Aaron K.F. Wong

Effect of Metformin on Mortality in Patients With Heart Failure and Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (DM) plus chronic heart failure (CHF) is a common but lethal combination and therapeutic options are limited. Metformin is perceived as being relatively contraindicated in this context, although mounting evidence indicates that it may be beneficial. This study was carried out to investigate the use of metformin therapy for treating patients with DM and CHF in a large population-based cohort study. The Health Informatics Centre-dispensed prescribing database for the population of Tayside, Scotland (population ∼400,000) was linked to the Diabetes Audit and Research in Tayside Scotland (DARTS) information system. Patients with DM and incident CHF from 1994 to 2003 receiving oral hypoglycemic agents but not insulin were identified. Cox regression was used to assess differences in all-cause mortality rates between patients prescribed metformin and patients prescribed sulfonylureas with adjustment for co-morbidities and other therapies. Four hundred twenty-two study subjects (mean ± SD 75.4 ± 0.5 years of age, 46.2% women) were identified: metformin monotherapy (n = 68, mean age 75.5 ± 1.1 years, 48.5% women), sulfonylurea monotherapy (n = 217, mean age 76.7 ± 0.7 years, 45.2% women), and combination (n = 137, mean age, 73.4 ± 0.7 years, 46.7% women). Fewer deaths occurred in metformin users, alone or in combination with sulfonylureas, compared to the sulfonylurea monotherapy cohort at 1 year (0.59, 95% confidence interval 0.36 to 0.96) and over long-term follow up (0.67, 95% confidence interval 0.51 to 0.88). In conclusion, this large observational data suggest that metformin may be beneficial in patients with CHF and DM. These findings need to be verified by a prospective clinical trial.

AMP-activated protein kinase pathway: a potential therapeutic target in cardiometabolic disease.

AMPK (AMP-activated protein kinase) is a heterotrimetric enzyme that is expressed in many tissues, including the heart and vasculature, and plays a central role in the regulation of energy homoeostasis. It is activated in response to stresses that lead to an increase in the cellular AMP/ATP ratio caused either by inhibition of ATP production (i.e. anoxia or ischaemia) or by accelerating ATP consumption (i.e. muscle contraction or fasting). In the heart, AMPK activity increases during ischaemia and functions to sustain ATP, cardiac function and myocardial viability. There is increasing evidence that AMPK is implicated in the pathophysiology of cardiovascular and metabolic diseases. A principle mode of AMPK activation is phosphorylation by upstream kinases [e.g. LKB1 and CaMK (Ca2+/calmodulin-dependent protein kinase], which leads to direct effects on tissues and phosphorylation of various downstream kinases [e.g. eEF2 (eukaryotic elongation factor 2) kinase and p70 S6 kinase]. These upstream and downstream kinases of AMPK have fundamental roles in glucose metabolism, fatty acid oxidation, protein synthesis and tumour suppression; consequently, they have been implicated in cardiac ischaemia, arrhythmias and hypertrophy. Recent mechanistic studies have shown that AMPK has an important role in the mechanism of action of MF (metformin), TDZs (thiazolinediones) and statins. Increased understanding of the beneficial effects of AMPK activation provides the rationale for targeting AMPK in the development of new therapeutic strategies for cardiometabolic disease.

Insulin Resistance Is Highly Prevalent and Is Associated With Reduced Exercise Tolerance in Nondiabetic Patients With Heart Failure

