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Update on the Canadian Diabetes Association 2008 clinical practice guidelines

Onil K. Bhattacharyya

MD PhD CCFP

Elizabeth A. Estey

MA

Alice Y.Y. Cheng

MD FRCPC

R

ates of diabetes are increasing in Canada,1 and family  physicians remain the main point of primary care for  people with diabetes.2 The challenge for physicians in this  context  is  to  design  realistic  treatment  plans  and  negoti- ate priorities to maximize health benefits for these patients. 

This  article  summarizes  recommendations  from  the  Canadian  Diabetes  Association  (CDA)  2008  clinical  prac- tice guidelines (CPGs). The guidelines are available on-line  at www.diabetes.ca/for-professionals/resources/2008- cpg/.  This  review  covers  the  care  of  adults  with  type  2  diabetes and gives particular attention to new recommen- dations.  To  assist  with  readability,  grading  and  evidence  levels  have  been  simplified  to  single  letters  (eg,  grade  A  recommendation = [A]). Table 1 summarizes the grading  system used by the CDA.

Glycemic control and diabetes

Targets for glycemic control. The  new  guidelines  rec- ommend a target hemoglobin A1c (HbA1c) level of ≤ 7% for  all patients with diabetes (A). A more aggressive target of 

≤ 6.5%  can  be  considered  for  some  patients  to  help  pre- vent  microvascular  complications,  but  this  benefit  must  be weighed against an increase in mortality in patients at  very high risk of cardiovascular (CV) events (A). 

The benefit of achieving the target HbA1c level of ≤ 7% for  microvascular risk reduction is well established.3 The 2003 

CPGs also suggested a more aggressive target of ≤ 6%, but 2  recent randomized controlled trials showed no macrovas- cular benefit to this target. The ACCORD trial demonstrated  that  a  therapeutic  strategy  to  lower  the  level  of  HbA1c  to 

< 6% in high-risk patients did not reduce the risk of macro- vascular disease and, in fact, was associated with a small  increase in mortality.4 The ADVANCE trial did not show this  increased mortality, but it also did not demonstrate macro- vascular benefit of lowering the HbA1c level below 6.5%; it  did, however, show a reduction in nephropathy in the inten- sive-control group.5 In contrast, the posttrial monitoring of  the  United  Kingdom  Prospective  Diabetes  Study  (UKPDS- PTM)  demonstrated  a  reduction  in  myocardial  infarction  and all-cause mortality in the subgroup with intensive gly- cemic control after a 10-year posttrial follow-up.6 The key  differences between the UKPDS-PTM and the ACCORD and  ADVANCE  trials  are  UKPDS-PTM’s  early  intervention  and  longer follow-up. This suggests that earlier intervention has  lasting benefit but that a target HbA1c level of ≤ 7% is more  appropriate in patients at high risk of vascular events who  have had diabetes for a long time. 

Monitoring glycemic control. Patients with type 2 dia- betes  taking  once-daily  insulin  and  oral  antihyperglyce- mic  agents  should  monitor  their  blood  glucose  at  least  once a day at different times (D), or more often if they are  on multiple doses of insulin (C). Because there is contra- dictory evidence about the benefit of self-monitoring of  blood  glucose  for  patients  who  are  not  taking  insulin,  self-monitoring  should  be  individualized  according  to  the type of treatment and level of control (D). 

Table 1. Criteria for assigning levels of evidence and grades to recommendations for clinical practice

GRADE OR

LEVEL CRITERIA

Grade A The best evidence is level 1

Level 1A Systematic overview or meta-analysis of high- quality randomized controlled trials or appropriately designed randomized controlled trial with adequate power to answer the question posed by the investigators

Level 1B Nonrandomized clinical trial or cohort study with indisputable results

Grade B The best evidence is level 2

Level 2 Randomized controlled trial or systematic overview that does not meet level-1 criteria Grade C The best evidence is level 3

Level 3 Nonrandomized clinical trial or cohort study Grade D The best evidence is level 4 or consensus Level 4 Other

Recommended targets for glycemic control

1. Patients should be treated to achieve a target HbA1c level of ≤ 7% to reduce microvascular complications in all (A) and macrovascular complications in type 1 diabetes (C).

2. To reach an HbA1c level of ≤ 7%, people with diabetes should aim for the following:

fasting plasma glucose or preprandial plasma glucose target of 4.0-7.0 mmol/L (B) and

2-hr postprandial plasma glucose target of 5.0-10.0 mmol/L (B).

