As indicated by the Canadian Heart Health Survey, over one third of Canadian adults have an atherogenic lipid profile and not surprisingly, in those with diabetes this statistic almost doubles(1). Atherogenic lipids, defined as elevated small dense low density lipoproteins (LDL) and decreased high density lipoproteins (HDL) are considered major risk factors for cardiovascular disease and the main focus of the recently released guidelines, Dyslipidemia in Adults with Diabetes(2) and Recommendations for the Diagnosis and Treatment of Dyslipidemia and Prevention of Cardiovascular Disease(3). These guidelines, released by the Canadian Diabetes Association (CDA) and the Canadian Cardiovascular Society (CCS) were revised to reflect recent clinical trial evidence in this area.
Cardiovascular disease (CVD) remains the primary cause of death in people with diabetes and as such warrants aggressive and proactive management. The first step to any treatment protocol involves appropriate screening and risk stratification, both of which are addressed in the new guidelines. To appropriately screen for dyslipidemia in adults, a fasting (>8 hours) lipid profile is recommended at diagnosis and again every one to three years. One change in terms of risk stratification in the new guidelines is the admission that not all individuals with diabetes need to be considered high risk for vascular events. Those who are newly diagnosed, younger, without complications from diabetes and without any other risk factors for CVD can be considered at low short term risk(2).
With the exception of those few individuals who can be considered at low risk, risk stratification is generally quite simple in most adults with either Type 1 or Type 2 diabetes. Most individuals with diabetes regardless of the type, should be considered at high risk for cardiovascular disease. While this is not a new consideration in the guidelines, new evidence has helped to solidify the statement. In the Insulin Resistance Atherosclerosis Study, ultrasounds demonstrated that people with diabetes without coronary artery disease already had extensive carotid atherosclerosis(4). Unfortunately however, grouping all individuals with Type 1 or Type 2 diabetes into a high risk category doesn’t identify additional factors that may impact their individual risk. Certainly factors related to their diabetes are also likely to play a role. Therefore, to better assess patients with diabetes, the risk engine recommended is The United Kingdom Prospective Diabetes Study (UKPDS) risk calculator, which uses traditional risk factors for CVD but includes both the duration of diabetes and the degree of glycemic control. This risk calculator can be found online at http://www.dtu.ox.ac.uk/riskengine/.
Traditionally, the Framingham Risk Score (FRS) has been used to assess and quantify an individual’s risk of a cardiac event in the short term (10 years). This risk engine includes information on cholesterol values, blood pressure, age, sex and smoking status. Individuals with a 10 year risk of 20% or greater are considered to be at high risk. The new recommendations from the CCS extend a 20% score to those who already have either coronary or vascular diseases (CAD, peripheral artery disease or cerebrovascular disease), most with Type 1 or Type 2 diabetes and a new addition of those with chronic kidney disease (defined as glomerular filtration rate of less than 30 mL/min/1.73 m2)(3).
One immediate concern is for those individuals with both diabetes and chronic kidney disease. While the treatment targets may not change as there is no further stratification beyond high risk, it has been noted that in individuals with both diabetes and chronic kidney disease, there is a substantial increase (approximately 25% in one study) in the rate of mortality between those with overt proteinuria compared to those without(5).
One additional risk calculator is addressed and uses data from the Canadian Heart Health Survey to identify short term risk in individuals both with and without diabetes. This calculator, unlike the others, has been validated for accuracy against lipid trials and appears to better represent actual risk compared to both the UKPDS and FRS which are known to underestimate risk. The calculator, known as the Cardiovascular Life Expectancy Model can be found at http://www.chiprehab.com/CVD.
As a final note on risk stratification, risk calculators measure only short term (10 year) risk of an event and therefore an individual may have a low short term risk but due to the nature of diabetes, be at high long term or lifetime risk. Practically speaking however, risk calculators can be useful in demonstrating to an individual with diabetes the impact of tight control of the “ABC’s”; A1C, Blood Pressure and Cholesterol.
The acceptance of triglycerides as a marker for cardiovascular disease has been debated many times over the years, with the latest consensus that mild hypertriglyceridemia (<4.5 mmol/L) is a marker for the presence of small dense LDL particles, particularly prone to oxidation and therefore indirectly linked with CVD. Upon oxidation, LDL particles are readily taken up in arterial walls increasing the likeliness of plaque formation. Marked hypertriglyceridemia (>10 mmol/L) however, tends to increase risk for pancreatitis and holds little additional risk for cardiovascular disease(2). Despite the indirect link between mildly elevated triglycerides and cardiac risk, there are no specific targets for control in the new guidelines. A lack of clinical trial data to support a specific target level, led the expert committee to encourage an optimal value of less than 1.5 mmol/L.
Pharmacological management of hyper-triglyceridemia is determined by the degree of the elevation. In those with marked hypertriglyceridemia, a fibrate is recommended, whereas in those with moderate hypertriglyceridemia either a statin or a fibrate may be used. The choice of a statin in this group is based on evidence in which several studies demonstrated a greater reduction in cardiovascular risk with statins compared to fibrates in people with diabetes(2). The statins, (3-hydroxy-3-methylglutaryl CoA reductase inhibitors) are one of the most prescribed medications in Canada6, because of both their efficacy in lipid lowering and the large body of clinical trial evidence demonstrating reduced cardiovascular mortality(7,8). New generation statins (such as rosuvastatin) can lower LDL levels by over 50%2 and have demonstrated anti-inflammatory and anti-thrombotic properties(9).
