Complications (p.57-82)

2003 CLINICAL PRACTICE GUIDELINES
Macrovascular Complications, Dyslipidemiaand HypertensionCanadian Diabetes AssociationClinical Practice Guidelines Expert Committee INTRODUCTION
Risk assessment of patients with diabetes
Approximately 80% of people with diabetes mellitus will die Patients with diabetes should be assessed to determine their as a result of a vascular event (1).Thus, in attempting to reduce risk of a vascular event. Although many are at high risk for a this excessive risk, all coronary risk factors in the person with vascular event (3) and should be treated as such, clinical diabetes must be addressed and treated aggressively (2).
assessment can identify those with diabetes whose risk levelmight be considered moderate. For example, younger VASCULAR PROTECTION
patients with a shorter duration of diabetes and without When deciding on appropriate treatment strategies, it is other risk factors for vascular disease and without other important to prioritize the treatment goals. Since some of complications of diabetes might be judged by the physician as the available treatments, such as angiotensin converting not falling in the high-risk category. Even in this group, how- enzyme (ACE) inhibitors and angiotensin II receptor antago- ever, it is important to consider that the average patient with nists (ARBs), have potential uses in controlling blood pres- newly diagnosed type 2 diabetes may have had the disease for sure (BP), as well as reducing the risks for cardiovascular disease (CVD) and nephropathy, it can be challenging to inte- There are several computer programs that predict vascular grate the data to make recommendations for one application risk in people with diabetes.The United Kingdom Prospective over another. Table 1 summarizes the priorities for vascular Diabetes Study (UKPDS) risk engine, based on this study’s and renal protection and recommended interventions.
cohort, provides such a calculation using not only traditionalrisk factors, but also the duration of diabetes and glycemic RECOMMENDATION
control (4,5).The Cardiovascular Life Expectancy Model alsoestimates the short-term CV risk of individual patients and 1.The first priority in the prevention of diabetes compares this risk to the Canadian population using data from complications should be reduction of cardiovascular (CV)risk by vascular protection through a comprehensive the Canadian Heart Health Survey. It can be used to estimate multifaceted approach (in alphabetical order): ACE the change in life expectancy associated with modifying spe- inhibitor and antiplatelet therapy (e.g. acetylsalicylic acid cific risk factors. Most importantly, this model, based on the [ASA]) as recommended, optimize BP and glycemic Lipid Research Clinics Follow-up Cohort, has been validated control, lifestyle modifications, optimize lipid control against lipid trials in patients with and without diabetes (6,7).
and smoking cessation [Grade D, Consensus].
A risk calculator (available in both French and English) basedon the Framingham Heart Study and the Cardiovascular LifeExpectancy Model is available online (8).
DYSLIPIDEMIA
Diabetes is associated with high risk for vascular disease, and
Dyslipidemia in type 2 diabetes
aggressive lipid management is generally necessary.The man- The most common dyslipidemia in type 2 diabetes consists of agement of dyslipidemia in patients with type 2 diabetes hypertriglyceridemia, low HDL-C and normal low-density requires attention to the full lipid profile, since hypertriglyc- lipoprotein cholesterol (LDL-C). Notwithstanding the nor- eridemia and low high-density lipoprotein cholesterol mal LDL-C, increased numbers of small, dense LDL parti- cles and elevated apolipoprotein (apo) B concentrations areoften present. The hypertriglyceridemia is due, in part, tothe presence of excess remnants of triglyceride (TG) -rich The initial draft of this chapter was prepared by Lawrence A. lipoproteins, while the low HDL-C points to a low number Leiter MD FRCPC FACP; Jeffrey Mahon MD MSc FRCPC; of HDL particles. Measurement of small, dense LDL particles Teik Chye Ooi MBBS FRCPC FRACP FACE; Steven Grover and remnants of TG-rich lipoproteins is still not widely avail- MD MPA FRCPC; Maria Kraw MD FRCPC; Gary Lewis MD able, but increased numbers of small, dense LDL particles will FRCPC; Ronald J. Sigal MD MPH FRCPC; George Steiner be reflected in an elevated plasma apo B. Other indices reflect these parameters, including the total cholesterol (TC) to HDL-C ratio (TC:HDL-C), which the Canadian Diabetes Studies have shown that the degree of LDL-C lowering Association 2003 Clinical Practice Guidelines for the Prevention with statins and the beneficial effects of lowering LDL-C apply COMPLICA
and Management of Diabetes in Canada recommend as an index equally well to people with and without diabetes (12-15).
of choice.Target levels for LDL-C and TC:HDL-C, and optimalTG and apo B (9) levels are provided in Table 2 and vary accord- Lifestyle interventions
ing to the person’s risk of a vascular event.