3. Further postprandial blood glucose lowering to

5.0-8.0 mmol/L might be considered if HbA1c targets are not reached with the postprandial target of 5.0-10.0 mmol/L (D).

Practice

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Pharmacologic management of type 2 diabetes. As  more  antihyperglycemic  agents  become  available,  care- ful consideration should be given to their advantages and  disadvantages. Figure 1 summarizes the key points from  the  guidelines.  Metformin  remains  the  initial  drug  for  type 2 diabetes, but the guidelines now support its use in  all people with diabetes, irrespective of body weight (D). 

When glycemic targets are not met with metformin alone,  1 or more agents from a different class should be added 

to metformin. The choice of second-line agents depends  on the desired (and undesired) characteristics of the treat- ment. The incretin agent, dipeptidyl peptidase-4 inhibitor,  is  a  new  option.  In  the  presence  of  marked  hypergly- cemia  (HbA1c ≥ 9%),  the  2008  CPGs  recommend  starting  combination  pharmacologic 

therapy  immediately,  concur- rent  with  lifestyle  changes  (D).  When  basal  insulin  is  added  to  antihyperglycemic  agents,  the  guidelines  rec- ommend  considering  insu- lin  analogues  (eg,  insulin  detemir  or  insulin  glargine)  instead  of  neutral  protamine  Hagedorn (NPH) to reduce risk  of  nocturnal  or  symptomatic  hypoglycemia (A).

Cardiovascular risk and diabetes

Cardiovascular  disease  (CVD)  is the number 1 cause of death  among  those  with  diabetes.7  Thus,  a  thorough  assessment  of  CV  risk  and  implementa- tion  of  a  treatment  plan  (if  necessary)  is  essential  for  all  patients with diabetes (D).

Cardiovascular risk assess- ment. The degree of benefit of  medical  intervention  is  based  on  patients’  absolute  risk  of  CV  events,  with  higher-risk  patients  deriving  greater  ben- efit.8  Thus,  identifying  those  at  high risk can ensure that those  who  are  most  likely  to  bene- fit  will  receive  treatment.  Age  is  among  the  strongest  predic- tors of risk, so the CDA recom- mends  that  men  45  years  and  older and women50 years and  older  should  be  considered  high risk. Patients below these  age cutoffs, but meeting any 1 

of the other important CV risk factors, should also be con- sidered high risk. 

Vascular protection. People with diabetes develop vas- cular disease approximately 15 years earlier than people  without  diabetes.9  The  concept  of  vascular  protection  was introduced in the 2003 CPGs, but it has been further  stratified  in  the  2008  version,  owing  to  evidence  that  shows  a  comprehensive  multifactorial  approach  to  vas- cular protection substantially reduces complications.10,11  All  patients  with  diabetes  should  receive  interventions  to reach target blood pressure (BP) of < 130/80 mm Hg  and HbA1c levels of ≤ 7%, to stop smoking, and to main- tain  healthy  diets,  physical  activity,  and  healthy  body 

Figure 1. Pharmacologic management of type 2 diabetes

Clinical assessment

Symptomatic hyperglycemia

with metabolic decompensation HbA1c < 9.0% HbA1c ≥ 9.0%

Initiate lifestyle interventions (eg, nutrition therapy, physical activity)

If no change in 3 months Initiatemetformin and

lifestyle interventions concurrently Consider initiating combination therapy:

metformin and another agent from a different class, including insulin, or insulin in symptomatic individuals Initiateinsulin with or

without metformin

Initiate metformin

If NOT at target

Add an agent best suited to your patient (see advantages and disadvantages below)

Agent HbA1c* Advantages Disadvantages

Sulfonylurea improved postprandial control associated hypoglycemia

newer sulfonylureas are associated requires 3-4 doses daily with less hypoglycemia weight gain

TZD durable monotherapy 6-12 wk for maximal effect

rare hypoglycemia weight gain

edema, rare CHF, rare fractures in females A-Glucosidase improved postprandial control GI side effects

inhibitor (acarbose) weight neutral

rare hypoglycemia

Insulin no dose ceiling weight gain

many types, flexible regimes associated hypoglycemia

in HbA1c

DPP-4 inhibitor to improved postprandial control new agent (long-term safety not known)

weight neutral

Weight-loss agent weight loss GI side effects (orlistat)

no hypoglycemia increased heart rate, BP (sibutramine)

If still NOT at target

Add another agent

Add bedtime basal insulin to other agent(s)

Intensify insulin regimen

Timely adjustments or additions of antiglycemic agents should be made to attain target HbA1c within 6-12 mo BP—blood pressure, CHF—congestive heart failure, DPP-4—dipeptidyl peptidase-4, GI—gastrointestinal, TZD—thiazolidinedione.

