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Secondary Prevention Of Stroke

5. Diabetes Management in Stroke

7e édition – 2020 MISE À JOUR


Recommendations

5.0 Patients with diabetes who have had an ischemic stroke or transient ischemic attack should have their diabetes assessed and optimally managed [Evidence Level A].

5.1 Diabetes Screening and Assessment
  1. Patients with ischemic stroke or transient ischemic attack should be screened for diabetes with either a fasting plasma glucose, or 2-hour plasma glucose, or glycated hemoglobin (A1C), or 75 g oral glucose tolerance test in either an inpatient or outpatient setting [Evidence Level C]. Refer to Diabetes Canada guidelines for details on screening methods.
  2. For patients with diabetes and either ischemic stroke or transient ischemic attack, glycated hemoglobin (A1C) should be considered as part of a comprehensive stroke assessment [Evidence Level B]. 

Refer to Prevention of Stroke Section 3 for information on blood pressure management in an individual with stroke and diabetes; refer to Prevention of Stroke Section 4 for information on lipid management in an individual with stroke and diabetes.

5.2 Diabetes Management
  1. Glycemic targets should be individualized to achieve:
    1. In general, A1c values should be targeted to ≤7.0% in patients with either type 1 or type 2 diabetes (and stroke or transient ischemic attack), as this target provides strong benefits for the prevention of microvascular complications [Evidence Level A].  For frail elderly populations, please refer to the current Diabetes Canada guidelines for target A1C levels at www.diabetes.ca 
    2. To achieve a target of A1c ≤7.0%, most patients with type 1 or type 2 diabetes should aim for a fasting plasma glucose or pre-prandial plasma glucose target of 4.0 to 7.0 mmol/L [Evidence Level B].
    3. The 2-hour postprandial plasma glucose target is 5.0 to 10.0 mmol/L [Evidence Level B]. 
    4. If A1C targets cannot be achieved with a postprandial target of 5.0 to 10.0 mmol/L, further postprandial blood glucose lowering, to 5.0 to 8.0 mmol/L, should be considered [Evidence Level C].  
  2. (New 2020) In patients with stroke and type 2 diabetes in whom glycemic targets are not achieved with standard oral antihyperglycemic medications, an antihyperglycemic agent with demonstrated benefit on major cardiovascular outcomes (for example, SGLT-2 inhibitors or GLP-1 receptor agonists) should be considered [Evidence Level B]. 

Note: For further recommendations on the use of SGLT-2 inhibitors and GLP-1 receptor agonists, please refer to the current Diabetes Canada guidelines at www.diabetes.ca.

 

Section 5.2 Clinical Consideration (New 2020)
  1. The Pioglitazone after Ischemic Stroke or Transient Ischemic Attack trial (Kernan WN, Viscoli CM, Furie KL, et al, 2016) suggested that while there is a benefit of pioglitazone for stroke prevention in patients with positive insulin resistance, it is offset by the increased risk of fractures and bladder cancer. A post-hoc analysis of patients in the trial with prediabetes and good drug adherence suggested a benefit of pioglitazone over placebo with regards to stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes. The decision to use this agent could be considered based on the specific risk profile for each patient.

Refer to the current Diabetes Canada Clinical Practice Guidelines for additional information.

Rationale +-

Diabetes is a major risk factor for cardiovascular disease and is recognized as an independent risk factor for ischemic stroke. The risk of stroke is 50% higher in persons with diabetes.  Most adults with type 1 or type 2 diabetes should be considered at high risk for vascular disease. The exceptions are younger adults with type 1 and type 2 diabetes with shorter duration of disease and without complications of diabetes (including established cardiovascular disease) and without other cardiovascular disease risk factors. Diabetes increases the risk of stroke and is a particularly potent risk factor in younger individuals, with studies suggesting an increase in stroke risk of as much as 10-fold in some younger subgroups. Overall, diabetes is considered a major risk factor for many conditions and is considered here as part of a comprehensive package supporting prevention and lifestyle management. 

