Stroke is the second most frequent cause of death worldwide and the second leading cause of long-term disability in industrialized countries. The incidence of stroke is considerable across the United States and European countries, with the subtypes of ischemic stroke and transient ischemic attack (TIA) being the most common events (80%–85%). Stroke incidence in European epidemiologic studies ranges from 114 cases/100,000 persons per year in France for first-ever stroke to 350 cases/100,000 persons per year in Germany for all stroke subtypes. Stroke prevalence estimates range from 1.5% in Italy to 3% in the United Kingdom and United States.

The epidemiologic Oxford Vascular Study analyzed the frequency of three types of vascular events (acute coronary, cerebrovascular, and peripheral) in a population of 91,106 inhabitants in Oxfordshire, United Kingdom, from 2002 to 2005. Cerebrovascular events (618 strokes and 300 TIAs), with a proportion of 45%, were more frequent than coronary vascular events, which affected 42% of the cohort and peripheral vascular events, with an incidence of 9%. The relative incidence of cerebrovascular events compared with coronary events was 1.19 (95% confidence interval [CI] 1.06–1.33) overall and 1.40 (1.23–1.59) for nonfatal events. Event and incidence rates rose steeply with age in all arterial territories ( Fig. 23.1 ). Similar data were shown by French investigators.

Age-specific event rates for nonfatal stroke ( red line ) , nonfatal myocardial infarction ( blue line ) , and nonfatal acute peripheral vascular events ( green line ) .

From Rothwell PM, Coull AJ, Silver LE, et al. Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories [Oxford Vascular Study]. Lancet. 2005;366:1773–1783.

The stroke incidence is higher in males than in females of the same age, based on age-adjusted data. The Global Burden of Disease (GBD) Study 2019 found that the age-standardized rate of stroke incidence globally decreased by 17.0% between 1990 and 2019 and was most pronounced in high-income countries, with a 33% decrease. The positive changes in stroke incidence are the result of a marked increase in primary care prescription of primary and secondary vascular preventive medications such as lipid-lowering, antihypertensive, and antithrombotic drugs and of some positive changes in lifestyle. Despite these positive developments, problems remain with patients’ lack of adherence to prevention strategies and with underuse of oral anticoagulation in patients with atrial fibrillation (AF) at high risk of stroke.

Stroke mortality rates have been decreasing consistently over time, with recent reports indicating a 56% reduction in stroke mortality between 1990 and 2019 in high-income countries. Such increased survival of stroke patients may be linked to advances in preclinical and hospital treatment in acute stroke (e.g., intravenous thrombolysis [IVT] and mechanical thrombectomy [MT]) and in neurorehabilitation.

The risk of stroke associated with diabetes has been assessed predominantly in people with type 2 diabetes because stroke is more common in that population than in the age group typical of persons with type 1 diabetes. Epidemiologic studies identified a twofold to fourfold increase in stroke risk for persons with diabetes, regardless of concomitant risk factors. In females, the risk is about 30% higher than in males. During the longest observation period of 30 years in the Framingham Heart Study, a 2.5- to 3.6-fold increased risk of stroke in patients with diabetes was found. The risk of stroke in people with diabetes is as high as that of people without diabetes who have already had a stroke.

Stroke risk in diabetes increases with diabetes duration: The duration of diabetes was independently associated with ischemic stroke risk according to data from the Northern Manhattan Study, adjusting for other risk factors. The observed risk increase associated with diabetes overall was 3% each year and tripled with diabetes duration of 10 years or longer ( Table 23.1 ).

Assuming a population-wide prevalence of diabetes of 10%, these epidemiologic findings indicate a diabetes-attributable risk of stroke of approximately 12%. Hence, one in eight cases of stroke may be attributable to diabetes. Taking into account overall stroke mortality in general and its observed increased risk in diabetes, cerebrovascular disease causes approximately 20% of deaths of patients with diabetes.

Not only in diabetes per se but also in prediabetic states, the risk for cerebrovascular disease is increased, although in general more modestly than with fully established diabetes. Prediabetes is defined as the condition in which glycemic variables are higher than normal but lower than the established diabetes thresholds. Prediabetes is a high-risk state for diabetes development: 5% to 10% of people with prediabetes will convert to diabetes each year.

