Update on the Canadian Diabetes Association 2008 clinical practice guidelines
Onil K. Bhattacharyya
MD PhD CCFPElizabeth A. Estey
MAAlice Y.Y. Cheng
MD FRCPCR
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
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 women 50 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.
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).
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).
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.
references
1. Public Health Agency of Canada. National diabetes fact sheet. Canada 2007. Ottawa, ON:
Public Health Agency of Canada; 2007. Available from: www.phac-aspc.gc.ca/ccdpc- cpcmc/diabetes-diabete/english/pdf/diabetes07_e.pdf. Accessed 2008 Dec 3.
2. Jaakkimainen L, Shah BR, Kopp A. Sources of physician care for people with diabe- tes. In: Hux JE, Booth GL, Slaughter PM, Laupacis A, editors. Diabetes in Ontario: an ICES practice atlas. Toronto, ON: Institute for Clinical Evaluative Sciences; 2003.
3. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of compli- cations in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837-53.
Erratum in: Lancet 1999;354(9178):602.
4. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358(24):2545-59.
5. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358(24):2560-72.
6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of inten- sive glucose control in type 2 diabetes. N Engl J Med 2008;359(15):1577-89.
7. Booth GL, Kapral MK, Fung K, Tu JV. Recent trends in cardiovascular complications among men and women with and without diabetes. Diabetes Care 2006;29(1):32-7.
8. Jackson R, Lawes CM, Bennett DA, Milne RJ, Rodgers A. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual’s absolute car- diovascular risk. Lancet 2005;365(9457):434-41.
9. Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular dis- ease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006;368(9529):29-36.
10. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358(6):580-91.
11. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial inter- vention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348(5):383-93.
12. ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358(15):1547-59.
13. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364(9435):685-96.
14. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366(9493):1267-78.
15. Collaboration AT. Collaborative meta-analysis of randomised trials of antiplate- let therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324(7329):71-86.
16. ETDRS Investigators. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. JAMA 1992;268(10):1292-300.
17. Schmittdiel J, Vijan S, Fireman B, Lafata JE, Oestreicher N, Selby JV. Predicted quality-adjusted life years as a composite measure of the clinical value of diabetes risk factor control. Med Care 2007;45(4):315-21.
18. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
BMJ 1998;317(7160):703.
19. CDC Diabetes Cost-effectiveness Group. Cost-effectiveness of intensive glycemic control, intensified hypertension control, and serum cholesterol level reduction for type 2 diabetes. JAMA 2002;287(19):2542-51.
20. Whelton PK, Barzilay J, Cushman WC, Davis BR, Iiamathi E, Kostis JB, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005;165(12):1401-9.
21. Petrella RJ, Koval JJ, Cunningham DA, Paterson DH. Can primary care doctors pre- scribe exercise to improve fitness? The Step Test Exercise Prescription (STEP) project.
Am J Prev Med 2003;24(4):316-22.
22. Kirk A, Mutrie N, MacIntyre P, Fisher M. Effects of a 12-month physical activity counselling intervention on glycaemic control and on the status of cardiovascular risk factors in people with type 2 diabetes. Diabetologia 2004;47(5):821-32.
23. Wolf AM, Conaway MR, Crowther JQ, Hazen KY, Nadler L, Oneida B, et al. Translating lifestyle intervention to practice in obese patients with type 2 diabetes: Improving Control with Activity and Nutrition (ICAN) study. Diabetes Care 2004;27(7):1570-6.
24. Norris SL, Zhang X, Avenell A, Gregg E, Brown TJ, Schmid CH, et al. Long-term non-pharmacologic weight loss interventions for adults with type 2 diabetes.
Cochrane Database Syst Rev 2005;(2):CD004095.
25. Harris SB, Petrella RJ, Leadbetter W. Lifestyle interventions for type 2 diabetes.
Relevance for clinical practice. Can Fam Physician 2003;49:1618-25.