Diabetes education has been identified as a key priority for people following a stroke, who receive a new diagnosis of diabetes at the time of stroke.  Those with prior history of diabetes have reported lack of understanding on the risks of stroke in people with diabetes, often citing they thought it was only a risk for heart disease, and not being aware of the connection with broader vascular risks.  Several people with stroke who also experienced heart conditions stated their blood glucose levels were monitored and discussed only during those appointments and questioned why stroke care did not include the same management.  Areas of concern voiced by people who have experienced stroke include whether they were tested for diabetes, the results of that testing, any cautions going forward or, if diabetes detected, they wanted to know how, when and by whom they were going to receive follow up care.  Feedback from people who have experienced stroke and their families emphasized the silos that exist in the current healthcare system and the need to provide seamless and coordinated care following a stroke, especially considering the number of people living with multiple comorbid conditions.

 

 
System Implications +-
  1. Coordinated diabetes awareness programs at the provincial and community levels that involve community groups, primary care providers (including physicians, nurse practitioners and pharmacists), and other relevant partners.
  2. Coordinated education and support programs for persons with diabetes to increase adherence and reduce ongoing risks for cardiovascular complications.
  3. Increased availability and access to education programs for healthcare providers across the continuum of care on management of patients with diabetes and stroke
  4. Continued alignment with recommendations and guidelines developed by Diabetes Canada.
  5. Universal and equitable access to cost-effective medicines for all people in Canada, regardless of geography, age, or ability to pay.
Performance Measures +-
  1. Proportion of the population with a confirmed diagnosis of diabetes (type 1 and type 2).
  2. Proportion of persons with diabetes presenting to hospital with a new stroke event.
  3. Proportion of patients presenting to hospital with a stroke who receive a subsequent diagnosis of diabetes during their hospitalization for stroke care.

Measurement Notes

  • Performance measure 1: Rates may be obtained for Canada from the Public Health Agency of Canada Diabetes Surveillance database.
  • Performance measures 1 and 2 should be standardized for age and sex.
  • Data sources may include physician order sheets, physicians’ or nurses’ notes, discharge summaries, or copies of prescriptions given to patients.
  • Blood values should be taken from official laboratory reports where possible.
  • Trends and benchmarks may be monitored and tracked through the National Diabetes Surveillance System data.
Summary of the Evidence +-

Diabetes Management Evidence Table and Reference List 

In persons with diabetes, the risk of stroke, particularly ischemic stroke is increased. Estimates from the InterStroke 1 study (O’Donnell et al. 2010) suggested that the odds of any stroke were increased by 36% among those with diabetes (60% for ischemic stroke). More recent estimates from the Interstroke 2 study (O’Donnell et al. 2016), are lower at 16% and 33% for any and ischemic stroke, respectively, although the population attributable risks (PAR) are similar between studies.  The PAR for ischemic stroke was 7.9% in Interstroke 1 and was 7.5% in the Interstroke 2 study. The independent contribution of diabetes is difficult to determine, since many risk factors for stroke, including hypertension, dyslipidemia and atrial fibrillation, are found more frequently in those with diabetes. The higher stroke risk may be due to the complex interplay between the various hemodynamic and metabolic components of the diabetes syndrome. In addition to the traditional risk factors, those specifically associated with the metabolic syndrome (insulin resistance, central obesity, impaired glucose tolerance and hyperinsulinemia), which are common in diabetes, also contribute to the increased risk. In persons with diabetes, stroke outcomes are worse, and are associated with increased mortality, more residual neurologic and functional disability and longer hospital stays. Lifestyle changes, tight glycemic control, antiplatelet drugs, such as aspirin and control of lipid levels with statins can all have beneficial effects. Blood pressure control is another vital aspect in reducing risk, and a number of recent studies have provided evidence supporting the use of angiotensin converting enzyme (ACE) inhibitors as first-line treatment in patients with diabetes. 

