Diabetes mellitus and stroke: A clinical update

Table 1 Risk of stroke in diabetes mellitus from different study populations

Study population	Follow-up (yr)	Relative risk (95%CI), gender
Framingham study, 5209 persons, 30-62 years old[10]	20	2.5 (M)
		3.6 (F)
Honolulu Heart Program, 7598 men, 45-70 years old[11]	12	2.0 (1.4-3.0)
United States, Nurse Study, 116177 women, 30-55 years old[12]	8	3.0 (1.6-5.7)
Finland, 1298 persons, 65-74 years old[13]	3.5	1.36 (0.44-4.18) M
		2.25 (1.65-3.06) F
Sweden, 241000 persons, 35-74 years old[14]	8	4.1 (95%CI: 3.2-5.2) M
		5.8 (95%CI: 3.7-6.9) F
United States (ARIC), 15792 persons, 45-64 years old[15]	6-8	2.22 (1.5-3.2)
United Kingdom, 7735 men, 40-59 years old[16]	16.8	2.27 (1.23-4.20)
Renfrew/Paisley, Scotland, 15406 person, 45-64 years old[17]	20	1.52 (0.72-3.21) M
		2.83 (1.63-4.90) F
Oldmsted County, Minnesota, 9936 persons, 40-70 years old[18]	15	3.5
United States, Hispanics, 503 persons, 70-90 years old[19]	3.5	3.5 M
		5.0 F
Asia, Australia, New Zealand, 161214 persons[20]	5.4	2.09
		2.49 Asian population

M: Male; F: Female.

Table 2 Stroke patterns and risk factors in diabetes vs non-diabetes group¹

Investigators, stroke type	Stroke study population	Stroke patterns diabetes vs non-diabetes	Significant stroke risk factors in diabetes
Jørgensen et al[27], 1994, all strokes	233 diabetes	ICH 1% vs 9%	Hypertension
	902 non-diabetes	Infarct 60% vs 68%
Olsson et al[28], 1990, all strokes	121 diabetes	ICH 6% vs 9%	Heart failure, ischaemic heart disease
	584 non-diabetes	Infarct 59% vs 55%
Kiers et al[29], 1992, all strokes	27 diabetes	ICH 19% vs 21%	N/A
	100 non-diabetes	Infarct N/A
Weir et al[30], 1997, all strokes	61 diabetes	ICH 7% vs 14%	Hypertension, hyperglycaemia
	750 non-diabetes	Infarct N/A
Megherbi et al[31], 2003, all storkes	937 diabetes	ICH 8.5% vs 11.5%	Hypertension
	3544 non-diabetes	Infarct 78% vs 72%
Arboix et al[32], 2005, ischaemic strokes	393 diabetes	Infarct 76% vs 51%	Ischaemic heart disease, previous ischaemic stroke, dyslipidaemia
	1447 non-diabetes
Hankey et al[33], 2013, all strokes	9795 diabetes	ICH 10% Infarct 82%	Hypertension, previous ischaemic stroke, ischaemic heart disease, nephropathy, high LDL cholesterol

¹Prospective series reported in the literature. ICH: Intracerebral haemorrhage; LDL: Low-density lipoprotein; N/A: Not available.

Table 3 Blood glucose targets for non-pregnant adults with diabetes¹

More stringent target (< 6.5%)

Short diabetes duration

Long life expectancy

T2DM treated with lifestyle or metformin only

No significant CVD/vascular complications

Less stringent target (< 8.0%)

Severe hypoglycaemia history

Limited life expectancy

Advanced microvascular or macrovascular complications

Extensive comorbidities

Long-term diabetes in whom general HbA1c targets are difficult to attain

Targets may be individualized based on:

Age/life expectancy

Comorbid conditions

Diabetes duration

Hypoglycaemia status

Individual patient considerations

¹More or less stringent targets may be appropriate for individual patients if achieved without significant hypoglycaemia. CVD: Cardiovascular disease; T2DM: Type 2 diabetes mellitus; HbA1c: Glycated hemoglobin.

Table 4 Relative risk for ischaemic stroke incidence dependent on history of hypertension and diabetes at baseline[64]

Variables	Relative risk (95%CI)
Hypertension only (sBP 140-159 mmHg)	1.29 (1.13-1.46)
Hypertension only (sBP ≥ 160/95 mmHg)	1.93 (1.48-4.16)
Diabetes only	2.48 (1.48-4.16)
Diabetes and hypertension (sBP 140-159 mmHg)	4.26 (2.90-6.25)
Diabetes and hypertension (sBP ≥ 160 mmHg)	4.90 (3.87-6.21)

sBP: Systolic blood pressure.