Although mild elevations in triglycerides may signal the presence of small dense LDL particles, another method to indicate the density of LDL exists. Due to the fact that there is one apolipoprotein B (apo B) per molecule of LDL, a laboratory measurement of apo B levels can be made to determine whether LDL elevations are due to an increase in the number of total particles or simply the size of the particle. Apo B has been shown to be a better marker for CVD than LDL cholesterol and therefore its measurement provides additional knowledge that may be useful in guiding the aggressiveness of treatment. Risk appears to be highest in individuals with apo B levels higher than 1.2 g/L (75th percentile of Canadian population)(10).
Unfortunately, while it may be known that apo B is a reliable marker for CVD when measured accurately, our current healthcare system does not allow for a widely available laboratory measurements. No recommendations were made in regards to apo B in the Dyslipidemia in Adults with Diabetes guidelines as there is no clinical trial evidence to support a specific target level. Despite this, the guidelines again support an optimal level of less than 0.9 g/L for individuals at high risk of CVD(2). In the CCS guidelines however, apo B draws much more attention. Risk stratification is much more complex in adults without diabetes and therefore new non traditional risk factors such as apo B, hs-CRP and lipoprotein (a) can assist a clinician in identifying an individual as either low, moderate or high risk.
Both guidelines focus on two traditional risk factors for CVD; LDL cholesterol and the TC/HDL ratio. In these latest guidelines, the target for LDL cholesterol has been lowered to be in line with evidence from recent clinical trials. First and foremost, the Treat to New Targets (TNT) trial, assessed the use of atorvastatin at either a 10 mg or 80 mg dose. At the end of the six years of the trial, the relative risk reduction was 22% for all cardiovascular events with an LDL treated to a target of 2.0 vs.2.5 mmol/L(11). To assess the safety of such a low target, a study called PROVE-IT demonstrated that there were no increase in adverse events and a lower rate of clinical events with LDL levels less than 2.0 mmol/L(12). Average reductions in LDL by approximately 40% can lower CAD events by approximately 60% over 5-10 years(13), making this an appropriate and clinically significant goal in line with current clinical trials and safety data.
Another addition to this set of guidelines is the emphasis on abdominal obesity. Because type 2 diabetes and CVD are closely linked with visceral fat, waist circumference (WC) has been shown to be a better indicator for identifying risk than using body mass index (BMI) alone. In a study of over 27, 000 subjects in INTERHEART, central adiposity indices (waist to hip ratio and WC) were better correlated with CVD events than BMI(14). BMI and WC should therefore be used in conjunction to provide a comprehensive assessment of body fat and its distribution.
An elevated WC according to most guidelines is >102 cm and >88 cm in males and females respectively. In the Dyslipidemia in Adults in Diabetes guidelines, weight reduction of 5-10% initial body weight is recommended. In the CCS guidelines, however, more detail is provided. An initial weight goal to achieve a BMI of 27 is encouraged, with an optimal goal of a BMI of 25 or less. In addition, a WC of less than 94cm for men and 80cm for women is recommended. It has been suggested that the North American WC cutoffs should be lowered to better correlate with a BMI of 25, and to better reflect changes based on age and ethnicity. The International Diabetes Federation (IDF) has specified region specific cutoffs that may aid in an accurate assessment in the meantime and are reflected in the targets outlined by the CCS.
Both guidelines provide some recommendations on the importance of lifestyle modifications for lipid management. The Dyslipidemia in Adults with Diabetes guidelines recommend the use of a low fat (less than 30%) diet with less than 10% from saturated and trans fat3. In a meta-analysis of the effect of decreasing total fat intake to less than 30% and maintaining saturated fatty acids (SFA) to less than 10% of total calories, LDL cholesterol was reduced by as much as 12%. Upon reducing the saturated fat to less than 7% of calories, as recommended by the American Heart Association and the National Cholesterol Education Program (NCEP), a further reduction (4%) was seen(15). No specific levels are recommended in the CCS guidelines, although a general statement encouraging a decrease in saturated and trans fat with a combined increase in mono and poly-unsaturated fats and fruits and vegetables is included.
Even with the significant advancements in pharmacological treatment for dyslipidemia, lifestyle therapy for cardiovascular risk reduction should not be forgotten. Numerous functional foods such as soluble fibre, almonds, phytosterols and omega 3 fatty acids may have a role to play in vascular risk reduction. The combination of these functional foods into a therapeutic diet was evaluated by Jenkins and colleagues at St. Michael’s Hospital. The PORTFOLIO study combined treatment with a low fat, vegetarian diet rich in soy protein, plant sterols, soluble fibre and almonds. This combination diet resulted in a significant 30% reduction in LDL cholesterol(16). Significant reductions in triglycerides can also be achieved through a number of lifestyle modifications. First and often most important in people with diabetes, is the tightening of glycemic control and weight loss. Dysglycemia and dyslipidemia are metabolically intertwined. An increase in the uptake of low glycemic carbohydrates, a reduction in alcohol intake and exercise may also help.
Aggressive treatment of dyslipidemia and other cardiac risk factors (such as A1C and blood pressure) are effective for those with and without diabetes. Majority of individuals with diabetes should be considered at high risk for vascular events and a combination of diet, exercise and medications may help to achieve new lower target levels of the ABC’s and drastically reduce the number of negative cardiac outcomes.
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