ISCHEMIC STROKE / PREVENTION / RISK FACTORS

Diabetes mellitus

Created 20/02/2023, last revision 09/04/2023

AHA/ASA guidelines 2014 – secondary stroke prevention

TIA/stroke patients should be screened for diabetes (fasting glycemia, HbA1c or oGTT) (IIa/C)
the choice of test and timing depends on the referring physician, the effect of intercurrent disease should be excluded
HbA1c seems to be a more accurate method than other methods in the acute phase

Definition

diabetes is a syndrome characterized by the inability of the body to process glucose and maintain its levels within physiological limits due to absolute (↓ secretion) or relative insulin deficiency (↑ resistance), resulting in altered glycide, fat, and protein metabolism
it is a heterogeneous group of diseases that accelerates the development of atherosclerosis and potentiates the development of microangiopathy; the increased risk of thrombotic events is also related to concomitant dyslipidemia, endothelial dysfunction, platelet hyperreactivity, and impaired fibrinolytic balance
diabetes increases cardiovascular morbidity and mortality and is an independent risk factor for stroke
- the risk of stroke is 1.8 to 6 times higher compared to the non-diabetic population, and the risk increases with poor compensation
- the risk is higher in the 20-65 year old population (5-14 times higher) [Khoury, 2013]
- patients with DM have a worse prognosis for stroke (3 times higher mortality) and a 2 times higher risk of stroke recurrence

diabetes is often associated with metabolic syndrome X
- hyperglycemia (DM or impaired GTT), insulin resistance
- dyslipidemia (in DM, typically ↑ TG and LDL)
- arterial hypertension
- abdominal obesity (waist circumference ≥ 102cm in men, ≥ 88cm in women)
the risk of cardiovascular disease (CVD) is increased in the presence of other vascular risk factors
- management of risk factors associated with metabolic syndrome in type 2 DM (T2DM) is essential for stroke prevention

Causes of insulin deficiency

absolute – destruction of β-cells of the islets of Langerhans
relative
- abnormal insulin
  - abnormal insulin molecule (mutation)
  - defective conversion of preproinsulin to insulin
  - circulating antibodies against insulin or the receptor
- insulin resistance of the target tissue
  - receptor defect
  - post-receptor disorder

Classification

Type 1 diabetes mellitus (T1DM)

autoimmune (5-10%) x idiopathic (no autoantibodies present)
defect in insulin secretion; if untreated, associated with ketoacidosis
most common in adolescents, but also in adults (LADA – Latent Autoimmune Diabetes in Adults), often in non-obese individuals
exogenous insulin must be administered

LADA (Latent Autoimmune Diabetes in Adults )

slow-onset T1DM
diagnosis usually made in individuals > 30 years of age, usually mistaken for T2DM
positive antibodies (autoimmunity), slower progression and diabetes manifestations are milder
initially well controlled by diet and PAD, does not lead to diabetic ketoacidosis, but gradually insulin dependence develops (months – years)

Type 2 diabetes mellitus (T2DM)

mostly in adults
there is enough endogenous insulin to prevent ketoacidosis, but levels are often either subnormal or relatively inadequate due to low tissue sensitivity (tissue insulin resistance)
obesity may contribute to resistance

MODY (Maturity-onset diabetes of the young)

approx. 5% of T2DM cases
- a group of monogenic diabetic disorders with familial occurrence and a well-defined mode of inheritance (usually AD)
- approx. 6 types (MODY1-6)
early manifestation (childhood, adolescence or early adulthood)
independent of obesity, individuals do not have metabolic syndrome
pathophysiology: genetically determined β-cell dysfunction without evidence of autoimmunity
- MODY due to mutations in glucokinase (MODY2) (responsible for the sensitivity of the β-cell to glycemia)
- MODY due to mutations in transcription of factors responsible for regulating insulin production in the β-cells)

Gestational diabetes mellitus

a disorder of glucose metabolism that occurs during pregnancy
- it is caused by a transient increase in insulin resistance and usually resolves after delivery
- blood sugar levels are only slightly elevated due to gestational diabetes, so women have no obvious difficulties
- the increased amount of glucose reaches the baby via the placenta, leading to excessive growth and an increased risk of diabetes in adulthood. Mothers are also at increased risk of developing T2DM in later decades
risk factor:
- age > 30 years
- overweight
- smoking
- family history of DM
diagnosis is made using an oral glucose tolerance test (oGTT)
- between 24-28 weeks of pregnancy
- in women at risk between 16-18 weeks of pregnancy

Other specific types

genetic defects of pancreatic B-cells
- monogenic DM type MODY 1-6 (Maturity-onset diabetes of the young) – about 5% of T2DM
- mitochondrial DNA mutations
genetic defects causing insulin resistance (lipoatrophic DM)
diseases of the exocrine pancreas (pancreatitis, pancreatic tumor, cystic fibrosis, hemochromatosis)
endocrinopathies (Cushing’s syndrome, acromegaly, pheochromocytoma, hyperthyroidism, etc.)
iatrogenic DM
other genetic syndromes associated with DM (Down syndrome, Klinefelter syndrome, Turner syndrome)