Individuals with type 2 diabetes are often overweight and There are very little clinical trial data to support recom- sedentary. Accordingly, lifestyle modification should be a mendations on TG target levels. Small, dense LDL particles major component of the management of dyslipidemia in increase above a breakpoint plasma TG level of approximate- these patients. In individuals with a body mass index (BMI) ly 1.5 mmol/L (10,11). Nonetheless, it is uncommon for a ≥25 kg/m2, weight reduction should be strongly recom- patient to have a significant elevation in serum TGs with mended. Even a modest weight loss of 5 to 10% of initial body LDL-C and TC:HDL-C at target levels. Thus, in order to weight can be associated with an improvement in the lipid pro- simplify the lipid targets, a specific target TG level is not pro- file of individuals with dyslipidemia and diabetes. An energy- vided, but a level of <1.5 mmol/L is considered optimal.
restricted, well-balanced diet is essential. Regular aerobic Recognizing the atherogenicity of small, dense LDL particles exercise helps individuals lose weight and maintain this weight and remnant lipoproteins and the important anti-atherogenic reduction over time (16), and may be associated with TG role of HDL particles, it is important to improve these meta- reductions and elevations in HDL-C. Regular exercise can also improve glycemic control in people with type 2 diabetes (17), Table 1. Priorities for vascular and renal protection
Clinical issue
Target population
Interventions
(in alphabetical order)ACE inhibitor, as indicatedAntiplatelet therapy (e.g. ASA), as indicatedBP controlGlycemic controlLifestyle modificationLipid controlSmoking cessation All people with diabetes who are hypertensive Treat according to hypertension guidelines (regardless of whether nephropathy is present) All people with diabetes who have nephropathy Treat according to nephropathy guidelines ACE = angiotensin converting enzymeASA = acetylsalicylic acidBP = blood pressure Table 2. Lipid targets and treatment initiation parameters*† in diabetes based on risk of
a vascular event
Risk level
LDL-C
TC:HDL-C
(mmol/L)
Moderate (younger age and shorter duration of diabetes and no other complications of diabetes and no other risk factors for vascular disease) * While TGs are not indicated as a treatment target, almost all individuals with hypertriglyceridemia can be identified as having anelevated TC:HDL-C.The optimal TG level is <1.5 mmol/L†Optimal apo B: <0.9 g/L for high-risk individuals and <1.05 g/L for moderate-risk individuals (9) apo = apolipoproteinHDL-C = high-density lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterolTC = total cholesterolTG = triglyceride 2003 CLINICAL PRACTICE GUIDELINES
and is associated with substantial reductions in CV morbidity RECOMMENDATIONS
and mortality in both type 1 (18) and type 2 diabetes (19,20).
2. People with type 1 or type 2 diabetes should be Pharmacologic interventions
encouraged to adopt a healthy lifestyle to lower their Large, recently published trials have demonstrated the benefits risk of CVD.This entails adopting healthy eating habits,achieving and maintaining a healthy weight, engaging in of statin therapy in both primary and secondary prevention regular physical activity, and stopping smoking [Grade D, of vascular disease. Subgroup analyses of these studies have shown similar benefits in the subsets of participants with dia-betes (12-14). As well, several studies have shown benefits 3. A fasting lipid profile (TC, HDL-C,TG and calculated LDL-C) should be conducted at the time of diagnosis of associated with fibrate treatment (21-23).
diabetes and then every 1 to 3 years as clinically indicated.