Intensive blood glucose management to reduce stroke and cardiovascular risk has been studied in several large RCTs. The Action to Control Cardiovascular Risk in Diabetes Study (ACCORD, glucose-lowering arm) investigators (Gerstein et al. 2008) assessed whether intensive therapy to target normal glycated hemoglobin (HbA1c) levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors. In this study, 10,251 patients with a median HbA1c level of 8.1% were randomly assigned to receive intensive therapy using multiple drugs including insulins and oral hypoglycemia agents, (targeting an HbA1c level <6.0%) or standard therapy (targeting a level from 7.0%-7.9%). The trial was stopped early due to mortality trends suggesting an increased rate of death from any cause associated with intensive therapy (HR=1.22, 95% CI 1.01-1.46, p=0.04).  Although at 4 months, mean HbA1c values had fallen to 6.7% (intensive group) and 7.5% (control group), there was no reduction in the risk of the primary outcome (nonfatal MI, nonfatal stroke or death from cardiovascular causes) associated with intensive glucose lowering (6.9% vs. 7.2%, HR=0.90, 95% CI 0.78-1.04, p=0.16). Patients in the intensive group required medical assistance for hypoglycemia more frequently (10.5% vs. 3.5%), and greater proportions gained >10 kg from baseline (27.8% vs. 14.1%) and experienced a serious nonhypoglycemic adverse event (2.2% vs. 1.6%). Another trial that examined intensive glucose control in persons with poorly-controlled diabetes was the Veterans Affairs Diabetes Trial (Duckworth et al. 2009). After a median duration of follow-up of 5.6 years, HbA1c values were significantly lower in the intensive glucose control group; however, there were no significant differences between groups on any of the primary or secondary outcomes, including the risk of stroke (26 vs. 36 events, HR=0.78, 95% CI 0.48-1.28) or TIA (19 vs. 13, HR=1.48, 95% CI 0.73-2.99). There were significantly more hypoglycemic events in the intensive therapy group. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial (Patel et al. 2008) randomly assigned patients (n = 11,140) with type 2 diabetes to undergo either standard glucose control or intensive glucose control, defined as the use of gliclazide (modified release) plus other drugs as required to achieve an HbA1c value of 6.5% or less. After a median of 5 years of follow- up, the mean HbA1c level was lower in the intensive-control group (6.5%) than in the standard-control group (7.3%). Intensive control reduced the incidence of combined major macrovascular and microvascular events (18.1% v. 20.0% with standard control; HR 0.90, 95% CI 0.82–0.98; p=0.01), as well as that of major microvascular events (9.4% v. 10.9%; HR 0.86, 95% CI 0.77–0.97; p=0.01), primarily because of a reduction in the incidence of nephropathy (4.1% v. 5.2%; HR 0.79, 95% CI 0.66–0.93; p=0.006), with no significant effect on retinopathy (p=0.50). There was no significant difference between groups in the risk of death from any cause (HR=0.93, 95% CI 0.83-1.06, p=0.28) or in the risk of fatal or nonfatal stroke or all cerebrovascular events associated with intensive intervention. Severe hypoglycemia was significantly more frequent in the intensive treatment group (HR=1.86, 95% CI 1.42-2.40, p<0.001).  The results of these three trials and UK Prospective Diabetes Studies 33 and 34 were included in a meta-analysis (Marso et al. 2010) which examined the benefit of intensive glycemic control for the prevention of vascular events, among persons with type 2 diabetes. At the end of follow-up (mean of 5 years), the mean HbA1c values were 6.6% (intensive) and 7.4% (control). There was no reduction in the risk of all-cause mortality, stroke or cardiovascular mortality associated with intensive glycemic treatment; however, there was a significant 14% reduction in nonfatal myocardial infarction (RR=0.86, 95% CI 0.77-0.97, p=0.015).