OBJECTIVES The purpose of this study was to establish the prevalence of insulin resistance (IR) among nondiabetic chronic heart failure (CHF) patients and to seek factors associated with IR in CHF, including the relationship of IR to functional class, exercise capacity, and disease severity in CHF. BACKGROUND Several lines of evidence suggest that CHF is an IR state. The prevalence of IR in CHF and its relation to CHF have not been fully defined. METHODS Fasting insulin resistance index (FIRI) was assessed in a cohort of 129 consecutive CHF patients (mean age 69.2 +/- 10.4 years; 76% males; body mass index 27.4 +/- 4.4 kg/m(2)). Patients underwent cardiopulmonary exercise testing and peripheral endothelial function testing by reactive hyperemia peripheral arterial tonometry (RH-PAT). RESULTS Prevalence of IR as defined by FIRI > or =2.7 was 61% in our cohort of CHF patients. There was a significant correlation between IR and waist circumference (r = 0.37; p < 0.01), serum triglycerides (r = 0.34; p < 0.01), high-density lipoprotein cholesterol (r = -0.22; p = 0.02), and serum leptin (r = 0.39; p = 0.03). Insulin resistance increased significantly with worsening New York Heart Association functional class (p < 0.01). The CHF patients with IR had a significantly lower exercise capacity and peak oxygen consumption than patients with an FIRI <2.7. The RH-PAT ratio was significantly lower in CHF patients with IR compared with CHF patients with an FIRI <2.7 (1.6 +/- 0.3 vs. 2.0 +/- 0.5; p < 0.05). CONCLUSIONS Insulin resistance is highly prevalent among nondiabetic CHF patients and is associated with decreased exercise capacity in patients with CHF. (Insulin Resistance: Heart Failure; NCT00486967).

The effect of metformin on insulin resistance and exercise parameters in patients with heart failure

Chronic heart failure (CHF) is an insulin‐resistant state. The degree of insulin resistance (IR) correlates with disease severity and is associated with reduced exercise capacity. In this proof of concept study, we have examined the effect of metformin on IR and exercise capacity in non‐diabetic CHF patients identified to have IR.

Insulin resistance: a potential new target for therapy in patients with heart failure.

There is increasing evidence to suggest that chronic heart failure (CHF) is an insulin resistant (IR) state and that the degree of IR correlates with the severity and mortality of CHF. The pathophysiology of IR in CHF has yet to be fully defined. Additionally, it remains to be determined if IR is merely a marker reflecting the severity of CHF or whether it contributes to the disease in CHF. If IR is truly a culprit that worsens CHF, it will potentially be a new target for therapy as strategies that can reverse IR in CHF may potentially result in an improvement in symptoms and even mortality in these patients. However, there are concerns regarding the use of certain insulin sensitizers, most notably, the thiazolidinediones (TZDs) which have been associated with increased risk of hospitalizations for CHF. Despite previous concerns of lactic acidosis (LA), there is now evidence that metformin may not only be safe but could potentially be useful in the setting of CHF. There are now ongoing prospective studies, including the TAYSIDE study, to determine if reversing IR with metformin will have beneficial effects in patients with CHF.

Thrombin generation and fibrinolytic activities among patients receiving reduced-dose alteplase plus abciximab or undergoing direct angioplasty plus abciximab for acute myocardial infarction

The purpose of this study was to determine the impact of these 2 reperfusion strategies (reduced-dose alteplase plus abciximab or direct angioplasty plus abciximab) on fibrinolytic and thrombin generation activities. The effect of reduced-dose alteplase plus abciximab and direct angioplasty plus abciximab on hemostatic factors is unknown. Of 70 patients with acute myocardial infarction of < or = 6 hours, 34 were randomized to reduced-dose alteplase (35 to 50 mg in 1 hour) and 36 to direct angioplasty. A standard bolus and infusion dose of abciximab was administered to all patients. Blood specimens were collected at baseline, and at 1, 4, 12, and 24 hours. The following parameters were assayed: fibrinogen, plasminogen and antiplasmin activities, tissue plasminogen activator antigen, D-dimer, prothrombin fragments F1 + 2, and thrombin/antithrombin III complexes. Among patients treated with reduced-dose alteplase plus abciximab, the fibrinogen level decreased by 28.4% in the first hour (11.7 +/- 3.4 vs 7.8 +/- 2.5 micromol/L, p <0.001). Correspondingly, plasminogen and antiplasmin activities decreased by 43.8% (p <0.001) and 59.1% (p <0.001), respectively. Prothrombin fragments F1 + 2 increased from 2.2 +/- 1.7 to 4.2 +/- 1.6 nmol/L (1 hour) (p <0.001) and thrombin/antithrombin III increased from 16.3 +/- 15.0 to 33.5 +/- 19.9 microg/L (1 hour) (p <0.001). Conversely, in the direct angioplasty group, there was a marginal elevation in fibrinogen level at 1 hour (10.2 +/- 2.4 vs 10.6 +/- 2.0 micromol/L, p = 0.064) despite a significant reduction in plasminogen and an increase in tissue plasminogen activator levels. There was no significant change in prothrombin fragments F1 + 2 and thrombin/antithrombin III levels. Thus, there was considerable fibrinolytic activity with reduced-dose alteplase plus abciximab; thrombin generation was not prevented. Among patients treated with direct angioplasty, there was some endogenous fibrinolytic activity, but there was no significant thrombin generation.