Table 5 Trials of statin therapy with individual participant data and relative reduction of cardiovascular event rate including stroke

Study	Randomized participants, age	Type of Prevention	Diabetes participants (%)	Intervention (mg/d)	Follow-up (yr)	Relative reduction of CVE rate
4S[92,93]	4444, 35-70 years old	Secondary	202 (4.50%)	S20-40	5.4	37%
CARE[94,95]	4159, 21-75 years old	Secondary	586 (14.10%)	P40	5.0	25%
LIPID[91,96]	9014, 31-75 years old	Secondary	1077 (11.9%)	P40	6.1	21%
ALLHAT-LLT[97]	10355, ≥ 55 years old	Primary	3638 (35%)	P40	4.8	11%
HSPC[89]	20536, 40-80 years old	Primary, secondary	5963 (29%)	S40	4.8	22% total 33% primary
ASCOT-LLA[98,99]	19342, 40-79 years old	Primary	2532 (13%)	A10	3.3	23%
CARDS[90]	2838, 40-75 years old	Primary	2838 (100%)	A10	3.9	37%

CVE: Cardiovascular event; S: Simvastatin; P: Pravastatin; A: Atorvastatin.

Table 6 Recommendations for cardiovascular risk factor management in patients with diabetes

Condition	Supporting literature
Hyperglycaemia
Targeting HbA1c < 6.5% to reduce cardiovascular events is not beneficial and is harmful when compared with a target of 7.0%	ACCORD[56], ADVANCE[57]
Hypertension
BP < 140/90 mmHg improves risk of cardiovascular and cerebrovascular outcomes (33)	UKPDS[55]
Targeting sBP < 120 does not improve cardiovascular outcomes and is associated with increased risk of adverse side effects	ACCORD-BP[69]
Antagonist of renin-angiotensin system is associated with cardiovascular benefits	HOPE[71]
Dyslipidaemia
All patients age > 40 yr, with or without history of atherosclerotic vascular disease, should receive statin therapy	HPSC[89], CARDS[90]
Use of ezetimibe with statin therapy can improve cardiovascular outcome in patients with a recent acute coronary syndrome and LDL > 50 mg/dL (1.3 mmol/L)	IMPROVE-IT[100]
Use of fibrates may be effective in selected patients with HDL < 34 mg/dL (0.9 mmol/L) and triglycerides > 204 mg/dL (2.3 mmol/L)	FIELD[101]
Obesity
Intensive lifestyle intervention with diet, physical activity, and medical therapy improves quality of life and physical function	Look AHEAD[81]
Metabolic surgery has been shown to improve long- term cardiovascular outcomes	SOS[82]
Antiplatelet therapy
Aspirin use in acute coronary syndrome treatment and in secondary prevention has been established	ISIS-2[127]
Clopidogrel use in secondary prevention reduces more cardiovascular outcomes and causes fewer bleeding complications compared to aspirin in diabetic patients	CAPRIE[116]
In patients with acute TIA or minor stroke, combination of clopidogrel and aspirin is superior to aspirin alone for reducing risk of stroke in the first 90 d without increasing risk of haemorrhage	CHANCE[117]
Use of aspirin in primary prevention has not been shown to improve cardiovascular outcomes	JPAD[128]
Low-dose aspirin use for primary prevention of cardiovascular disease in adults who have a 10% or greater 10-yr cardiovascular risk, are not at increased risk of bleeding, and are willing to take daily aspirin for at least 10 yr	USPSTF[129]

ACCORD: Action to Control Cardiovascular Risk in Diabetes; UKPDS: United Kingdom Prospective Diabetes Study; ACCORD-BP: Action to Control Cardiovascular Risk in Diabetes-Blood Pressure; HOPE: Heart Outcomes Prevention Evaluation; CARDS: Collaborative AtoRvastatin Diabetes Study; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes; Look AHEAD: Look Action for HEAlth in Diabetes; CAPRIE: Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events; CHANCE: Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events; JPAD: Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes; USPSTF: United States Preventive Services Task Force;; sBP: Systolic blood pressure; LDL: Low-density lipoprotein; HDL: high density lipoprotein.