Nutrition
Adequate composition of food intake is the cornerstone of managing nutritional disease, such as insulin resistance and type 2 diabetes. The official recommendations in Europe and the United States have consistently promoted food that contained little fat (approximately 25%) and a substantial amount of carbohydrates (45%–60%) [
60,
61]. The result of low fat and high carbohydrate consumption in the United States is an increasingly obese population [
62••]. The results of the INTERHEART study [
63] raised increasing concerns about these recommendations and led to reconsideration of the physiologic principles of metabolism: carbohydrate restriction improves glycemic control and reduces insulin fluctuations, which both are primary targets that do not need weight loss [
64••,
65•] but improve all features of the metabolic syndrome. Positive effects on insulin resistance, serum triglyceride and HDL levels, glucose control, and cardiovascular risk factors have been consistently demonstrated without any adverse effects, given the need to reduce antidiabetic medications stepwise (by 50% to 80%) to avoid hypoglycemia. The beneficial effects of low-carbohydrate diets have been confirmed in randomized long-term studies [
66,
67]. Noteworthy, beneficial effects of carbohydrate restriction on postmeal endothelial dysfunction were demonstrated in individuals with abdominal obesity and in those with atherogenic dyslipidemia [
68,
69].
Improved cardiac function by low-carbohydrate nutrition in type 2 diabetes was shown in a pilot study or indirectly via tight caloric restriction (400 kcal per day) in obese individuals with diabetes [
70,
71]. In severe obesity, randomized long-term studies have confirmed improvement in cardiac function after weight loss due to a low glycemic index diet or bariatric surgery [
72]. Large dietary studies based on reduced caloric intake by increased vegetable consumption have proven benefits for CAD risk [
73].
Extending their traditional recommendations, the American Diabetes Association in 2008 stated that low–glycemic index foods (ie, between 40 and 130 g/day of low-glycemic carbohydrate or less than 26% of a nominal 2000 kcal diet) that are rich in fiber and other macronutrients may improve outcome [
60].
There now is ample evidence that the nutritional therapy in type 2 diabetes with insulin resistance should be carbohydrate restriction. The available studies did not reveal any associated harm. If such a straightforward approach can alleviate a condition for which there is no known effective drug, its potential should be vigorously applied and explored.
Insulin Sensitizers
Because of the basic and adverse consequences of insulin resistance in patients with diabetes, this review focuses on insulin sensitizers such as biguanides, TZDs, and glucagon-like peptide 1 (GLP-1).
Metformin has been associated with improved outcome in both the prospective United Kingdom Prospective Diabetes Study and in patients with diabetes and HF in an observational Canadian study [
74,
75]. More recently, it was shown to improve LV diastolic function [
76]. Unfortunately, the use of metformin is contraindicated because of a perceived increased risk of lactic acidosis in HF, although the supporting evidence is lacking both for lactic acidosis and for the policy of stopping metformin 48 h before and after procedures in cardiac patients [
77]. A recent meta-analysis on the use of antidiabetic drugs in patients with HF concluded that metformin was not associated with any adverse events, but instead had a reduced mortality risk [
78].
TZDs were designed to increase insulin sensitivity. However, prospective studies are scarce because of the warnings against the use of TZDs in patients with HF symptoms [
79]. More recent data suggest that these risks are controllable and acceptable, being in the range of 5% to 15% for TZD-induced fluid retention that is part of the insulin-sensitizing action in the renal collecting ducts, but not necessarily a symptom of worsening myocardial function [
80]. In patients with diabetes without cardiac disease, diastolic function was improved by pioglitazone in an MRI study [
81]. In patients with HF (New York Heart Association class I–II), rosiglitazone improved glycemic control and did not adversely affect LV ejection fraction [
82]. Observational data and a retrospective study reported some reduction in the risk of death despite a smaller increase in the risk of readmission for HF by the use of TZDs [
83,
84]. Recently, concerns have been raised regarding the cardiovascular side effects of rosiglitazone, which now is available in the United States with additional restrictions but is not available any more in Europe.