* = <1.0% decrease, = 1.0%-2.0% decrease, = >2.0% decrease.

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weight. On top of these interventions, those found to be  at high risk should be prescribed angiotensin-converting  enzyme  (ACE)  inhibitors  or  angiotensin  II  receptor  blockers  (ARBs),12  lipid-lowering  medications  (particu- larly  statins),  and  possibly  acetylsalicylic  acid  (ASA).  It  is important to note that ARBs are now included in the  CPGs  as  an  alternative  to  ACE  inhibitors.  Specific  refer- ence  to  statins  is  also  new  and  reflects  the  growing  lit- erature on the benefits of these medications for high-risk  groups.13,14  Recommendations  regarding  ASA  have  also  been  modified,  because  ASA  therapy  has  been  shown  to have less of a cardioprotective effect in patients with  diabetes than in those without diabetes, and to have no  benefit  in  primary  prevention.15,16  Thus,  the  2008  CPGs  state  that  low-dose  ASA  therapy  (81  to  325  mg)  could  be considered in people with stable CVD (D) but clinical  judgement  should  be  exercised  regarding  its  use  in  pri- mary prevention (D). 

Cardiovascular risk

assessment recommendations

1. All patients with diabetes should be assessed for cardiovascular risk annually (D).

2. Patients with diabetes are considered high risk if they are male ≥ 45 y or female ≥ 50 y (B) or

male < 45 y or female < 50 y with any of the following (D):

- macrovascular or microvascular disease, - 2 or more cardiac risk factors (eg, first-degree relative with premature coronary or cerebrovascular disease, smoking, hypertension, dyslipidemia), - an extreme single risk factor (eg, systolic blood pressure > 180 mm Hg or low-density lipoprotein level > 5.0 mmol/L), or

- diabetes for longer than 15 y and age > 30 y.

Recommendations for vascular protection

1. For vascular protection for all individuals with diabetes ([A]

for patients older than 40 y with type 2 diabetes and microalbuminuria; [D] for all others), aim for the following:

HbA1c level ≤ 7.0% (see glycemic control), blood pressure < 130/80 mm Hg, smoking cessation,

physical activity, healthy diet, and healthy body weight.

2. For high-risk patients, prescribe 1 or more of the following:

angiotensin-converting enzyme inhibitor or angiotensin receptor blocker ([A] for those with vascular disease;

[B] for other high-risk groups),

a lipid-lowering medication, particularly statins (see Treatment of dyslipidemia), or

acetylsalicylic acid (for secondary prevention).

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Treatment of hypertension. Strict  control  of  BP  improves  morbidity  and  mortality  in  patients  with  dia- betes.3,17-19  The  CDA  recommends  that  BP  be  measured  at  every  visit  and  hypertension  be  diagnosed  accord- ing  to  the  national  hypertension  guidelines  (www.

hypertension.ca/chep).  Treatment  targets  remain  sys- tolic BP < 130 mm Hg (C) and diastolic BP < 80 mm Hg (B). 

Clinical trials have shown that multiple medications and  titrations are required to achieve these targets.18,20 A sum- mary  of  recommended  first-line  and  combination  medi- cations is provided in Table 2, but it is important to note  that ACE inhibitors and ARBs are given special consider- ation as first-line treatment agents because of their renal  benefits  (D)12  and  that a-blockers  are  not  recommended  as first-line agents for patients with diabetes (A).

Treatment of dyslipidemia. Dyslipidemia  is  a  well-recognized  risk  factor  for  CVD.  Fasting  lipid  levels  should be measured at the time of diagnosis and every  1 to 3 years afterward (D). The primary target of therapy  is  the  low-density  lipoprotein  cholesterol  level  (LDL-C)  (≤ 2.0 mmol/L in patients at high risk [A]); the secondary  target is the ratio of total cholesterol (TC) to high-density 

lipoprotein cholesterol (HDL-C) (< 4 mmol/L in patients  at  high  risk  [D]).  Statins  are  the  first-line  treatment  for  dyslipidemia in patients with diabetes. If targets cannot  be  achieved  with  statins  alone,  combination  therapy  with ezetimibe, fibrate, or niacin can be considered (B),  although  there  are  no  completed  trials  demonstrating  clinical outcomes. Hypertriglyceridemia (triglyceride lev- els  > 10.0  mmol/L)  should  be  treated  with  fibrates  to  reduce the risk of pancreatitis (D).