A meta-analysis of 129 studies involving 10,069,955 individuals prediabetes showed a significant higher risk ratio for stroke of 1.14 compared with normoglycemic controls. Impaired glucose tolerance carried a higher risk stroke than impaired fasting glucose.

When impaired glucose tolerance was measured by oral glucose tolerance test (OGTT) as in the Japanese Hisayama study, 2-hour values of the OGTT of 11.1 mmol/L were associated with a more-than-doubled risk for stroke (in males, hazard ratio [HR] 2.71; in females, HR 2.19).

Glycated hemoglobin (HbA1c) concentrations are also associated with the risk of stroke even below diabetes thresholds. In an analysis of adults without diabetes participating in the community-based Atherosclerosis Risk in Communities (ARIC) study, HbA1c concentrations—adjusted for potential confounders and for other vascular risk factors—of greater than 6% were associated with two to three times increased risk of stroke. The adjusted HRs for ischemic stroke according to baseline HbA1c are displayed in Fig. 23.2 .

Adjusted hazard ratios for ischemic stroke according to baseline glycated hemoglobin. Blue line : Restricted-cubic-spline model with 4 knost; red line : 3-Knot linear spline model (knots at 5.0%, 5.5%, and 6.0%).

Modified with permission from Selvin E, Steffes MW, Zhu H, et al. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med. 2010;362:800–811.

Since it is not possible for ethical reasons to prospectively compare an antiglycemic treatment with an untreated control group, the only way to assess the therapeutic effect is to prospectively compare a group of conventionally treated patients with diabetes with a group of intensively treated patients. In the 1441 patients with type 1 diabetes (aged 13–40 years) enrolled in the Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study, intensive glucose management for 6.5 years reduced the risk of cardiovascular composite events (nonfatal MI, stroke, or cardiovascular deaths) significantly by 57% over a mean follow-up period of 17 years, compared with individuals under conventional treatment. However, the absolute numbers of stroke were low, with only one event in the intensive treatment group and five in the conventional treatment group. The target preprandial blood glucose in the intensively treated group was 70 to 120 mg/dL (<180 mg/dL postprandial); the mean HbA1c values were approximately 2% lower than in the conventional treatment group (7.4% vs. 9.1%).

In patients with type 2 diabetes in the UKPDS study, intensive treatment with sulfonylureas or insulin did not significantly reduce cardiovascular outcomes compared with conventional diet therapy. However, in the substudy within the UKPDS in which obese patients received metformin as a first-line treatment, the generally small risk of stroke was reduced significantly by 42% compared with the group receiving conventional treatment (3.3 vs. 6.2 events per 1000 patient-years).

Three more recent large long-term trials (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation [ADVANCE]; Action to Control Cardiovascular Risk in Diabetes [ACCORD]; Veterans Affairs Diabetes Trial [VADT]) also compared the effects of intensive versus standard treatment in individuals with long-standing type 2 diabetes and a high risk of cardiovascular and cerebrovascular events. In the ADVANCE, VADT, and the ACCORD studies, no difference in cardiovascular outcomes—including stroke—could be found between the two glucose-lowering strategies.

No beneficial effects of tight glucose management over a mean period of 5 years could be found in a meta-analysis of 34,533 patients with type 2 diabetes (HR, 0.96; 95% CI, 0.83–1.1). A similar result was communicated in a Cochrane review summarizing the findings from 34,912 patients with type 2 diabetes from 28 randomized trials. The duration of intervention varied from 3 days to 12.5 years. Targeting intensive glycemic control did not reduce the risk ratio (RR) of nonfatal stroke significantly (95% CI, 0.84–1.19).

Taken together, to date, insufficient data are available to prove that intensive and tight glycemic control per se improves occurrence of stroke—in particular in type 2 diabetes. Treatment of patients with a high risk of stroke must balance the risk of recurrent hypoglycemia against the potential advantages of lower targets of HbA1c.

