Diabetes and heart failure often coexist, with the prevalence of diabetes ranging from 10% to 47% in heart failure patients [1] and up to 40% or more in hospitalized heart failure patients [2]; the prevalence of heart failure in diabetic patients is 4 times higher than in the non-diabetic group [3]. Diabetes and heart failure can interact, and in patients with heart failure, either reduced ejection fraction heart failure (HFrEF) or preserved ejection fraction heart failure (HFpEF), the combination of diabetes can increase the risk of hospitalization and death. Several recent clinical trials have shown that novel glucose-lowering drugs improve the prognosis of patients with heart failure [4,5].
The choice of a glucose-lowering drug is based on multiple clinical considerations, including route of administration, hypoglycemic response, renal function, contraindications, and adverse effects. So, how should oral hypoglycemic agents be selected for patients with heart failure?
- Metformin
Metformin is primarily used clinically to lower basal and postprandial blood glucose in patients with diabetes. This drug is safe in heart failure patients with normal or moderately reduced renal function (i.e., glomerular filtration rate valuation eGFR > 30 ml/min/1.73 m²) who are stable, and has evidence of reduced mortality and heart failure hospitalization rates in heart failure patients compared with insulin and sulfonylureas [6]. However, there are no large studies analyzing the effect of metformin on the risk of heart failure in patients with type 2 diabetes, so it is unclear whether metformin is effective in reducing the risk of heart failure. Metformin is inexpensive and has some weight-reducing effects, so it is very widely used in the clinic.
But be aware that metformin is contraindicated in patients with acute heart failure and lactic acid buildup. Metformin should be used with great caution in patients with metabolic acidosis including ketoacidosis, heavy alcohol abuse, and during intravascular iodine contrast examinations, and needs to be taken strictly as prescribed.
- Sulfonylureas
Sulfonylureas include glimepiride, gliclazide, glipizide, glipizide, and glibenclamide (which are less commonly used in clinical practice because of their tendency to cause hypoglycemia). These drugs mainly stimulate the body to secrete insulin to play a role in lowering blood sugar. Monotherapy can reduce glycated hemoglobin by 1% to 2% and can be combined with a variety of other hypoglycemic drugs, but hypoglycemia is likely to occur when combined with lenazepam and insulin.
Sulfonylureas are divided into short-acting and intermediate- and long-acting formulations. If the patient’s postprandial blood glucose rises, the short-acting agent is preferred; if the fasting blood glucose rises or if both fasting and postprandial blood glucose are high, the medium- and long-acting agents are preferred.
Hypoglycemia is the most common adverse effect of sulfonylurea therapy. To reduce the risk of hypoglycemia, it is important to start with a small dose of sulfonylurea and gradually adjust the dosage according to blood glucose monitoring results, usually every 1 to 2 weeks. Long-term treatment with sulfonylureas should be closely monitored for hypoglycemia and weight gain.
There is still a lack of large studies of sulfonylureas in patients with heart failure combined with diabetes, and the limited data suggest that sulfonylureas may increase the rate of heart failure hospitalization in patients with diabetes. Based on the available data, metformin and SGLT-2 inhibitors are preferred over sulfonylureas in patients at high risk of heart failure and with established heart failure.
- Thiazolidinediones
Thiazolidinediones, which include rosiglitazone and pioglitazone, lower blood sugar by increasing the body’s sensitivity to insulin. Thiazolidinediones can decrease glycated hemoglobin by 1.0% to 1.5%. This class of drugs is less likely to cause hypoglycemia when used alone, but can increase the risk of hypoglycemia when used in combination with insulin or other proinsulin secretagogues.
Common adverse effects of thiazolidinediones include weight gain and edema, which can increase the risk of fractures. They have also been shown to increase the risk of heart failure events in patients with diabetes and are therefore not recommended for use in patients with established heart failure.
- Glucagon-like peptide-1 receptor agonists
Glucagon-like peptide-1 (GLP-1) receptor agonists include liraglutide, exenatide, and benalutide. These drugs can reduce glycated hemoglobin by 0.78% to 1.48% and also have a weight-reducing effect, with a low risk of hypoglycemia and a good safety profile when used alone.
