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European Journal of Heart Failure 2009 11(1):39-47; doi:10.1093/eurjhf/hfn018
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

A randomized trial of the impact of strict glycaemic control on myocardial diastolic function and perfusion reserve: a report from the DADD (Diabetes mellitus And Diastolic Dysfunction) study

Christina Jarnert1,*, Lena Landstedt-Hallin2, Klas Malmberg1, Anders Melcher3, John Ohrvik1, Hans Persson2 and Lars Rydén1

1 Cardiology Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden
2 Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
3 Clinical Physiology Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden

* Corresponding author: Department of Cardiology, Karolinska University Hospital, 171 76 Stockholm, Sweden. Tel: +46 8 517 700 00, Email: christina.jarnert{at}karolinska.se

See page 3 for the editorial comment on this article (doi:10.1093/eurjhf/hfn033)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Aims: Myocardial diastolic dysfunction (MDD) and impaired coronary flow reserve (CFR) are early signs of myocardial involvement in patients with diabetes. The important question of whether this may be reversed by glucose normalization has not been tested in a controlled clinical trial. We hypothesized that strict glycaemic control, particularly if insulin based, will improve MDD and CFR.

Methods and results: Thirty-nine type 2 diabetes patients (mean age 61.0 ± 7 years) with signs of diastolic dysfunction were randomly assigned to strict metabolic control by insulin (I-group; n = 21) or oral glucose lowering agents (O-group; n = 18). MDD and CFR were studied with Doppler-echocardiography including Tissue Doppler Imaging and myocardial contrast enhanced echocardiography. Fasting glucose (I-group = –2.2 ± 2.1; O-group –1.5 ± 0.8 mmol/L) and HbA1c were normalized (–0.6 ± 0.4 and –0.7 ± 0.4%, respectively) in both groups, but this did not significantly improve MDD in either of the groups (P = 0.65). There was no difference in CFR before and after improved glycaemic control.

Conclusion: The hypothesis that strict glycaemic control would reverse early signs of MDD and improve CFR in patients with type 2 diabetes could not be confirmed, despite achieved normalization. Whether it is possible to influence a more pronounced diastolic dysfunction, particularly in less well-controlled diabetic patients, remains to be established.

Key Words: Type 2 diabetes • Glucose lowering treatment • Myocardial diastolic dysfunction • Coronary blood flow • Echocardiography • Doppler tissue imaging

Received June 13, 2008; Revised August 27, 2008; Accepted October 23, 2008


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
Type 2 diabetes mellitus is associated with substantial cardiovascular morbidity and mortality1 mainly, but not only, related to coronary artery disease. The Reykjavik study recently revealed that there is a strong association between dysglycaemia and heart failure, even after adjustments for traditional risk factors including ischaemic heart disease. The relation between increasing levels of glucose and new onset of heart failure was almost linear making links between glucometabolic perturbations and myocardial dysfunction likely.2 Diastolic dysfunction is often the first manifestation of myocardial involvement in diabetic patients. A combination of myocardial metabolic and structural changes have been suggested as the underlying pathophysiological mechanism, among them hyperglycaemia and oxidative stress causing accumulation of advanced glycation end products and increased interstitial fibrosis.3,4 Other early expressions of cardiac involvement are endothelial dysfunction and decreased arterial elasticity, compromising myocardial microcirculation and coronary flow reserve (CFR).5–8

Preliminary observations suggest that early myocardial and microcirculatory dysfunction, induced by elevated glucose levels, are dynamic and may be reversed by improved metabolic control.9,10 This parallels observations that strict glycaemic control may retard the process of diabetes-related atherosclerosis11 and that early institution of glucose lowering agents already at the stage of impaired glucose tolerance or newly detected diabetes12 may decrease the number of subsequent coronary events.