In the UKPDS, the variables that predicted the 188 incident strokes in DM included duration of diabetes, age, sex, smoking, systolic blood pressure (SBP), dyslipidemia, and the presence of AF. Modifiable risk factors for stroke accompanying diabetes have been targeted for stroke prevention in several randomized controlled trials.

Twenty to thirty percent of ischemic strokes are caused by cardiac embolism, most commonly from the left atrium and its appendage in nonvalvular AF. Diabetes, together with previous stroke, hypertension, advancing age, congestive heart failure, female sex, and atherosclerosis, is one of the major risk factors for stroke in individuals with AF (see the discussion of pathophysiology and subtypes of ischemic stroke in diabetes) and counts for one point in the nine-point CHA ₂ DS ₂ -VASc score, which is used for the calculation of an individual’s stroke risk in AF.

Primary stroke prevention with adjusted-dose warfarin, a vitamin K antagonist (VKA), with a target international normalized ratio (INR) of 2.0 to 3.0, reduces the RR of first-ever stroke in individuals with AF with a moderate vascular risk profile by approximately two-thirds compared with a placebo (annual stroke risk 1.8% vs. 4.6%), with a slight increase in the annual rates of intracranial hemorrhage (0.4% vs. 0.2%) or major extracranial bleeding (approximately 2% vs. 1%). For secondary stroke prevention, warfarin with a target INR of 2.0 to 3.0 also reduces the risk of recurrent stroke significantly by approximately two-thirds compared with placebo (annual stroke risk 3.9% vs. 12.3%) and is associated with an annual increase in major bleeding (2.8% vs. 0.7%; HR, 3.20, 95% CI, 0.91–11.3). Aspirin is not an adequate strategy to replace warfarin or direct oral anticoagulants (DOACs) because it does not significantly reduce the risk of stroke. Particularly in older patients, aspirin is often prescribed with the assumption that it will cause fewer bleeding complications than warfarin. However, not only is aspirin not efficacious in stroke prevention in AF, but it also causes a similar rate of intracraniableeding compared with warfarin. The Birmingham Atrial Fibrillation Treatment of the Aged (BAFTA) trial compared warfarin and aspirin in patients aged 75 years or older with a 14% prevalence of diabetes and demonstrated a twofold increased stroke rate with aspirin versus warfarin without a significant difference in major intracranial or extracranial hemorrhage (1.9% vs. 2.0%).

Despite its great efficacy in stroke prevention, oral anticoagulation with VKAs such as warfarin is sometimes poorly managed; register data show that only approximately 50% to 70% of suitable patients receive no or inadequate anticoagulant treatment.

Four DOACs have been proven to be successful competitors with warfarin. The direct thrombin inhibitor dabigatran etexilate and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban were shown in large prospective trials to be at least as efficacious and safe as warfarin. These four DOACs have all shown noninferiority in prevention of ischemic stroke compared with VKAs, with better safety, consistently limiting the number of intracranial hemorrhages by about 50%.

The impact of diabetes on stroke preventive therapy with DOACs where evaluated in a meta-analysis, which showed that in patients with DM the relative and absolute risk reduction of the composite outcome of stroke and systemic embolism, CVD death, and intracranial bleeding compared with warfarin were even more pronounced than in patients without diabetes.

In general, oral anticoagulants are not used for prevention of strokes caused by arteriosclerosis. The only possible exception is a combination of low-dose rivaroxaban (2.5 mg twice daily) and aspirin (100 mg once daily), which showed superiority over rivaroxaban (5 mg twice daily) or aspirin alone in the COMPASS trial in risk patients with clinical atherosclerosis. In a stroke outcome-focused subgroup analysis, there was a significant better stroke prevention by the combination rivaroxaban plus aspirin in patients with DM compared with patients without DM with an RR of 0.63 (95% CI, 0.43–0.90) ( Table 23.3 ).

Carotid artery stenosis is one of the macrovascular complications of diabetes. The presence of an atherosclerotic stenotic lesion in the extracranial internal carotid artery or carotid bulb has been associated with an increased risk of stroke. Randomized trials have shown that carotid endarterectomy (CEA) in appropriately selected patients with carotid stenosis modestly reduces stroke risk compared with patients treated by medical management alone.

