We propose that targeting the source of excess fuel rather than the destination of the fuel is the appropriate way to treat hyperglycemia in patients with diabetes and heart failure. Therapeutic approaches to lowering the substrate supply are especially important in the presence of heart failure, given the alterations in cardiac metabolism.
Diet and exercise improve glycemic control in patients with type 2 diabetes, as illustrated by the findings of several meta-analyses.
24 Exercise can benefit patients who already have diabetes and help to prevent type 2 diabetes in those who are at high risk. This is another example of lowering substrate supply. Given the epidemic of obesity in the United States, bariatric surgery has also had beneficial effects on glycemic control, as well as on cardiac function and metabolism. In participants in a study designed to define muscle metabolic and cardiovascular changes after bariatric surgery,
25 weight loss resulted in lower fasting glucose levels and in an early reversal of maladaptive processes, through a decrease in metabolic gene expression in the patients' systemic metabolism and skeletal muscle. This suggested a reversal of insulin resistance. Furthermore, left ventricular relaxation impairment, evaluated by means of tissue Doppler imaging, became normal 9 months after bariatric surgery.
25
Perhaps the best results in diabetic patients with heart failure have been obtained with metformin (1–2 g/d in divided doses) for glycemic control. Metformin decreases hepatic glucose production and decreases intestinal absorption of glucose.
26 In a systematic review and meta-analysis of controlled studies evaluating antidiabetic agents and outcomes in patients with heart failure and diabetes,
27 metformin was the only antidiabetic agent not associated with harm. Metformin was associated with reduced all-cause death, whereas TZDs were associated with an increased risk of hospital admission for heart failure. Results from another case-control study, nested within the General Practice Research Database cohort (United Kingdom), confirmed the benefits of trial-proven antifailure therapies in diabetic patients and supported the use of metformin-based treatments to lower glucose levels in heart-failure patients.
28 Compared with patients who were not given antidiabetic drugs, the current use of metformin monotherapy or metformin with other agents was associated with lower mortality rates. Those studies suggested that the use of metformin in patients with diabetes and heart failure is both safe and effective. However, metformin was previously considered to be contraindicated in patients with heart failure, because of the potential production of lactic acidosis. In 2006, the FDA removed the heart-failure contraindication from the use of metformin, although a caution still exists.
29
A retrospective cohort analysis of patients with diabetes and advanced systolic heart failure
30 revealed that patients who took metformin had a trend toward improved survival, compared with those who did not take metformin. One-year survival in metformin-treated and non-metformin-treated patients was 91% and 76%, respectively (relative risk, 0.37; 95% confidence interval [CI], 0.18–0.76;
P=0.007). Another study, of a national cohort of 6,185 patients with diabetes and heart failure who were being treated at Veterans Affairs Medical Centers, revealed that metformin therapy was associated with fewer deaths. The mortality rate in 232 patients who were given metformin was 16.1%, compared with 19.8% in 285 patients who were not given metformin (hazard ratio, 0.76; 95% CI, 0.63–0.92;
P <0.01).
31 Metformin is first-line therapy for noninsulin-dependent diabetes, but its use in patients with heart failure has been limited. Although an added benefit clearly appears to exist, there is still a need for prospective trials that involve the use of metformin in patients with heart failure.
Glucagon-like peptide (GLP-1) analogs such as exenatide (Byetta®, Amylin Pharmaceuticals, Inc.; San Diego, Calif) (FDA-approved in 2005) and dipeptidyl peptidase 4 (DPP-4) inhibitors such as sitagliptin (Januvia®, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.; Whitehouse Station, NJ) (FDA-approved in 2006) appear promising in that they augment the pancreatic response to meals, decrease gastric emptying, and reduce glucose levels without cardiovascular risk.
32–34 Alpha-glucosidase inhibitors such as acarbose inhibit the upper-gastrointestinal enzymes that convert complex polysaccharide carbohydrates into monosaccharides. This slows the absorption of glucose and results in a slower rise in postprandial glucose levels.
35 Sodium-glucose cotransporter 2 (SGLT-2) is the major cotransporter involved in glucose reabsorption in the kidney. Clinical trials are currently under way to investigate the safety and efficacy of SGLT-2 inhibitors such as dapagliflozin.
36,37 Finally, centrally acting drugs may be effective. Although traditionally used to treat Parkinson's disease and pituitary tumors, bromocriptine is a dopamine agonist approved by the FDA in 2009 as therapy for type 2 diabetes under the trade name Cycloset® (VeroScience LLC; Tiverton, RI).
38,39 The aforementioned therapies all have one thing in common: they lower the substrate supply without promoting substrate uptake. shows these therapeutic approaches.
| TABLE I. Therapies for Glycemic Control in Diabetic Patients with Heart Failure |
Lowering Agents