The results of the Heart Protection Study (HPS) provid- Apo B can also be measured to accurately estimate ed important new insights (24). In this large study involving atherogenic particle number. More frequent testing >20 000 subjects, a similar benefit in terms of risk ratio should be done if treatment for dyslipidemia is initiated reduction was observed in subjects with baseline LDL-C >3.5 mmol/L, 3.0 to 3.5 mmol/L and <3.0 mmol/L. All 4. Most people with type 1 and type 2 diabetes should be randomized subjects were included in this analysis. The considered at high risk for vascular disease [Grade A, recently published results in the 5963 subjects with diabetes Level 1 (20,27,28)]. However, some people with type 1 showed similar risk reductions among people with or with- or type 2 diabetes may be considered at moderate risk, out diabetes, irrespective of sex, vascular disease or lipid such as younger patients with shorter duration of levels (LDL-C <3.0 mmol/L or ≥3.0 mmol/L), type of dia- disease and without complications of diabetes and without other risk factors [Grade A, Level 1 (4,20,29)].
betes and glycosylated hemoglobin (A1C) (15).These resultsled to speculation that whatever the existing serum LDL-C 5. Patients with diabetes should be treated to achieve the level, lowering it further with the use of a statin (simvastatin following target lipid goals: for patients at high risk of a in the HPS) is beneficial. However, the HPS did not demon- vascular event: LDL-C <2.5 mmol/L and TC:HDL-C<4.0; and for patients at moderate risk of a vascular strate the effect of treating LDL-C to any particular preset tar- event: LDL-C <3.5 mmol/L and TC:HDL-C <5.0 [Grade D, gets. In a post-hoc analysis of the entire study sample, the Consensus]. Although current evidence does not support investigators also found similar event reductions in individuals specific targets for apo B or TG, the optimal TG level with baseline LDL-C values <2.6 mmol/L, but this post-hoc is <1.5 mmol/L, and the optimal levels for apo B are analysis was not performed in the subset of people with dia- <0.9 g/L for high-risk patients and <1.05 g/L for betes who had baseline LDL-C values <2.6 mmol/L.
moderate-risk patients [Grade D, Consensus].
The following considerations should guide the choice of 6.The following should be considered when choosing pharmacologic agent to treat dyslipidemia (Table 3,Table 4): treatments for patients with dyslipidemia: • 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) • In cases where LDL-C is above target, a statin reductase inhibitors (statins) are the drugs of choice to should be prescribed [Grade A, Level 1A (15)].
• In high-risk patients with TG levels of 1.5 to 4.5 Table 3. Treatment of dyslipidemia
mmol/L, HDL-C <1.0 mmol/L, and LDL-C at target,either a statin [Grade A, Level 1A (15)] or fibrate Lipid status
Therapy*
[Grade B, Level 2 (22,23)] can be prescribed. In patients with marked hypertriglyceridemia (TG level >4.5 mmol/L), a fibrate should be prescribed • When monotherapy fails to achieve lipid targets, the addition of a second drug from another class should be considered [Grade D, Consensus].
lower LDL-C,TC:HDL-C and apo B.At higher doses, they have modest TG-lowering and HDL-C-raising effects, but are usually insufficient to correct these lipid abnormalities.
Treatment with a statin can also be considered in patients *When monotherapy plus lifestyle modification fail to achievelipid targets, the addition of a second drug from another class >40 years of age with an LDL-C level ≤2.5 mmol/L (15).
• Bile acid sequestrants (cholestyramine resin and colestipol HCl) may also be used to lower LDL-C and apo B, but HDL-C = high-density lipoprotein cholesterolLDL-C = low-density lipoprotein cholesterol they tend to elevate TG levels and are therefore not often very useful in diabetic dyslipidemia.
• Treatment with a cholesterol absorption inhibitor (eze- HYPERTENSION
timibe), either as monotherapy or in combination with BP targets
COMPLICA
a statin, may be considered to lower LDL-C.
The recommended BP targets are ≤130/80 mm Hg. Systolic • Fibrates are recommended to lower TGs, raise HDL-C BP >130 mm Hg and diastolic BP >80 mm Hg are the and improve TC:HDL-C. Fibrates also shift the size of thresholds recommended to initiate treatment and apply LDL particles from small to large, and may paradoxical- regardless of whether nephropathy is present. Vascular pro- ly raise LDL-C levels in 10 to 15% of patients.They may tection and control of hypertension are more important than also raise creatinine and homocysteine levels.
measures aimed solely at protecting renal function (Table 1) • Nicotinic acid (niacin) is an alternative drug that increases HDL-C and lowers TG levels. It is also an Results of the Hypertension Optimal Treatment (HOT) effective LDL-C-lowering and apo B-lowering agent.
and UKPDS 38 trials provide strong evidence for the diastolic Although it should be used with some caution because it BP target of 80 mm Hg (30,31). Both trials demonstrated clin- can increase insulin resistance and cause deterioration of ically important reductions in microvascular and macrovascu- glycemic control (25), there is now evidence that the lar complications (30,31), CV death (30) and diabetes-related adverse effects of niacin on glycemia may have been death (31) in patients with diabetes who were randomized to treatments yielding diastolic BP as low as 81 mm Hg.