Diagnostic evaluation

Dg. criteria for diabetes mellitus

Fasting Plasma Glucose (FPG) ≥ 6.7 mmol/L (≥ 120 mg/dL) (fasting > 8 hours) – repeated testing required
glycemia at any time during the day ≥ 11.1 mmol/l (≥ 200 mg/dL) regardless of the last meal
GTT (75g glucose in water) : ≥ 11.1 mmol/L (≥ 200 mg/dL)
- glucose tolerance test for the detection of gestational diabetes is slightly different (see here)
glycated hemoglobin (HbA1c) ≥ 48 mmol/mol
- normal value< 38
- border-line value 38-48
clinical symptoms (polyuria, polydipsia)

Impaired Fasting Glucose (IFG)

fasting glycemia 5.6 – 6.7 mmol/L (100.5-120 mg/dL)

Impaired glucose tolerance (IGT)

after /2h 7.8- 11.1 mmol/L (140-199 mg/dL)
more about glucose test here

Must be confirmed by repeated measurements

Management

→ management of acute hyperglycemia
→ management of acute hypoglycemia
→ continuous insulin therapy protocol

The main goals of long-term diabetes management

I. Achievement or approaching normoglycemia in the long term

intensive treatment of chronic hyperglycemia in diabetic patients reduces the risk of developing microvascular complications (positive effect on the development of macroangiopathy has not be proven)

II. Careful compensation of associated risk factors and comorbidities (especially in T2DM)

target BP < 130/80 mmHg
- monotherapy or combination; always use ACEI or sartan to prevent and treat DM nephropathy, in non-diabetics it reduces the risk of developing diabetes
correction of dyslipidemia
treatment of obesity
- in diabetic patients with BMI > 30.0 kg/m2, sibutramine or lipase inhibitors (orlistat) may be indicated in combination with diet and exercise or other pharmacotherapy
treatment and prevention of diabetic nephropathy (ACEIs, sartans)

pharmacological treatment differs between type 1 and type 2 diabetes
- T1DM requires insulin treatment
- T2DM treatment starts with lifestyle modification measures and metformin; if the combination of oral antidiabetic drugs and all measures fail to achieve the desired glycemic control, a decision must be made on adding insulin

Quality Indicators for Diabetes Care

*Target values for metabolic syndrome therapy*
Fasting glycemia ( ≥ 8 h after last meal) an indicator of the development of glycemia during the night and morning predictor of cardiovascular complications	≤ 6 mmol/L
Glycemia 1-2 hod. after meal independent risk factor for heart and large vessel disease	≤ 7,5 mmol/L
HbA1c (glycated hemoglobin) an indicator of long-term DM compensation – the so-called “long sugar” the more sugar in the blood, the more it binds to hemoglobin, the higher the risk of late complications (vascular, nervous) reflects the average glycemia in the previous 3 months (lifetime of the erythrocyte) previously HbA1c expressed in %, now in mmol HbA1c/mol Hb HbA1c value in mmol/mol corresponds to 10 times the original value in % – e.g. originally HbA1c 5.5% – now 55 mmol/mol	non-diabetics < 38 mmol/mol diabetics (well controled) 43-53 mmol/mol
Blood pressure → arterial hypertension	< 130/80 mmHg
Lipids → dyslipidemia
Body mass index (BMI)	19-25
Waist circumference (men/women)	< 94 cm / < 80 cm
The finding of borderline or mildly abnormal renal function (see below) should lead to more intensive treatment of diabetes and arterial hypertension to achieve the best possible compensation slightly elevated serum creatinine concentration (men 115-133 and females 107-124 µmol/L) decreased glomerular filtration rate (< 60 ml/min/1.73 m2, ≤ 1.0 ml/s/1.73 m2) microalbuminuria (30-300 mg/24 h) or albumin/creatinine ratio men 2.5-30, females 3.0-30 g/mol creat.) proteinuria > 300mg/24h

Non-pharmacological measures

diet
- diabetic diets with 175 g, 200 g or 225 g of carbohydrates or reduction diets
- limit the intake of animal fats, processed meat (sausages, minced meat, fast food) and juices
- increase intake of vegetable fats, nuts, fiber, coffee, and fish
physical activity
- take into account age, type of diabetes, weight and presence of associated complications
- e.g. at least 30 minutes of walking per day
weight reduction of at least 5-10%

Insulin

Peroral antidiabetics (PADs)

start therapy with the lowest possible dose
if there is an inadequate response, increase the dose, but do not use the maximum dose; instead, switch to a combination of antidiabetic drugs

Management of other vascular risk factors

→ overview of vascular risk factors

→ arterial hypertension