Studies of the possibilities to improve early signs of myocardial dysfunction in diabetes patients by means of strict glycaemic control have been hampered by a lack of adequate techniques. Ultrasound technology is, however, available for the quantitative assessment of myocardial function13 and perfusion.14 Tissue Doppler allows direct quantification of diastolic left ventricular (LV) function as measured by early diastolic myocardial velocity. This parameter changes unimodally in the course of increasing diastolic dysfunction15 as opposed to the traditionally studied mitral inflow pattern, which changes in a bimodal way. Moreover, contrast-enhanced myocardial echocardiography has been used for the repetitive assessment and quantification of myocardial and muscular perfusion.14 It is one of few methods for repeated, in vivo assessments of myocardial blood volume.16,17 Preliminary observations by von Bibra et al.10 indicate that optimized glycaemic control, especially if insulin-based, may improve left ventricular diastolic function and myocardial blood flow reserve during stress. Since this observation was based on a pilot study it needs confirmation.

The DADD study tests the hypothesis that strict, in particular insulin based, glucose control improves diastolic function and myocardial flow reserve in patients with type 2 diabetes and early signs of diastolic dysfunction.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 References
 
Study population
A total of 121 patients with type 2 diabetes mellitus were screened for participation in the DADD study, out of which 40 comprised the study population (Figure 1).


Figure 1
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  		Figure 1 Flow chart for the study population.

 
The majority of screened subjects were recruited by advertisements in the local press, at the diabetes day care clinic at Karolinska University Hospital and primary care clinics in the Stockholm County Council and at the Stockholm Association for diabetes patients. Patients who were interested in participating were interviewed about their medical history by a research nurse. Those apparently free from cardiovascular disease and without ongoing insulin treatment were invited to the clinic. The subsequent screening process included a thorough case history, physical examination, and the following laboratory specimens; fasting plasma glucose (FPG), glycated haemoglobin A1c (HbA1c), serum creatinine and Glutamic Acid Decarboxylase (GAD) antibodies. The screened patients were investigated with transthoracic Doppler-echocardiography and Tissue Doppler Imaging (TDI). All tests were performed in the morning after 12 h of fasting.

Included patients fulfilled the following inclusion criteria: Type 2 diabetes mellitus, age between 40 and 70 years and an FPG ≥7.0 mmol/L or HbA1c >5.5% (Mono-S). At echocardiography, patients were required to have normal systolic and impaired diastolic function according to criteria outlined by the Mayo clinic18–20 as listed in Table 1. Exclusion criteria were ongoing insulin treatment, GAD antibodies, atrial fibrillation, clinical signs of ischaemic heart disease (defined as stable or unstable angina pectoris, previous or ongoing myocardial infarction), clinical signs or symptoms of heart failure or clinically significant valvular heart disease, symptomatic peripheral vascular disease, poorly controlled hypertension defined as a resting supine blood pressure of >160/95, impaired renal function defined as S-creatinine >150 µmol/L, signs of LV hypertrophy defined as septal wall thickness >13 mm, and echocardiographic recordings of insufficient quality (poor echo window). Patients recently (<3 months) started on beta-blockade, diuretics, blockers of the renin–angiotensin system (ACE-inhibitors or angiotensin receptor blockers) or statins were excluded as well as patients with any concomitant illness that could interfere with the completion of the study protocol (Figure 1).


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  		Table 1 Myocardial systolic and diastolic function at randomization by treatment group as defined by echocardiography and tissue Doppler imaging (number of patients)

 
Endpoints
The change in LV diastolic function as measured by TDI, comparing values obtained at baseline and after 4 months of intensified treatment was used as the primary endpoint. Secondary endpoints were changes in myocardial blood flow reserve as expressed by contrast-enhanced echocardiography and in LV systolic function as recorded by TDI.

Echocardiography
All echocardiographic investigations were performed at the same time of the day and in a constant relation to meals and other investigations with a Siemens Sequoia c512, rev 8.0, (Siemens Medical Systems, Mountain View, CA) equipped with a 4V1C transducer and designed for TDI and real-time echo contrast imaging (Contrast Pulse Sequencing). The echocardiograms, including flow velocity Doppler, were performed according to standards outlined by the American Society of Echocardiography.21–23 Left atrial (LA) volume was calculated in the apical four-chamber view by the single plane area length method.24 Left ventricular systolic function was assessed by calculating the Wall Motion Index (WMI) using a 17-segment model.25 The systolic function was considered normal if WMI ≤1.1.