However, the risk of stroke in patients undergoing intensive contemporary medical treatment has fallen significantly since the mid-1980s. Recent estimates suggest that the stroke risk in patients undergoing contemporary best medical treatment is overlapping that of patients who have undergone surgery in historical randomized trials such that the advantages of CEA demonstrated in older trials in such patients are the subject of controversies.

In patients with symptomatic carotid artery stenoses, CEA was of some benefit for participants with 50% to 69% symptomatic stenosis (moderate-quality evidence) and highly beneficial for those with 70% to 99% stenosis (moderate-quality evidence). Therefore the 2021 guidelines from the American Heart Association/American Stroke Association (AHA/ASA) recommend CEA after nondisabling ischemic stroke within the past 6 months and ipsilateral severe (70%–99%) carotid artery stenosis, provided that perioperative morbidity and mortality risk is lower than 6%. Patients with asymptomatic carotid artery stenosis should receive lifestyle interventions and intensive treatment of all vascular risk factors. Prophylactic CEA performed with less than 3% morbidity and mortality is regarded as useful in highly selected patients with asymptomatic carotid stenosis of minimum 60%.

Carotid artery stenting (CAS) as an alternative to CEA has shown higher rates of periprocedural strokes, which were largely driven by more minor strokes following CAS than CEA. Rates of death, major stroke, ipsilateral stroke, and MI were comparable between CEA and CAS.

CAS as an alternative to CEA is reasonable in patients in whom anatomic or medical conditions are present that increase the risk for surgery (such as radiation-induced stenosis or restenosis after CEA). CAS may be considered particularly in patients with significant cardiovascular comorbidities predisposing to cardiovascular complications with CEA.

Both intervention methods, CEA and CAS, had not been studied in randomized trials exclusively in patients with diabetes. In CEA, both periprocedural and long-term risks are higher in patients with diabetes than without; for example, pooled data from the European Carotid Surgery Trial (ECST) and North American Symptomatic Carotid Endarterectomy Trial (NASCET) found a significant 1.45 periprocedural risk of complications for patients with versus without diabetes (9.7% vs. 7.0%; RR, 1.45; 95% CI, 1.05–2.02). For CAS in patients with diabetes, a meta-analysis showed a nonsignificantly increased risk of perioperative and long-term complications compared with patients without diabetes. However, the benefit of both carotid interventions for stroke reduction remains despite the potentially higher risk in patients with diabetes, as a higher rate of vascular events is also seen in the control arms without diabetes. Thus, in part, even a higher absolute risk reduction of strokes could be observed.

Patients with a recent cerebrovascular event and severe stenosis (70%–99%) of major intracranial arteries are at a high annual risk of approximately 23% for recurrent stroke in the territory of the stenotic artery, despite treatment with aspirin and standard management of vascular risk factors. As a promising prevention strategy, percutaneous transluminal angioplasty and stenting (PTAS) was studied in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial with early and long-term results. The enrollment of the study was halted after 451 randomized patients because of the high risk of stroke or death within 30 days of enrollment in the PTAS arm (self-expanding wingspan stent) relative to the medical arm. Of the participants, 46% had type 2 diabetes. The 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke, 12.5%; fatal stroke, 2.2%), almost threefold higher than in the medically managed group with 5.8% (nonfatal stroke, 5.3%; nonstroke-related death, 0.4%). Beyond 30 days, stroke in the same brain territory occurred in 13 patients in each group. An analysis of patient and procedural factors that may have been associated with periprocedural cerebrovascular events in the trial found that diabetes was one of the major factors that were significantly associated with ischemic events, with an OR of 4.5 (95% CI, 1.3–16.1) associated with diabetes. The early benefit of aggressive medical management over stenting with the wingspan stent for high-risk patients with intracranial stenosis persisted over the extended follow-up period of 32.4 months. Based on this study, in severe intracranial stenosis, the following aggressive medical management is recommended: dual platelet inhibition with aspirin at a dose of 325 mg/day together with clopidogrel at a dose of 75 mg/day for the first 90 days after the incident event; management of the primary risk factors such as elevated SBP and elevated LDL cholesterol levels; and management of secondary risk factors (diabetes, elevated nonhigh-density lipoprotein cholesterol levels, smoking, excess weight, and insufficient exercise) with the help of a lifestyle modification program. The corresponding targets of intervention were SBP of less than 140 mm Hg (<130 mm Hg in patients with diabetes) and an LDL cholesterol level of less than 70 mg/dL. Thus stenting in intracranial stenosis cannot be recommended at this time.

