2003 CLINICAL PRACTICE GUIDELINES
Macrovascular Complications, Dyslipidemiaand HypertensionCanadian Diabetes AssociationClinical Practice Guidelines Expert CommitteeINTRODUCTION 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
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
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
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-
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
and mortality in both type 1 (18) and type 2 diabetes (19,20).
2. People with type 1 or type 2 diabetes should be
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-
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
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
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 ventricularRECOMMENDATION 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
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
have a variety of alterations in platelet function that can pre-
Canadian Hypertension Society. Available at: http://www.
dispose them to increased platelet activation and thrombosis,
including increased platelet turnover (39), enhanced aggre-
Cardiovascular Risk Profile. Available at: http://www.
gation (40) and increased thromboxane synthesis (41). A
chiprehab.com/CVD/. Accessed November 7, 2003.
number of prevention trials have shown a reduction in MI
UKPDS Risk Engine, Diabetes Trials Unit, The Oxford
with ASA therapy, although no benefit was seen in stroke
Centre for Diabetes, Endocrinology & Metabolism.
prevention (30,42-44). The Antithrombotic Trialists’
Available at: http://www.dtu.ox.ac.uk/riskengine/.
Collaboration reported a meta-analysis of 195 randomized
trials of antiplatelet therapy published up to 1997, including9 trials with almost 5000 patients with diabetes. Although
there was a significant proportional reduction in vascular
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Title Companion to Statistical Modelling in RAuthor Murray Aitkin, Brian Francis, John Hinde, Ross Darnell <firstname.lastname@example.org>Maintainer Ross Darnell <email@example.com>Suggests lattice, foreign, gdata, car, dglm, gnm, MASS, npmlreg,survivalDescription This package accompanies Aitkin et al, StatisticalModelling in R, OUP, 2009. The package contains some functions and datas
a cura di Alberto Scanzi FEDERICO ALBORGHETTI E LA GUERRIGLIA DI PALAZZAGO 15/09/1848- 18/11/1848 ----------------------------------------------------------------------------------------- I fatti che prendono il nome di “ La guerriglia di Palazzago” avvennero nei mesi di settembre/novembre 1848 e si svolsero nella zona compresa tra la Val San Martino e i monti dell’Albenza , fra