Table 4. Indications to guide choice of lipid medication (in alphabetical order by class)
Drug class, generic name
Effect(s)
Other considerations
(trade name)
• Tend to elevate TGs and are therefore • Inhibits intestinal cholesterol absorption either as monotherapy or in combination with a statin • May paradoxically raise LDL-C levels in (Lipidil Micro®/Lipidil Supra®, generic) • Shift LDL from smaller to larger particles effects, but are usually insufficient tocorrect these lipid abnormalities apo = apolipoprotein HDL-C = high-density lipoprotein cholesterolHMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme ALDL-C = low-density lipoprotein cholesterolTC = total cholesterolTG = triglyceride 2003 CLINICAL PRACTICE GUIDELINES
The evidence for a systolic BP target of 130 mm Hg is less incidence of selected secondary outcomes in the diuretic strong and includes 2 prospective cohort studies (27,28) and group, and the lower cost of diuretics suggest that diuretics the normotensive Appropriate Blood Pressure Control in should be used before the other ALLHAT drug classes for Diabetes (ABCD) trial (32). In the cohort studies, direct patients with diabetes, hypertension and no nephropathy relationships were observed between higher systolic BP lev- (36). However, a complete description of the ALLHAT els and death, coronary artery disease, nephropathy and pro- results in the subgroup with diabetes—including whether liferative retinopathy (27,28). Although this relationship there were any differences among the 3 drug classes in their extended to systolic BP as low as 110 mm Hg, the Canadian effects on microvascular outcomes, such as nephropathy, or Diabetes Association Clinical Practice Guidelines Expert on macrovascular outcomes in those with nephropathy at Committee did not judge the evidence to be sufficient to rec- baseline—was not available at the time of development of ommend a systolic BP target lower than 130 mm Hg. Results the Canadian Diabetes Association 2003 Clinical Practice of the normotensive ABCD trial also support the systolic BP Guidelines for the Prevention and Management of Diabetes in target of 130 mm Hg (32), but, again, not to a level that jus- Canada. Therefore, a thiazide-like diuretic was not recom- tified a Grade A recommendation. Stronger evidence for the mended as first-line therapy before the other drug choices.
optimal systolic BP target awaits completion of the Action to Multiple drugs will often be required to approach, if not Control Cardiovascular Risk in Diabetes (ACCORD) trial in meet, the recommended BP targets. For example, in the which thousands of people with diabetes are being random- UKPDS, 29% of subjects randomized to tight BP control ized to systolic BP targets of <120 mm Hg or <140 mm Hg.
required at least 3 antihypertensive drugs by the trial’s end (31).
The issue of which drug to use first may therefore be less Treatment of hypertension
important than the need to use more than 1 drug to control If BP cannot be controlled with lifestyle intervention in peo- BP in most people with diabetes.The prospect of prescribing ple with diabetes without nephropathy, any 1 of the follow- several antihypertensive drugs to patients with diabetes can ing drugs is recommended as the initial choice of therapy, in be discouraging, particularly when the same people are like- the following order:ACE inhibitor,ARB, cardioselective beta ly to need several other drugs to reach the stringent lipid and blocker or thiazide-like diuretic. This recommendation glycemic targets that are now advocated. For each patient, reflects the results of studies that have compared, as a pre- treatment decisions will have to weigh the potential benefits specified primary goal, clinically important vascular outcomes of lowered BP against the potential adverse effects of in people with diabetes who were randomized to either a drug polypharmacy.This judgement can be guided by the fact that from the studied class or to placebo (33,34), or to an active a direct relationship exists between the size of the incremen- comparator control group (35-37). Because the efficacy of tal BP reduction and subsequent reduction in hypertension- long-acting calcium channel blockers (CCBs) has not been related complications (27,28). While any reduction in BP is proven in similarly designed trials, but was demonstrated in associated with a lower risk of complications, small reduc- post-hoc analyses of randomized trials (38), CCBs remain an tions in BP are associated with small reductions in risk.Thus, attractive option for patients unable to use drugs from any of it may be reasonable to be less aggressive (e.g. not adding a third or fourth antihypertensive drug) in patients whose BP In the Antihypertensive and Lipid-Lowering Treatment to is already close to 130/80 mm Hg and for whom the clini- Prevent Heart Attack Trial (ALLHAT), >12 000 people with cian is especially concerned about possible side effects from diabetes were randomized to treatment with a CCB, ACE additional drug therapy. Larger BP reductions are associated inhibitor, thiazide-like diuretic or alpha-adrenergic blocker with larger reductions in risk—justifying a more aggressive (36,37), and CV outcomes were compared over 5 years. Early approach in the patient with diabetes whose BP levels are termination of the alpha-adrenergic blocker arm occurred because of excess heart failure relative to the diuretic arm (37).
