Subjects and methods
Patients
We included 40 patients with chronic HF and dysregulated T2D (HbA1c≥7.5% (58 mmol/mol)). The patients were stable on optimal HF medication, in New York Heart Association (NYHA) class 2–3, and had left ventricular ejection fraction (LVEF)≤45%. We excluded patients who had significant cardiac valve disease, physical or psychological disability, severe angina, were unable to give informed consent, and whose age was below 18 years.
Design
Patients were recruited and randomized 1:1 between September 2010 and November 2012 in blocks of 8–4 months of either optimization (OPT) or no optimization (non-OPT) of glycemic control by drawing sealed envelopes in an open-labeled design. All patients were assigned to an outpatient diabetes clinic regardless of the randomization outcome, and they were told not to change their antidiabetic medication unless instructed to do so. The treatment target for the OPT group was HbA1c<7.5% (58 mmol/mol). Glycemic control was optimized by assessment of the daily blood glucose profile, adjustment of the insulin dosage, use of oral antidiabetics, and by supply of dietary advice provided by a trained dietician during contacts to the outpatient clinic and tailored to the individual patient's needs. Events of sensed or measured hypoglycemia (blood glucose <4 mM) were registered.
Patients randomized to the non-OPT group were instructed to continue their prescribed antidiabetic medication, but doses were reevaluated and reduced if necessary in case of hypoglycemia. Antidiabetic treatment was intensified if blood glucose measurements increased and HbA1c reached a level above 10% (86 mmol/mol). Anticongestive medications were not altered during the study period.
The primary outcome was defined as changes in left ventricular contractile reserve capacity function from baseline to follow-up measured by dobutamine stress echocardiography. Secondary outcomes were changes in resting echocardiographic measures of systolic and diastolic function, CPX capacity, muscle strength, fat and lean tissue mass measured by DXA, and N-terminal pro-brain natriuretic peptide (NT-proBNP).
Echocardiography
Echocardiography was performed by a single operator. Sonovue (Bracco, Initios Medical AB, Copenhagen, Denmark) was administered intravenously to enhance the left ventricular endocardial border delineation. LVEF was measured using the biplane-modified Simpson's method and wall motion scoring (WMS) by registering the contractile function of each segment. Peak systolic longitudinal mitral plane velocities during the ejection phase (S′max) were measured by tissue Doppler imaging and global strain by two-dimensional speckle tracking. Measurements were performed at rest and during the dobutamine stress test. However, Sonovue was only administered at rest and at peak dobutamine levels. We assessed the left ventricular diastolic function from the E/A ratio and E/e′ ratio. The parameters were estimated as the average of either three (sinus rhythm) or five (atrial fibrillation) consecutive heart beats. All echocardiographic investigations were blinded prior to analysis. During the dobutamine stress test, blood pressure and heart rate were registered, and echocardiography was performed after 3 min at each dobutamine stress level (5, 10, 20, 30, 40 µg/min/kg).
Six minutes hall-walk test
The patients performed a 6 min hall-walk test (6-MWT) on a straight 50 m indoor course after echocardiography and at least 30 min of rest.
CPX test
Patients performed a staged exercise bicycle test using a ZAN600 CPET (nSpire Health GmbH, D-97723 Oberthulba, Germany) with stages lasting 1 min and with increments of 10 W/min. Blood pressure, heart rate, and ECG were measured repeatedly every second minute. Oxygen consumption was measured continuously.
Muscle strength, body composition, and questionnaire
Muscle strength was measured by hand-grip strength (Jamar hydraulic hand dynometer (5030J1) Sammons Preston Rolyan, USA) according to the manufacturer by trained technical staff that were unaware of the randomization. The strength of each hand was defined as the average of three repeated measurements. Body composition was investigated by dual-energy X-ray absorptiometry (DXA) scanning on a Hologic Dicovery W (Santax Medico, Denmark). Whole-body lean tissue mass and fat tissue mass were measured, and the patients filled out the self-reported 12-item short form health survey (SF-12).
Blood samples
Blood samples were analyzed for creatinine, urea, electrolytes, alanine-aminotransferase, HbA1c, hemoglobin, low-density lipoprotein (LDL), triglycerides, non-esterified fatty acids (NEFA), insulin-like growth factor 1 (IGF-1), and NT-proBNP, cortisol, metanephrines, glucagon, C peptide, and insulin levels.
Statistics
On the basis of the previous investigations of the reproducibility of echocardiography, a design with 40 enrolled patients, an expected drop-out of 10%, a significance level of 5%, a power of 80%, and a coefficient of variation of ∼ 5%, we expected to be able to detect changes in left ventricular function in the order of 4%.
Baseline characteristics are presented as numbers for categorical variables and mean±SD or median (25–75th centile). For comparison between groups at baseline, Student's unpaired t test was used for normally distributed data, Wilcoxon rank sum test for skewed data, and Fischer's exact test. Outcome measurements were analyzed using a repeated measurement mixed-effects linear model (xtmixed) unless stated otherwise. p Values refer to the interaction of our intervention (ie, glycemic optimization) on time unless reported otherwise. Post hoc t tests based on the mixed effect model were used to assess development over time and during dobutamine stimulation in each group and between the groups. The results of the estimated mean difference are presented with SEM unless stated otherwise. Stata V.12 (College Station, Texas, USA) was used for statistics.
Ethics statement
Data were collected according to the protocol at the Department of Cardiology, Department of Endocrinology and Metabolism, and the Department of Medicine, Viborg, Denmark. The protocol was approved by the Central Denmark Region Committee on Health Research Ethics (ID: 20090047) and conducted according to the Declaration of Helsinki. Informed written consent was obtained from each patient. The project is registered at http://www.clinicaltrial.gov identifier NCT01213784.