Additional agents can also be added to standard regimens to improve glycemic control in patients with type 2 diabetes who have trouble achieving their blood glucose targets. One such agent is selective inhibitor of sodium glucose cotransporter (SGLT-2), which has been shown to reduce glycated hemoglobin levels and improve cardiovascular outcomes. Recent RCTs include CREDENCE (Perkovic et al. 2019, Mahaffey et al. 2019), DECLARE–TIMI 58 (Wiviott et al. 2019), CANVAS (Neal et al. 2017, Zhou et al. 2019) and EMPA-REG OUTCOME (Zinman et al. 2015). The proportion of patients with established atherosclerotic cardiovascular disease in these trials was 50% (CREDENCE), 40.6% (DECLARE), 65.6% (CANVAS) and 100% (EMPA-REG). A systematic review & meta-analysis including the results from three of these trials (EMPA-REG OUTCOME, CANVAS Program, and DECLARE-TIMI 58), which compared empagliflozin, canagliflozin and dapagliflozin vs. placebo, reported SGLT2 reduced the risk of a major adverse cardiac event by 11% (HR=0·89, 95% CI 0·83–0·96, p=0·0014); however, the benefit was only seen in persons with established atherosclerotic CVD. The overall risk of ischemic stroke was not reduced significantly in the SGLT2 group (HR=0.97, 95% CI 0.86-1.10), nor was the risk reduced significantly in persons with established atherosclerotic CVD, or in those with multiple risk factors (Zelniker et al. 2018). The CREDENCE trial was stopped prematurely due to efficacy.  After a median of 2.6 years of follow-up, the event rate of the primary outcome (a composite of end stage kidney disease, doubling of the serum creatinine level, or renal or cardiovascular death) was significantly lower in the canagliflozin group (43.2 vs. 61.2 per 1000 patient-years; HR= 0.70; 95% CI 0.59 to 0.82). The risk was reduced significantly in both the primary and secondary prevention groups. The risk of cardiovascular death, myocardial infarction or stroke was also reduced significantly by 20%. 

The glucagon-like peptide 1 receptor (GLP-1), liraglutide, is another example of an agent that may be added to standard regimes. Many large, RCTs have evaluated their effectiveness within the past 5 years, including REWIND (Gerstein et al. 2019), PIONEER 6, (Husain et al. 2019), HARMONY (Hernandez et al. 2018), EXCEL (Holman et al. 2017), SUSTAIN-6 (Marso et al. 2016) and LEADER (Marso et al. 2016). All of these trials included persons with type 2 diabetes, with established cardiovascular risk factors +/- a previous cardiovascular event who were treated with various GLP-1 agents (albiglutide, liraglutide, semaglutide, exenatide, dulaglutide) or placebo for a duration of 2.1 to 5.4 years. The risk of the primary outcome, major cardiovascular event, was reduced significantly from 8% to 24%. When the results of these trials were included in two systematic reviews, the risk of nonfatal and total stroke were significantly lower in the treatment group, with no significant reduction in the risk of fatal stroke (Barkas et al. 2019, Bellastella et al. 2019). 

Insulin resistance, while widespread in persons with type 2 diabetes, is also present in persons who have suffered a stroke or TIA. Treatment with Pioglitazone has recently been investigated (Kernan et al. 2016). In the Insulin Resistance After Stroke (IRIS) study, 3,876 patients, ≥40 years with stroke or TIA within previous 6 months, with insulin resistance were randomized to receive pioglitazone with a target dose of 45 mg daily or placebo for 5 years. The risk of the primary outcome (fatal or non-fatal myocardial infarction or fatal or non-fatal stroke) was significantly lower for patients in the pioglitazone group (9.0% vs. 11.8%, HR=0.76, 95% CI 0.62-0.93, p=0.007), as was the risk of the development of diabetes over the study period (3.8% vs. 7.7%, HR=0.48, 95% CI 0.33-0.69, p<0.001). The risk of stroke was not significantly reduced for patients in the pioglitazone group (6.5% vs. 8.0%, HR=0.82, 95% CI 0.61-1.10, p=0.19) and the frequency of adverse events including bone fracture, weight gain, edema, shortness of breath and liver enzyme abnormalities was significantly higher in the pioglitazone group. In another trial (PROspective pioglitAzone Clinical Trial In macroVascular Events), treatment with pioglitazone for persons with type 2 diabetes and extensive macrovascular disease did not reduce the risk of the primary outcome (HR=0.90, 95% CI 0.80-1.02, p=0.095) or the risk of stroke (HR=0.81, 95% CI 0.61-1.07), after an average of 32 months (Dormandy et al. 2005).


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