, an aggressive approach aimed at associated CVD risk factors, including dyslipidemia, is warranted. Lifestyle interventions aimed at reducing the risk of developing both type 2 diabetes and coronary artery disease (CAD) are essential.
  • For more information on the aforementioned trials, refer to Canadian Diabetes Association Clinical Practice Guidelines: Chapter 24.

TABLE 2A

Additional lipid markers of CVD risk
  • The TC/HDL-C ratio is a sensitive and specific index of CVD risk and is considered to be an important determinant of the need for lipid-lowering therapy.
    • An elevated TC/HDL-C ratio is usually associated with a low HDL-C and/or elevated TG, both of which are commonly seen in individuals with diabetes
    • The elevated TC/HDL-C ratio is considered to represent a source of lipid-derived, residual risk in treated patients. This form of dyslipidemia is considered more responsive to lifestyle modification (e.g. an increase in physical activity and weight reduction) and improvements in glycemic control than is an isolated LDL-C elevation. Accordingly, initial treatment should consist of intensifying lifestyle modification strategies and improving glycemic control through the use of glucose-lowering therapies as needed.
  • In patients achieving goal LDL-C with statin therapy, the routine addition of fibrates or niacin for the sole purpose of further reducing CV risk should not be used [Grade A, Level 1].
    • The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial highlight the importance of maintaining LDL-C lowering as the primary focus of treatment
      • Neither fenofibrate (used in ACCORD) nor niacin (used in AIM-HIGH) showed any added clinical benefit compared to statin therapy alone.
  • For individuals on statin therapy but not at LDL-C target, a combination of statin therapy with second-line agents may be used to achieve the LDL-C goal [Grade D, Consensus].
  • Statins should not be used in combination with gemfibrozil due to an increased risk of myopathy and rhabdomyolysis.
  • A TG level <1.5 mmol/L is considered optimal since below this level there are fewer associated metabolic abnormalities, such as low HDL-C, small dense LDL particles and postprandial lipemia.
  • For those who have serum TG >10.0 mmol/L, a fibrate should be used to reduce the risk of pancreatitis [Grade D, Consensus] while also optimizing glycemic control and implementing lifestyle interventions (e.g. weight loss, optimal dietary strategies, reduction of alcohol).
  • When there is no overriding concern for acute pancreatitis and when there is evidence of hyper-TG in association with an elevated apo B or high non-HDL-C, it would be reasonable to consider a statin as first-line therapy with the subsequent addition of a fibrate or niacin as needed.
  • Evidence has emerged to support the use of apo B in the management of patients with dyslipidemia.
    • Apo B has repeatedly been shown to be a better risk marker for CVD events than LDL-C.
    • The measurement of apo B is most clinically useful in the individual with hyper-TG since it provides an indication of the total number of atherogenic lipoprotein particles in the circulation.
    • Because hyper-TG is commonly seen in people with diabetes, knowledge of the apo B level may guide the aggressiveness with which lipid-lowering therapy is pursued (i.e. more aggressive therapy in individuals with an elevated apo B level).
    • Based on available evidence, an optimal level of apo B can be considered to be at least ∼<0.9 g/L or, as supported by the CARDS study in subjects with diabetes, ≤0.8 g/L.
  • A linear relationship between apo B and non-HDL exists over a broad range.
    • A non-HDL-C level of 2.6 mmol/L is approximately equal to an apo B of 0.8 g/L and may be considered alternate goals of therapy.

