Impact of Glucose-Lowering Drugs on CV Disease in T2 Diabetes
Impact of Glucose-Lowering Drugs on CV Disease in T2 Diabetes
It is conclusively established that the microvascular complications of diabetes (retinopathy, nephropathy, and neuropathy) are directly related to the severity and duration of hyperglycaemia, as reflected by the HbA1c. However, macrovascular complications are the primary cause of mortality, with myocardial infarction (MI) and stroke accounting for 80% of all deaths in T2DM patients. In a Finnish cohort of T2DM patients without prior MI, the 7-year incidence of MI was double that of non-diabetic subjects and similar to that of non-diabetic subjects with a prior MI. Recurrence of major atherosclerotic events in T2DM individuals with a prior MI is very high, ~6% per year, and death rate in T2DM patients is approximately two-fold greater than in matched non-diabetic individuals, even after adjustment for other CVRFs. Further, the relationship between glycaemia and increased CV risk starts within the normal blood glucose range without evidence of a threshold effect. In a population-based study of health claims in Ontario (379 003 with diabetes and 9 018 082 without diabetes), the transition from low-to-high CVD risk occurred 14.6 years earlier in the diabetic group.
The load of CVRFs includes hypertension, dyslipidaemia (reduced HDL-cholesterol, elevated triglycerides, and small dense LDL particles), obesity (especially visceral), physical inactivity, sub-clinical inflammation, and endothelial dysfunction. This cluster, referred to as metabolic or insulin resistance syndrome, consistently predicts atherosclerotic CVD (ATCVD). Many studies have reported an association between insulin resistance/hyperinsulinaemia and ATCVD in the general population. Moreover, in cross-sectional analyses insulin treatment in T2DM patients is consistently associated with the presence of ATCVD even after adjusting for multiple CVRFs. However, in most studies insulin resistance was not measured directly and control for statistical confounding was incomplete. Thus, in a cohort of carefully phenotyped non-diabetic subjects baseline insulin resistance (as measured by the euglycaemic insulin clamp technique) was independently associated with a small increment in the intima-media thickness of the common carotid artery (carotid intima-media thickness, C-IMT)—an antecedent of CVD and a measure of the atherosclerotic burden in T2DM—in men but not in women. Also, in a study of 11 644 T2DM patients attending hospital-based diabetes clinics insulin treatment was not an independent predictor of incident CVD. Finally, in the ORIGIN trial in 12 537 T2DM patients with prior CVD or CVRFs insulin treatment for a median of 6.2 years had a neutral effect on CVD outcomes and modestly reduced C-IMT progression.
Cardiovascular disease and diabetes are among the leading global and regional causes of death; between 1990 and 2016 CVD deaths increased by 25%. In a recent comparative assessment of the global burden of metabolic risk factors for CVD, 60% of worldwide CVD deaths in year 2010 was attributable to four modifiable cardiometabolic risk factors: high BP, blood glucose, BMI, and serum cholesterol. These findings are similar to those reported in the INTERHEART study in 2004.
Type 2 Diabetes and Atherosclerotic Cardiovascular Disease
It is conclusively established that the microvascular complications of diabetes (retinopathy, nephropathy, and neuropathy) are directly related to the severity and duration of hyperglycaemia, as reflected by the HbA1c. However, macrovascular complications are the primary cause of mortality, with myocardial infarction (MI) and stroke accounting for 80% of all deaths in T2DM patients. In a Finnish cohort of T2DM patients without prior MI, the 7-year incidence of MI was double that of non-diabetic subjects and similar to that of non-diabetic subjects with a prior MI. Recurrence of major atherosclerotic events in T2DM individuals with a prior MI is very high, ~6% per year, and death rate in T2DM patients is approximately two-fold greater than in matched non-diabetic individuals, even after adjustment for other CVRFs. Further, the relationship between glycaemia and increased CV risk starts within the normal blood glucose range without evidence of a threshold effect. In a population-based study of health claims in Ontario (379 003 with diabetes and 9 018 082 without diabetes), the transition from low-to-high CVD risk occurred 14.6 years earlier in the diabetic group.
The load of CVRFs includes hypertension, dyslipidaemia (reduced HDL-cholesterol, elevated triglycerides, and small dense LDL particles), obesity (especially visceral), physical inactivity, sub-clinical inflammation, and endothelial dysfunction. This cluster, referred to as metabolic or insulin resistance syndrome, consistently predicts atherosclerotic CVD (ATCVD). Many studies have reported an association between insulin resistance/hyperinsulinaemia and ATCVD in the general population. Moreover, in cross-sectional analyses insulin treatment in T2DM patients is consistently associated with the presence of ATCVD even after adjusting for multiple CVRFs. However, in most studies insulin resistance was not measured directly and control for statistical confounding was incomplete. Thus, in a cohort of carefully phenotyped non-diabetic subjects baseline insulin resistance (as measured by the euglycaemic insulin clamp technique) was independently associated with a small increment in the intima-media thickness of the common carotid artery (carotid intima-media thickness, C-IMT)—an antecedent of CVD and a measure of the atherosclerotic burden in T2DM—in men but not in women. Also, in a study of 11 644 T2DM patients attending hospital-based diabetes clinics insulin treatment was not an independent predictor of incident CVD. Finally, in the ORIGIN trial in 12 537 T2DM patients with prior CVD or CVRFs insulin treatment for a median of 6.2 years had a neutral effect on CVD outcomes and modestly reduced C-IMT progression.
Cardiovascular disease and diabetes are among the leading global and regional causes of death; between 1990 and 2016 CVD deaths increased by 25%. In a recent comparative assessment of the global burden of metabolic risk factors for CVD, 60% of worldwide CVD deaths in year 2010 was attributable to four modifiable cardiometabolic risk factors: high BP, blood glucose, BMI, and serum cholesterol. These findings are similar to those reported in the INTERHEART study in 2004.
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