Longitudinal LV myocardial velocities were measured with low gain pulsed tissue Doppler in the apical four-chamber view by positioning the sampling gate (3 mm) at the septal and lateral parts of the mitral annulus (during screening at the septal part only) and calculated as an average of the septal and lateral recordings. Systolic (S), early diastolic (É), and late diastolic peak velocities (Á) were determined from at least three representative cardiac cycles and expressed as the average of these values.

Diastolic function was assessed by the following variables: ratio of maximal mitral flow velocities (E/A, including a Valsalva manoeuvre), E/É, É, É/Á, and LA volume indexed for body surface area.

Myocardial contrast echocardiography
Low mechanical index myocardial contrast echocardiography (MCE) was performed at rest and during maximal dipyridamole (0.84 mg/kg) induced vasodilatation.

The contrast agent (SonoVue, Bracco, Milano, Italy) was given intravenously by means of an infusion pump (VueJect, Bracco Res.SA, Plan- les- Duates, Switzerland) at a rate of 0.8–1.0 mL/min with a parallel infusion of saline (180 mL/h) to assure constant blood concentration. Imaging started after at least 2 min of contrast infusion. Images were recorded in apical six-chamber views as clips comprising 250 frames at 20 frames/s resulting in 12.5 s acquisition time, at incremental micro-bubble replenishment to be digitally stored pending analysis. Micro-bubble destruction was set at a mechanical index of 1.9 and standardized to one heart cycle. No post-processing was used. Gain was adjusted for optimal visualization of contrast echoes in the myocardium. The signal intensity (SI) was measured off-line on a work station (Research- ArenaTM 1.0, TomTec Imaging Systems GmbH, Germany) with dedicated software (Axius Auto Tracking Contrast Quantification Siemens Medical Systems, Mountain View, CA). A region of interest (ROI) was outlined by hand from the four-chamber view limited to the septal wall excluding the most basal part to avoid areas less well reproduced due to uneven ultrasound intensity and attenuation artefacts. End-systolic frames were analysed and SI expressed as log compressed data during contrast replenishment fitted to an exponential function giving the two primary components of myocardial flow: the initial slope providing a measure of flow velocity and SIplateau that correlates to myocardial capillary blood volume,14,16 the product of which constitutes the myocardial blood flow index (MBFI). Another ROI was placed in the ventricular cavity, close to the septum, to measure blood pool SI. After log decompression the SIplateau was normalized for the blood pool SI to obtain a myocardial blood volume index (MBVI).

Study protocol
The study was designed as a Prospective, Randomized, Open, Blind Evaluation (PROBE) with all analyses performed by personnel unaware of treatment allocations (Figure 2). All eligible patients were randomly allocated either to insulin (I-group) or oral glucose lowering agents (O-group) with the aim of achieving strict metabolic control. The randomization list was generated by a computer and kept in sealed envelopes to be opened after the decision to include a patient in the study. The patients received standardized instructions with the intention of maintaining stable dietary habits and physical activity during the study period. Sulphonylurea treatment was stopped 2 weeks before randomization, while metformin treatment was maintained. All patients performed self-monitoring of blood glucose (using ACCU-CHEK® Compact Plus, Roche, Basel, Switzerland) and entered their FPG-values in a diary. The 4 month long study period commenced when the patient had reached the glycaemic target of a self-monitored FPG <5.0 mmol/L for at least three consecutive days or after a maximum titration period of eight weeks whatever came first. Patients in group I were started on a long lasting insulin analogue, glargine (Lantus®, Aventis Pharma, Stockholm, Sweden) administered once daily. Those not reaching the glycaemic target were in addition prescribed a rapid acting insulin analogue aspart (Novo Rapid®, Novo Nordisk, Copenhagen, Denmark) to meals. Insulin was up titrated until the set blood glucose target was achieved. Patients in Group O were treated with oral glucose lowering agents, always initiated with metformin (Metformin®, Meda). If the postprandial values were high after 3 weeks on metformin, repaglinide (Novonorm®, Novo Nordisk, Copenhagen, Denmark) was added. The treatment regimen was not changed during the four study months apart from minor adjustments related to hypoglycaemic episodes or gastrointestinal side effects. During the study period each patient visited the research clinic at least four times. In addition a study nurse contacted the patient every 2 weeks to check and discuss self-monitored blood glucose values. If needed the patient was offered extra visits.