Insulin sensitization therapy and the heart: focus on metformin and thiazolidinediones.

Chronic heart failure (CHF) is an insulin-resistant (IR) state and the degree of IR is related to disease severity and poor clinical outcome in CHF. IR may be pathophysiologically linked with CHF. Therefore, IR may represent a new target for treatment in CHF. Metformin and thiazolidinediones (TZDs) are effective diabetic therapies that are insulin sensitizers. TZDs are contraindicated in CHF because their use is associated with increased incidence of CHF as a result of their effects on renal sodium reabsorption and vascular permeability. There is evidence to suggest that metformin may be both safe and useful in CHF.

067 Metformin in insulin resistant LV dysfunction, a double-blind, placebo controlled trial (Tayside trial)

Introduction Chronic heart failure (CHF) is increasingly recognised as an insulin resistant state and the degree of insulin resistance (IR) has been shown to correlate with disease severity and clinical outcome. However, these association studies do not distinguish between cause and effect. It is not certain if IR is merely a marker reflecting the severity of disease in CHF or if it is the culprit in the pathogenesis of CHF. If it is a culprit that worsens CHF, improving it may lead to better clinical outcome. Aims The purpose of our study was to determine if reversing IR in non-diabetic CHF patients results in clinical benefits. Methods and Results In a double-blind, placebo controlled trial, 62 non-diabetic insulin resistant CHF patients (mean age, 65.2±8.0 yrs; male, 90%; LVEF, 32.6±8.3%; NHYYA I/II/III/IV 11/45/6/0) were randomised to receive 4 months of either metformin (n=39, 2 g per day) or matching placebo (n=23). IR was defined by Fasting Insulin Resistance Index (FIRI) of ≥2.7. Cardiac-pulmonary exercise testing, echocardiography, flow mediated dilatation, EndoPAT (a measurement of endothelial dysfunction), 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, anthropometric measurements, FIRI and biomarkers were assessed at baseline and after 4 months of intervention. Compared to placebo, metformin decreased FIRI (from 5.8±3.8 to 4.0±2.5, p<.001), decreased fasting glucose (from 5.6±0.6 to 5.2±0.4 mmol/L, p=0.005), reduced fasting insulin (from 26.8±14.3 to 20.2±10.4 mU/L, p<.001), reduced serum HbA1c (from 5.7±0.3% to 5.5±0.3%, p=.002), decreased serum leptin (from 16.6±23.3 to 12.1±16.5 ng/ml, p<0.05) and resulted in a weight loss of 1.9 kg (p<.001). Metformin treatment significantly improved NYHA functional class (from 1.89±0.5 to 1.75±0.5, p=0.046). Although peak exercise parameters and endothelial function did not differ between treatment groups, sub-maximal parameters were significantly improved with metformin therapy, notably VE/VCO2 slope (from 32.9±15.9 to 28.1±8.8, p=0.05) and ventilatory class (from 1.90±0.9 to 1.5±0.9, p=0.021). Conclusion This novel study provides supportive evidence that metformin is a safe treatment in non-diabetic CHF which improves glucose homeostasis but more importantly, results in significant improvement in NHYA class, VE/VCO2 slope and ventilatory class, all of which are important prognostic markers in CHF. Reversing IR may represent a new therapeutic strategy in CHF.

