Diabetes Management Evidence Tables and Reference List
In persons with diabetes, the risk of stroke is increased, with a higher risk of ischemic, rather than hemorrhagic stroke. 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 persons 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 from 8.1% at baseline 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 hypoglycaemia 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. Empagliflozin is an example of a selective inhibitor of sodium glucose cotransporter (SGLT-2) that has been demonstrated to reduce glycated hemoglobin levels and improve cardiovascular outcomes. A recent large RCT included 7,020 adults with type 2 diabetes, an estimated glomerular filtration rate of ≥30mL/min and established cardiovascular disease (Zinman et al. 2015). In this trial, the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME), patients were randomized to receive 10 mg or 25 mg of empagliflozin, or placebo once daily for the duration of the trial. Background glucose-lowering therapy was also used, as required. After a median of 3.1 years follow-up, the risk of the primary outcome, which was a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke, was significantly reduced in the empagliflozin group (10.5% vs. 12.1%: HR=0.86; 95.02% CI 0.74- 0.99; p<0.001 for noninferiority; p=0.04 for superiority, both dose levels combined), but was not associated with a significantly reduced risk of fatal or nonfatal stroke. Although no recommendations have been made in the current Best Practices Update, the glucagon-like peptide 1 receptor, liraglutide, is another example of an agent that may be added to standard regimes. In the LEADER trial, (Marso et al 2016), 16% of patients had sustained a previous stroke. Patients in the intervention arm of the trial received 1.8 mg liraglutide daily for a median duration of 3.8 years. The risk of the primary outcome (death from cardiovascular causes, nonfatal MI, or nonfatal stroke) was significantly lower in the liraglutide group (HR=0.87, 95% CI 0.78–0.97, p=0.01 for superiority). The NNT to prevent one case of the primary outcome over 3 years was 66.
Lower blood pressure targets (<130/80 mm Hg) have been recommended for persons with diabetes by several organizations, including the most recent guidelines published by Hypertension Canada’s 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. A Cochrane review (Arguedas et al. 2013) included the results from 5 RCTs that compared ’lower’ blood pressure targets (any target <130/85mmHg) with ’standard’ targets (<140-160/90-100 mmHg). Participants were adults with type 2 diabetes and elevated blood pressure, or already receiving treatment for elevated blood pressure. In the single trial aimed at reductions in systolic blood pressure (ACCORD 2010) intensive BP control was not associated with reductions in total mortality (RR= 1.05, 95% CI 0.84-1.30) but was associated with reduction in the risk of stroke (RR=0.58, 95% CI 0.39 to 0.88, p= 0.009); however, serious adverse events, attributed to therapy occurred more often in patients in the intensive group (3.3% vs. 1.3%, p<0.001). In n the 4 trials aimed at reductions in diastolic blood pressure, intensive BP control was not associated with reductions in total mortality (RR= 0.73, 95% CI 0.53-1.01, p=0.054) or stroke (RR= 0.67, 95% CI 0.42-1.05, p=0.077).
The Treating to New Targets study (Shepherd et al. 2006) demonstrated that intensive lipid-lowering therapy with atorvastatin 80 mg/day provided significant clinical benefit beyond atorvastatin 10 mg/day in patients with patients with stable coronary artery disease and diabetes and LDL cholesterol levels of < 3.36 mmol/L. High-dose statin therapy was associated with a 25% reduction in major cardiovascular events. After a median follow-up period of 4.9 years, the primary end point (time to first major cardiovascular event), occurred less frequently in the high-dose group (17.9% vs. 13.8%, HR= 0.75, 95% CI 0.58–0.97; p = 0.026). Significant differences between the groups in favour of atorvastatin 80 mg were also observed for time to cerebrovascular event (HR 0.69, 95% CI 0.48–0.98; p = 0.037) and time to any cardiovascular event (HR 0.85, 95% CI 0.73–1.00; p = 0.044). There were no significant differences between the treatment groups in the rates of treatment-related adverse events or persistent elevations in liver enzymes.
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).