TABLE 2B

Statin Therapy and Incident Diabetes
  • Although statins are the cornerstone of lipid-altering therapy for CVD risk reduction in people with or without diabetes, recent evidence has suggested that chronic statin use is associated with an increased risk of incident diabetes.
  • Although this finding is of little relevance to patients with established diabetes, it may be of relevance to patients who are at risk for developing diabetes irrespective of statin treatment, such as those who are obese and/or who manifest metabolic syndrome.
  • However, even these patients with risk factors for the development of diabetes enjoy a marked benefit in CVD risk reduction through the LDL-C–lowering effects of statins, which appears to far outweigh any small risk of new-onset diabetes.
  • Accordingly, these recent analyses do not affect the recommendation that statins are the preferred agents for lowering LDL-C in most instances, including in patients with established diabetes or in those with risk factors for developing the disease
Table 1: Dyslipidemia components associated with type 2 diabetes and metabolic syndrome
  • Increased TG and TG-rich lipoproteins
  • Increased postprandial TG
  • Low HDL-C
  • Low apo AI
  • Small HDL, prebeta-1 HDL, alpha-3 HDL
  • Increased apo B
  • Increased LDL particle number
  • Small, dense LDL
  • Increased apo C-III
  • Increased non-HDL-C
  • Increased oxidized and glycated lipid
Apo, apolipoprotein; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; TG, triglyceride
Return to text
Table 2A: First-line therapy to achieve a primary lipid target of LDL-C ≤ 2.0 mmol/L
Statins*
Generic name Trade Name Considerations
Atorvastatin
Lipitor and generics
Statins are drugs of choice to lower LDL-C and have modest TG-lowering and HDL-C raising effects at higher doses
Fluvastatin Lescol
Lovastatin Mevacor and generics
Pravastatin Pravachol and generics
Rosuvastatin Crestor and generics
Simvastatin Zocor and generics

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.

Note: Refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Ottawa, ON: Canadian Pharmacists Association) for product monographs and complete prescribing information.

∗ Prevention of statin-induced myopathy requires attention to factors that increase risk, such as age >80 years (especially women); small body frame and frailty; higher dose of statin; multisystem diseases (e.g. chronic renal insufficiency due to diabetes); multiple medications; hypothyroidism; perioperative periods; alcohol abuse; excessive grapefruit juice consumption; and specific concomitant medications, such as fibrates (especially gemfibrozil) (refer to specific statin package inserts for others)

† Listed in alphabetical order.

Return to text
Table 2B: Other lipid-modifying medications
Drug Class* Generic name * Principal Effect Other Considerations

Bile acid sequestrants

- Cholestyramine resin (Questran)

- Colesevelam (Lodalis)

- Colestipol HCl (Colestid)

- Lowers LDL-C

- GI intolerability, which worsens with increasing doses

- May elevate TG

- Colesevelam has A1C-lowering effect

Cholesterol absorption inhibitor

- Ezetimibe (Ezetrol) - Lowers LDL-C

- Less effective than statins as monotherapy

- Effective when used in combination with a statin to further lower LDL-C

Fibrates

- Bezafibrate (Bezalip SR and generic 200 mg)

- Fenofibrate (micronized/microcoated/nano crystals) (Lipidil Supra, Lipidil EZ, and generics)

- Gemfibrozil (Lopid)

- Lowers TG

- Variable effect on LDL-C

- Highly variable effect on - HDL-C (more effective at raising HDL-C when baseline TG is high)

- May increase creatinine and homocysteine levels; however, favourable effects on renal function have been noted with long-term fenofibrate treatment

- Do not use gemfibrozil in combination with a statin due to increased risk of myopathy and rhabdomyolysis

Nicotinic acid

- Extended-release niacin (Niaspan, Niaspan FCT)

- Immediate-release niacin (generic, nonprescription)

- Long-acting (e.g. “no-flush”) niacin (generic, nonprescription) not recommended

- Raises HDL-C

- Lowers TG

- Lowers LDL-C

- Can cause dose-related deterioration of glycemic control

- Extended-release niacin has similar efficacy and better tolerability than immediate-release niacin

- Long-acting niacin should not be used due to increased hepatotoxicity and decreased efficacy

A1C, glycated hemoglobin; GI, gastrointestinal; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.

Note: Refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Ottawa, ON: Canadian Pharmacists Association) for product monographs and complete prescribing information.

∗ Listed in alphabetical order.

† See Table 2A footnote for prevention of myopathy

Return to text

For definitions of the levels of evidence cited in this chapter, please refer to the Guideline Recommendations: Levels of Evidence.

If you would like more details on vascular protection in patients with diabetes, please refer to Clinical Practice Guidelines: Chapter 22.

If you would like more details on this topic, please visit the Canadian Diabetes Association Clinical Practice Guidelines: Chapter 24.