P13 Anti-inflammatory effects of metformin – useful in cardiovascular disease?

Background Metformin is the first line drug treatment for type 2 diabetes (T2D). Along with its anti-hyperglycaemic properties, metformin is also associated with beneficial effects in cardiovascular disease (CVD). In observational studies, metformin has been associated with fewer adverse CV events.1 How metformin induces these effects is unclear as its mechanism of action is still to be determined. Inflammation, including NF-κB signalling, has been recognised as a contributing factor to both diabetes and CVD with metformin recently reported to have effects upon inflammatory signalling.2,3 In this study, we have utilised primary cells and human plasma to investigate the anti-inflammatory effects of metformin and how this may be useful in CVD. Results In mouse hepatocytes, TNFα-dependent IκB degradation and expression of pro-inflammatory mediators were inhibited by metformin and the IKKβ inhibitor BI605906. These effects upon NF-κB signalling could be separated from metabolic effects as BI605906 did not replicate metformin’s actions upon lipogenic gene expression, glucose production or AMPK activation. Analysing the plasma from a non-diabetic heart failure cohort,4 metformin use was associated with suppression of several plasma cytokines. Conclusion This study has demonstrated that the anti-inflammatory effects of metformin are separate from its anti-hyperglycaemic actions. This knowledge indicates that metformin may be harnessed for use in ‘at risk’ CVD groups irrespective of diabetes status. References Evans, et al. Diabetologia 2006;49:930–6 Isoda, et al. Arteriosclerosis, Thrombosis, and Vascular Biology 2006;26:611–7 Woo, et al. PLoS One 2014;9:e91111 Wong, et al. European Journal of Heart Failure 2012;14:1303–10

011 HbA1c and mortality in diabetic individuals with heart failure: an observational cohort study

Background Controversy exists regarding the importance of glycaemic control in patients with type 2 diabetes mellitus (T2DM) and chronic heart failure (CHF) based on conflicting reports that had used a single baseline HbA1c. Objective To examine the relationship between the mean of all HbA1c measures after CHF diagnosis and outcome in a large cohort of T2DM patients with incident CHF. Design Retrospective, observational cohort study. Setting Tayside, Scotland. Patients T2DM patients with incident CHF between 1993 and 2010. Measurement A weighted mean HbA1c was calculated using all available HbA1c measures following CHF diagnosis and patients were grouped into five categories of HbA1c (≤6%, >6–≤7%, >7–≤8%, >8–≤9% and >9%). We subsequently compared diet and drug treated populations. The relationship between mean HbA1c and all-cause deaths after CHF diagnosis was assessed. Results 795 patients with T2DM met study criteria. Median follow-up of 3.8 years saw 491 (61.8%) deaths. Cox regression model, adjusted for all other significant predictors, with the middle HbA1c category (>7–≤8%) as the reference, showed a U shaped relationship between HbA1c and outcome. (<6% [HR 95% CI 1.78 (1.26 to 2.52)]; >6–≤7% [1.29 (1.01 to 1.66)] and >9% [1.38 (1.03 to 1.84)]. We found a similar relationship in the drug treated sub-group. However in the diet only group, low HbA1c was associated with the lowest risk of death (≤7% [0.17 (0.07 to 0.39)]). Conclusions In patients with T2DM and CHF, our observational study shows that in drug treated patients there was a U shaped relationship between HbA1c and mortality with the lowest mortality risk in patients with modest glycaemic control (HbA1c, >7–≤9%). However in diet treated patients, lower HbA1c was associated with lower mortality risk.