The main adverse effects are gastrointestinal reactions such as nausea, vomiting, and anorexia, which generally decrease with the duration of treatment. It can be one of the options for starting glucose-lowering therapy in patients with type 2 diabetes, especially in overweight or obese patients.
Several large studies have shown that some GLP-1 receptor agonists such as liraglutide reduce the risk of major adverse cardiovascular events and death in patients with diabetes; in patients with diabetes combined with heart failure, the results were neutral, neither reducing nor increasing the risk of hospitalization for heart failure.
- DPP-4 inhibitors
Dipeptidyl peptidase-4 (DPP-4) inhibitors, including selegiline, vildagliptin, saxagliptin, alogliptin, and ligliptin, lower blood glucose by inhibiting DPP-4 in the body. DPP-4 inhibitors lower glycated hemoglobin by an average of 0.7% and lower both postprandial and fasting blood glucose. It can be used as monotherapy for type 2 diabetes or in combination with other glucose-lowering drugs.
In terms of risk of hospitalization for heart failure, there is no evidence of cardiovascular benefit with DPP-4 inhibitors. Selegiline and ligliptin are neutral for risk of hospitalization for heart failure and may be considered for the treatment of patients with heart failure combined with diabetes, whereas saxagliptin increases the risk of hospitalization for heart failure and is not recommended for patients with diabetes who are at risk of heart failure or have a prior history of heart failure.
- SGLT-2 inhibitors
Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are a new class of glucose-lowering drugs, including dagliflozin, enagliflozin, and cagliflozin. These drugs lower blood glucose by inhibiting the reabsorption of glucose by the kidneys so that excess glucose is never excreted from the urine. The main adverse effects are infections of the genitourinary system. Patients should also be aware of hypotension when using them.
Several studies have now demonstrated that SGLT-2 inhibitors reduce cardiovascular death or all-cause mortality in people at high risk for atherosclerotic cardiovascular disease and also significantly reduce the risk of heart failure hospitalization and cardiovascular death in patients with heart failure with reduced ejection fraction [5,6]. Therefore, SGLT-2 inhibitors can be considered as the preferred and essential therapeutic agent for heart failure patients with glomerular filtration rate valued eGFR >30 ml/min/1.73 m2 combined with diabetes mellitus.
- α-glucosidase inhibitors
The main α-glucosidase inhibitor class of glucose-lowering drugs used in clinical practice includes acarbose and voglibose. These drugs lower blood glucose by reducing and delaying the absorption of glucose in the small intestine, and are more effective against postprandial hyperglycemia. Glucosidase inhibitors do not stimulate insulin secretion, and the use of this class of drugs alone usually does not trigger hypoglycemia. Adverse effects are mainly gastrointestinal symptoms, bloating, abdominal pain, diarrhea, nausea, and vomiting.
There is insufficient clinical evidence to confirm that α-glucosidase inhibitors improve patient prognosis, especially in patients with heart failure. However, there are some unique features of this class of drugs. The diet of the Chinese population is dominated by carbohydrate-rich foods such as rice and noodles. Carbohydrates are absorbed 2 hours after a meal and are the main cause of elevated blood glucose. Glucosidase inhibitors can reduce the post-meal glucose absorption which is more in line with the actual dietary habits of the Chinese population. In addition, these drugs are not absorbed into the blood, especially voglibose, which is almost always excreted through the feces, and is taken with meals, not meals, and is very easy to adjust.
- Insulin agonists
Glinides are non-sulfonylurea insulinotropic agents, and these include drugs such as repaglinide and nateglinide. They can be used alone or in combination with biguanides and thiazolidinediones. The glinides are more effective in reducing postprandial glucose and, when used alone, generally do not cause hypoglycemia, but do increase body weight. There is insufficient evidence that this class of drugs improves prognosis.
Dr. Jing Cui of Beijing Anzhen Hospital, Capital Medical University, contributed to this article