First promising results were shown by GLP-1, which is secreted in the intestine in response to oral ingestion of glucose and stimulates insulin secretion, suppresses glucagon secretion, delays gastric emptying, and increases satiety. Because of its short half-life (1–2 min) due to cleavage by the ubiquitous dipeptidyl peptidase-4 (DPP-4), long-acting analogues of GLP-1 (exenatide, liraglutide) and inhibitors of DPP-4 (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin) have been developed.
GLP-1 does not cause hypoglycemia and has promising effects on the cardiovascular system. Nitric oxide–dependent endothelial function is increased in healthy individuals and in patients with diabetes [
85,
86]. Both GLP-1 and its analogue exenatide reduce ischemia/reperfusion injury in experimental studies. There are small human studies demonstrating beneficial effects of GLP-1 on LV ejection fraction in ST-elevation anterior MI with LV dysfunction after successful reperfusion [
87]; in coronary artery bypass grafting [
88]; and in HF [
89]. Also, the use of DPP-4 inhibitors demonstrated beneficial effects on postprandial glycemia, lipidemia, and oxidative stress in patients with type 2 diabetes [
90,
91] and, after a single morning dose, on postprandial endothelial function [
92]. DPP-4 inhibitors administered before an oral load of glucose, 75 g, demonstrated improved LV performance and mitigated stunning during dobutamine stress in patients with CAD, but undefined as for coexisting diabetes [
93]. Further studies are needed to determine whether synthetic GLP-1 mimetics and DPP-4 inhibitors are able to reproduce the beneficial effects of GLP-1. Some answers may be expected from ongoing studies on cardiovascular outcomes in patients with diabetes with GLP-1 analogues or DPP-4 inhibitors. These studies focus on diabetic metabolism (efficacy of lowering blood glucose in coronary care unit or of maintaining β-cell function), on the limitation of infarct size in acute coronary syndrome, or on global myocardial function in combination with granulocyte-colony stimulating factor and cardiovascular risk.
Glucose-lowering Antidiabetic Therapy
A large body of clinical studies intending to improve outcomes through tight glycemic control have produced controversial results and conflicting implications for optimal antidiabetic therapy in at-risk patients with CAD [
94••]. Despite the evidence that glucose control matters in patients with diabetes, more cautious approaches are required to avoid the risks from increased hypoglycemic events in tight control and other complications associated with the intensity of pharmacological treatment with several antidiabetic drugs simultaneously. These concerns led to new official treatment recommendations in 2008 [
95,
96] that suggested aggressive glucose control for patients in intensive care units with significant hyperglycemia (> 180 mg/dL, 10 mmol/L) to target glucose values between 90 and 140 mg/dL (5–7.8 mmol/L) and, for the other hospitalized patients, subcutaneous insulin for maintaining plasma glucose levels lower than 180 mg/d (10 mmol/L).
Given the major impact of postprandial hyperglycemia on metabolic complications, it is of concern that most therapeutic studies ignore this measurement. In addition, the different stages of insulin resistance should be taken into account for therapeutic strategies aimed at achieving an ideal glucose target. Finally, with respect to the nutritional induction of postprandial hyperglycemia (particularly in type 2 diabetes), carbohydrate restriction may circumvent the dangers of insulinemic and hyperglycemic peaks in insulin resistance without the risk of hypoglycemic events once antidiabetic therapy is adapted to the nutritional and metabolic changes, and without the risk of side effects from multiple glucose-lowering drugs. Applying such causal therapy, a fasting serum glucose level around 110 mg/dL and postprandial values around 140 mg/dL may be achieved.
In summary, patients with significant hyperglycemia benefit most from immediate insulin-based strategies aimed at improving glucose control, and those patients with stable glucose control should receive immediate carbohydrate restriction combined with meticulous adaptation of their individual antidiabetic regimen.