This is the reason to avoid alpha-adrenergic blockers, at least as RECOMMENDATIONS
first-line therapy, for the treatment of hypertension.
More recently, the primary ALLHAT results were report- 7. Lifestyle interventions to reduce BP, including achieving and maintaining a healthy weight, and limiting sodium ed (36). No differences were observed in people with dia- and alcohol intake, should be considered [Grade D, betes among the 3 remaining drug classes with respect to the primary outcome (fatal coronary heart disease or nonfatalmyocardial infarction [MI]), but a lower rate of prespecified 8. BP should be measured at every diabetes visit.
Patients with systolic BP >130 mm Hg or diastolic secondary vascular outcomes, including heart failure, BP >80 mm Hg should have their BP remeasured occurred among those randomized to the thiazide-like on a separate visit [Grade D, Consensus]. diuretic. Although glycemic control was also worse in thisgroup relative to the ACE inhibitor and CCB groups (36), the lack of differences in the primary outcome, the lower controlled hypertension (30). Patients who cannot tolerate ASA should substitute an alternate antiplatelet agent such 9. Persons with diabetes should be treated to target a COMPLICA
as clopidogrel (Plavix™). Due to the increase in platelet systolic BP <130 mm Hg [Grade C, Level 3 (27,28,32)]and a diastolic BP ≤80 mm Hg [Grade A, Level 1A (30)].
turnover and thromboxane synthesis in people with diabetes, Systolic BP >130 mm Hg and diastolic BP >80 mm Hg it has been suggested that multiple daily dosing of ASA may are the thresholds recommended to initiate treatment be preferred in this population, although no clinical endpoint data have confirmed this hypothesis.Antiplatelet agents should 10. For people with diabetes, no diabetic nephropathy, and not be used in patients with inherited or acquired bleeding BP levels >130 mm Hg and/or >80 mm Hg despite disorders, recent gastrointestinal bleeding or serious renal or lifestyle modification, any 1 of the following drugs is hepatic failure. ASA should not be used in patients <21 years recommended as the initial choice of therapy, in the of age due to an increased risk of Reye syndrome.
following order [Grade D, Consensus for the order].
• ACE inhibitor [Grade A, Level 1A (33)];• ARB [Grade A, Level 1A for co-existent left ventricular RECOMMENDATION
hypertrophy (LVH) (34); Grade B, Level 2 if LVH is not 13. Unless contraindicated, low-dose ASA therapy (80 to 325 mg/day) is recommended in all patients with • cardioselective beta blocker [Grade B, Level 2 (35)]; diabetes with evidence of CVD, as well as for those • thiazide-like diuretic [Grade A, Level 1A (36)]; or individuals with atherosclerotic risk factors that • long-acting CCB [Grade B, Level 2 (38)].
increase their likelihood of CV events [Grade A, 11. If BP targets cannot be reached despite the use of 1 of the above drug choices as monotherapy, use of 1 ormore of these or other antihypertensive drugs in combination should be considered [Grade D, Consensus].
OTHER RELEVANT GUIDELINES
Definition, Classification and Diagnosis of Diabetes and
12. Alpha-adrenergic blockers are not recommended as first-line agents for the treatment of hypertension in persons with diabetes [Grade A, Level 1A (37)].
Screening and Prevention, p. S10Targets for Glycemic Control, p. S18Physical Activity and Diabetes, p. S24 ANTIPLATELET THERAPY
People with diabetes have a 2- to 4-fold increased morbidity Management of Obesity in Diabetes, p. S46 and mortality due to CVD. Platelet dysfunction in diabetesmay contribute to this increased risk. Patients with diabetes RELATED WEBSITES
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