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1.
The glucose treatment goal for most patients with diabetes mellitus is to achieve a hemoglobin A1c < 7% and avoid wide swings in blood glucose. Hemoglobin A1c goals may be higher or lower for individual patients depending on clinical presentation. For example, less stringent A1C goals (e.g., <8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin [72].
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2.
Diabetes mellitus is a major risk factor for CVD, which warrants more aggressive treatment of other common CVD risk factors (e.g., overweight or obesity, high blood pressure, dyslipidemia, cigarette smoking) [73].
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3.
Patients with diabetes mellitus have more aggressive thresholds for implementing lipid therapy. Patients with diabetes mellitus 40–75 years of age benefit from at least moderate-intensity statin therapy, regardless of estimated 10-year atherosclerosis CVD (ASCVD) risk. Patients with diabetes mellitus with CVD or multiple CVD risk factors might best benefit from high intensity statins [50].
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4.
While some uncertainty exists in the degree by which glucose control alone reduces CVD, clinical trial evidence supports intensive glycemic control may significantly reduce coronary events without an increased risk of death; however, the optimum mechanism, speed, and extent of HbA1c reduction may differ with different populations [74].
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5.
Metformin has favorable effects on CVD risk factors (glucose, insulin, lipids, body weight, and possibly blood pressure), and is often a first line agent when treating type 2 diabetes mellitus. While data supports metformin in reducing CVD risk, the robustness of CVD outcomes data is lacking relative to some other anti-diabetes agents. Thus, metformin is considered as providing a potential benefit in reducing CVD [75]. A confounder is that metformin (and comprehensive lifestyle management) was commonly used as background therapy for CVD outcomes trials of other anti-diabetes agents that have demonstrated reduction in CVD risk. Thus, metformin and weight management and physical activity often remain first-line therapies for patients with type 2 diabetes mellitus [75]. Additional pharmacotherapy may include anti-diabetes mellitus agents known to have CVD outcomes benefits, [e.g., some sodium glucose transporter 2 (SGLT2) inhibitors and some glucagon like peptide-1 (GLP-1) receptor agonists], whose use should be considered independently of baseline hemoglobin A1c or individualized hemoglobin A1c goal [75].
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6.
SGLT2 inhibitors reduce glucose levels and contribute to modest weight loss. Clinical trials support empagliflozin and canagliflozin as effective in treating atherosclerotic CVD, and empagliflozin, canagliflozin, and dapagliflozin as effective in treating heart failure. In patients with atherosclerotic CVD or heart failure treated with comprehensive lifestyle intervention and metformin, SGLT2 inhibitors having CVD benefits should be considered as next line therapy [4], [75].
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7.
Some GLP-1 receptor agonists have clinical trial evidence supporting a reduction in atherosclerotic CVD (e.g., liraglutide, semaglutide, dulaglutide). In patients with atherosclerotic CVD treated with comprehensive lifestyle intervention and metformin, GLP-1 receptor agonists having CVD benefits should be considered as next line therapy [4], [75].
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8.
Sulfonylureas have neutral effects on CVD; but sulfonylureas increase body weight and increase the risk of hypoglycemia. Severe hypoglycemia may promote cardiac dysrhythmias and increase the risk of sudden death. In patients with CVD, or at risk for CVD, sulfonylureas are among the last anti-diabetes mellitus agents to consider, except perhaps when cost is a major barrier to use of other anti-diabetes agents for glucose control [75].
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9.
Regarding other oral anti-diabetes mellitus agents, pioglitazone has some data to support reduction in atherosclerotic CVD; however, pioglitazone increases body weight and increases the risk of congestive cardiomyopathy. Dipeptidyl peptidase-4 inhibitors have a neutral effect on body weight and atherosclerotic CVD; saxagliptin may increase the risk of hospitalization for heart failure [75].
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10.
Regarding other injectables (beyond GLP-1 receptor agonists), insulin increases the risk of weight gain, increases the risk of hypoglycemia, but generally has a neutral effect on atherosclerotic CVD and heart failure [75].
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