Screening for coronary artery disease. Asymptomatic  cardiac  ischemia  is  common  among  those  with  diabe- tes.  Many  patients  who  present  with  myocardial  infarc- tion  have  no  preceding  symptoms.  To  identify  those  with established coronary artery disease in the absence  of  symptoms,  the  2008  CPGs  recommend  that  baseline  electrocardiograms be conducted in all individuals older  than 40 years of age (D).

Lifestyle modification and diabetes

Lifestyle  modifications  are  important  for  treat- ment  and  prevention  of  diabetes.  Many  of  the  2008  recommendations  on  nutrition  and  exercise  are  the  same  as  or  similar  to  those  in  the  2003  guidelines. 

One  new  recommendation  is  that  patients  be  referred  to  and  supported  by  exercise  specialists.  Structured  physical  activity  counseling  by  health  care  provid- ers  increases  physical  activity  and  produces  modest,  sustained  weight  loss21-24;  the  effects  of  simply  rec- ommending  that  patients  exercise  more,  which  most  clinicians do, are less certain.25

Conclusion

Clinical  practice  guidelines  are  designed  to  enable  health  care  providers  to  engage  with  the  evidence  and  better apply it in their practices. For conditions like type  2  diabetes,  which  are  complex  and  multidimensional,  treatment  plans  should  be  developed  and  discussed  with  patients.  This  might  require  stepwise  introduction  of  various  treatments  and  tests,  and  continued  patient 

Table 2. Hypertension medication for patients with diabetes

DIABETIC POPULATIOn InITIAL MEDICATIOns ADDITIOnAL MEDICATIOns

BP ≥ 130/80 mm Hg

or albuminuria ACE inhibitor (A) ARB (A/B)*

Thiazide-like diuretic (A) DHP CCB (B)

Cardioselective b-blocker (B) Non–DHP CCB (B)

Isolated systolic

hypertension ACE inhibitor (B) ARB (B)

Thiazide-like diuretic (B) Long-lasting DHP CCB (C)

N/A

ACE—angiotensin-converting enzyme, ARB—angiotensin receptor block- er; DHP CCB—dihydropyridine calcium channel blocker.

*(B) for patients with non–left ventricular hypertrophy; (A) for all others.

Recommendations for treatment of hypertension

1. Blood pressure (BP) should be measured at every diabetes clinic visit and hypertension should be diagnosed according to the national hypertension guidelines (D).

2. Treatment should target BP < 130/80 mm Hg ([C] for systolic BP; [B] for diastolic BP).

3. Most people require multiple BP-lowering medications to reach BP targets. Pharmacologic recommendations are summarized in Table 2.

4. Lifestyle interventions to reduce BP (eg, healthy weight, low sodium intake) should be encouraged alongside pharmaceutical interventions (D).

Recommendations for treatment of dyslipidemia

1. Fasting lipid levels TC, HDL-C, TG, and LDL-C should be measured at the time of diagnosis and then every 1-3 y.

2. The primary target of therapy for adults is LDL-C (A); the secondary target is the TC/HDL-C ratio (D).

3. Adults at high risk of vascular events should be treated with statins to achieve LDL-C levels ≤ 2.0 mmol/L (A).

4. TC/HDL-C ratio < 4.0 mmol/L should be targeted through glycemic control and lifestyle modification (D).

5. If TG levels are > 10 mmol/L, treat with a fibrate to prevent pancreatitis (D).

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education,  so  that  patients  understand  the  value  that  each intervention has for optimizing their health. 

Dr Bhattacharyya is a Clinician Scientist at the Li Ka Shing Knowledge  Institute of St Michael’s Hospital in Toronto, Ont; an Assistant Professor in  the Department of Family and Community Medicine and the Department of  Health Policy, Management, and Evaluation at the University of Toronto; and  a member of the Executive Committee of the Clinical and Scientific Section  of the Canadian Diabetes Association (CDA) (2008). Ms Estey is Research  Coordinator at the Li Ka Shing Knowledge Institute. Dr Cheng is an endocri- nologist at Credit Valley Hospital and St Michael’s Hospital and an Assistant  Professor (adjunct) in the Department of Medicine at the University of Toronto. 

Competing interests

Dr Bhattacharyya is on the executive committee of the clinical and scientific  section of the Canadian Diabetes Association (CDA) and on the Guideline  Dissemination and Implementation Committee of the CDA. Dr Cheng served on  the expert and steering committees for the CDA 2008 guidelines.

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