α-glucosidase inhibitors: Acarbose may reduce the risk of CV events, but the evidence for this effect is limited, conflicting, and inconclusive (Holman, 2018).
Biguanides: Metformin can cause lactic acidosis, and because of this, current guidelines recommend that metformin not be used in patients who have unstable CHF, patients who have CHF and are hospitalized, or patients who have CHF an eGFR of 30 ml/minute. Metformin can be used in patients with stable CHF and an eGFR > 30 mL/minute or a serum creatine < 1.5 mg/dL, and for these people, the risk of lactic acidosis is very low (Nesto, 2019). There is evidence that for patients who have type 2 diabetes, metformin may reduce the risk of developing CHF, reduce mortality from CHF, and improve the progression of the disease, but these conclusions have not been confirmed by large-scale research (Dziubak et al., 2018).
For certain type 2 diabetic patients, e.g., those who are obese, who have established CAD, or who are taking insulin, metformin can decrease the risk for and incidence of CV events like MI and stroke, and it may decrease mortality caused by diabetes, but the evidence for these benefits comes from two randomized, placebo-controlled studies, and several observational cohort studies (McCulloch, 2018b)
Colesevelam: Colesevelam can help reduce the risk of developing CAD.
Dipeptidyl peptidase IV (DPP- IV) inhibitors: The SAVOR-TIMI study clearly showed that the use of saxagliptin for patients with type 2 diabetes significantly increased the risk for hospitalization heart failure (Cryer 2019b). However, the prescribing information for the other DPP-IV inhibitors states that these drugs should be used cautiously in patients who have heart failure or kidney failure. At this time, no causal mechanism of action linking DPP-IV inhibitors with heart failure has been identified, it is not clear if the risk for heart failure is specific to saxagliptin or it is a class effect shared by all the DPP-IV inhibitors, or the increased risk is likely only in patients who have CVD, heart failure, or kidney disease (Dugan et al., 2019). A recent literature review and the ADA 2019 Standards of Care both concluded that alogliptin, linagliptin, and sitagliptin do not increase the risk for heart failure (ADA, 2019b). (Note: Alogliptin is no longer manufactured)
The DDP-IV inhibitors have not been shown to harm the development of ASCVD (Dugan et al., 2019).
GLP-1 receptor agonists: The GLP-1 receptor agonists are recommended by the ADA for type 2 diabetes and CVD (ADA, 2019). Moreover, for patients whose HbA1c is not controlled by metformin or who cannot take metformin (ADA, 2019).
Liraglutide has an FDA-approved use for reducing the risk of major CV events: death from CV, MI, and stroke.
Research has confirmed that liraglutide can reduce the risk for significant CV effects, but this protective effect appears to vary between the GLP-receptor agonists (ADA, 2019b). Semaglutide may reduce this risk, but extended-release exenatide and lixisenatide do not appear to have this benefit (ADA, 2019b). Although the ADA recommends using GLP-1 receptor agonists for patients who have type 2 diabetes and CVD, the 2019 Standards of Medical Care Pharmacologic - Approaches to Glycemic Treatment states that for this situation, a GLP-1 receptor agonist with proven CVD benefit should be used. Proven CVD benefit means it has a label indication of reducing CV events. For GLP-1RA evidence strongest for liraglutide > semaglutide > exenatide extended-release (ADA, 2019).
There is no evidence that the GLP-1 receptor agonists increase the risk of developing heart failure or increase the risk of being hospitalized because of heart failure (ADA, 2019b).
SGLT2 receptor inhibitors: The SGLT2 receptor inhibitors are recommended by the ADA for patients who have type 2 diabetes and CVD, and canagliflozin and empagliflozin both have an FDA-approved use for reducing the risk of major CV events - death from CVD, MI, and stroke - in patients who have type 2 diabetes (ADA, 2019). Evidence from placebo-controlled trials of canagliflozin and empagliflozin clearly showed that both drugs significantly reduced death from CVD and reduced the incidence of MI and stroke (ADA, 2019b). The ADA also recommends using canagliflozin or empagliflozin for patients whose HbA1c is not controlled by metformin or who cannot take metformin and who have CHF, and again, there is strong evidence that these SLGLT2 receptors reduce the risk of hospitalization from CHF and they may prevent the development of CHF, as well (ADA, 2019b). The ADA 2019 Standards of Care - Pharmacologic Approaches to Glycemic Treatment states: Both empagliflozin and canagliflozin have shown a reduction in HF in CVOTs (Cardiovascular outcomes trials).
Sulfonylureas: The second-generation sulfonylureas used in the United States, glimepiride, glipizide, and glyburide, do not appear to increase the risk for major CV events (Powell et al., 2018). Compared to metformin DPP-IV inhibitors, GLP-1 receptor agonists, and thiazolidinediones, their risk for this is higher. However, data on sulfonylureas and CV risk have been limited to small studies that were not specifically designed to study the CV safety of the sulfonylureas, and direct, controlled trials of this issue have not been done (Powell et al., 2018).
There is little information about the sulfonylureas and the risk for heart failure, and the available data cannot be used to determine their safety vis a vis heart failure (Powell et al., 2018). It is interesting to note that the ADA recommends that for patients taking metformin, who have not attained glycemic control, and who have CHF, the sulfonylureas are considered a second-line choice to be used if an SGLT2 receptor inhibitor or a GLP-1 agonist is not successful.
Thiazolidinediones: Pioglitazone does not increase the risk of CV events or CVD disease-related death, and it may slow the progression of CVD (DeFronzo et al., 2019). Research on rosiglitazone and its increased risk for CV events have been inconclusive (Asleh et al., 2018). Both pioglitazone and rosiglitazone can increase the risk of developing heart failure, and the prescribing information for both drugs contains a US Boxed Warning stating that pioglitazone and rosiglitazone can cause or exacerbate CHF and that they should not be used for patients who have symptomatic heart failure or who have NYHA class III or IV heart failure.
Table 2: New York Heart Association Functional Classification
|Class I||Cardiac disease, but no symptoms and no limitations in ordinary physical activity, e.g., no shortness of breath when walking or climbing stairs|
|Class II||Mild symptoms (mild shortness of breath or angina) and slight limitation during ordinary activity|
|Class III||Marked limitation inactivity due to symptoms, even during less-than-ordinary activity, e.g., walking short distances (20-100 m). Comfortable only at rest|
|Class IV||Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients|
Insulin: Insulin has not been associated with an increased risk for CV events or CHF (cheng, 2019).
Amylinometic: Pramlintide has not been associated with an increased risk for major CV events (Herrman et al., 2016).