If one analyzes the patient characteristics in acute stroke studies, approximately one-fifth of all stroke patients have diabetes. The prevalence of DM ranges between 10% and 30%, depending on the cohort studied.

PSH occurs not only in the acute stroke phase in patients with preexisting DM but also in patients without a prior diagnosis of diabetes. PSH can occur in all subtypes of strokes. The frequency found in various studies depends on the following:

• 1.

  The definition of the threshold of hyperglycemia (fasting glucose from 6.0 to 7.8 mmol/L)

• 2.

  The definition of the duration of the acute poststroke period (12–96 hours)

• 3.

  The frequency of blood glucose testing (single test on admission vs. repeated single tests vs. continuous glucose monitoring)

• 4.

  The nutritional status of patients (no nutrition vs. parenteral nutrition vs. intravenous nutrition)

With a glucose limit value of 7.0 mmol/L, the frequency of PSH is approximately 40% to 50%, at least twice as high as the diabetes prevalence in stroke patients. PSH may have a dynamic progression with various patterns with respect to latency and duration of PSH, namely, “initial” or “delayed” PSH peaks as well as “two peaks” and permanent hyperglycemia. The PSH pattern distribution varied significantly between patients with and without diabetes; whereas patients with diabetes more frequently had permanent hyperglycemia, patients without diabetes more frequently had initial PSH peaks ( Table 23.5 . Only 15% of patients with diabetes but 70% of those without diabetes showed a permanent normoglycemic state within 24 hours poststroke.

This possible variability of PSH over time explains that frequencies and patterns of PSH in various studies depend on the respective times of glucose measures. This makes it difficult to interpret and compare different studies.

If one takes the previously described prevalence rates, half of patients with PSH have a preexisting disturbance of glucose metabolism such as diabetes or prediabetes. In nonpreexisting diabetes, a postulated cause of PSH is a neurometabolic “stress hyperglycemia” with the activation of the hypothalamus-pituitary-adrenal (HPA) axis with the release of cortisol and adrenaline and subsequent glycolysis and gluconeogenesis. The neuroanatomic correlates of central autonomic dysregulation in PSH were studied with magnetic resonance imaging (MRI) in 229 affected patients without diabetes with stroke. A clear and significant correlation between the occurrence of PSH and the location of the infarct in the right insular and operculum region could be detected. Both brain structures are involved in the regulation of the sympathetic nervous system.

The findings with regard to neuronal damage mechanisms of PSH mainly result from experimental studies performed on animals and a few patient examinations with functional cerebral imaging. These have shown that there is not one single damage mechanism but rather a complex interaction of various “neurotoxic” effects. Table 23.6 summarizes the potential direct and indirect mechanisms of neuronal damage by hyperglycemia during the acute phase of ischemic stroke.

Table 23.6

Hyperglycemic Damage Mechanisms in Acute Ischemic Stroke

Parenchyma toxicity (anaerobic/glucose metabolism)	Acidosis Lactate accumulation Increase of the NMDA receptor–dependent cellular calcium flux Inflammation Increased formation of free radicals Increased expression of matrix metalloproteinase 9 (MMP-9)
Vascular damage and perfusion defect	Endothelial dysfunction Reduced vessel reactivity Inflammation Prothrombotic state—for example, activation of plasminogen activator inhibitor 1 (PAI-1) Reduced NO production
Impairment of the blood-brain barrier	Edema formation Increased rate of hemorrhage
Noncerebral effects	Immune system Shift in fluid balance Disruption in peripheral perfusion
Consequences of the insulin deficit	Increased formation of free fatty acids with prothrombotic effect and reduction in vessel reactivity

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