Figure 2
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  		Figure 2 Study design.

 
An echocardiographic investigation including TDI and myocardial perfusion studies before and after dipyridamole infusion was performed before randomization and after 4 months of intensified glucose lowering treatment at the same time of the day and in constant relation to meals and other investigations. After approximately 1 hour at the out patient department the patients were sent to the nearby echo laboratory where they rested in a supine position for 20 min, prior to initiation of the echocardiographic evaluation. Measurements started with flow and tissue Doppler measurements followed by MCE.

The study was conducted according to the Declaration of Helsinki, and the study protocol was approved by the Regional Ethics Committee.

All patients gave their informed, written, and oral consent to study participation.

Laboratory tests
Laboratory tests were performed according to normal, laboratory routines. The following tests were obtained at the time of randomization and the final visit: GAD-antibodies, FPG, HbA1c, and albumin–creatinine ratio. All analyses were performed at the central laboratory at Karolinska University Hospital. HbA1c was analysed by high performance liquid chromatography presented as Mono S with a measurement interval of 2.9–17.2%, reference value <5.3%. Swedish HbA1c = 0.989 x International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) HbA1c + 0.88%; r2 = 0.996; National Glycohemoglobin Standardization Program (NGSP)–HbA1c=0.915 (IFCC–HbA1c) + 2.15% (r2 = 0.997).26

Statistics
Sample size was based on observational data from our laboratory,10 in which É increased by ~1.0 cm/s for an insulin-induced decrease in fasting glucose of 3.8 ± 2.6 mmol/L but no change when glycaemic control was intensified by means of oral glucose lowering drugs. It was assumed that a difference in É by at least 1.0 cm/s between the two treatment arms would be of clinical relevance. Based on the observational study, the standard deviation of the change in É among patients before and after improved treatment was assumed to be 0.9 cm/s. With these assumptions, a power of 80%, and a significance level of 5%, approximately 15 patients would be needed in each treatment arm assuming a normal shift model and performing a t-test. To allow for dropouts and the use of non-parametric tests it was judged reasonable to aim for a total of 40 patients.

The statistical analysis was performed on the per protocol population, i.e. randomized patients without major protocol violations. Continuous variables are summarized as mean±SD or as median and total range while categorical variables are presented as counts and proportions (%). Differences in continuous variables between groups were assessed by Kruskal–Wallis one-way analysis of variance. Associations between echocardiographic and glucometabolic variables were assessed by linear regression models. No corrections for multiple testing were performed. A two-sided P < 0.05 was considered statistically significant. All statistical analyses were performed in SAS for Windows XP Pro platform version 9.1.3, SP 4 (SAS Institute Inc., Cary, NC, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
Thirty-nine of the randomized patients completed the study according to the protocol. One patient from the O-group, who stopped taking all glucose lowering drugs 20 weeks after randomization, was excluded as a protocol violator (Figure 1).

Patient characteristics
All patients had a normal systolic and an impaired diastolic function (Table 1). Of the 21 patients in the I-group, 16 fulfilled 1 of the echocardiographic inclusion criteria and five patients fulfilled 2. Among the 18 patients randomized to the O-group, nine fulfilled 1, seven fulfilled 2, and two fulfilled 3 of the echocardiographic inclusion criteria. Pertinent clinical characteristics at baseline are presented in Table 2. Age, sex, and risk factors for cardiovascular disease were comparable between the two groups while hypertension and treatment with ACE- inhibitor/angiotensin receptor blockers was slightly more frequent among patients in the O-group. All patients had a normal albumin–creatinine ratio.


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  		Table 2 Pertinent patient characteristics by treatment group

 
Details of the patient’s diabetic history are presented in Table 3. The duration of disease was similar in the two groups. Two patients, one each in the I- and O-groups, were diagnosed as latent autoimmune diabetes in adults (LADA) due to their high level of GAD-antibodies (data not shown). Glucose lowering treatment was comparable between the groups at randomization and subsequently amended according to the protocol. By the end of the study all patients in the I-group were treated with insulin and eight continued metformin, while this drug was discontinued in one patient due to a propensity for low glucose values. Patients randomized to the O-group were all given metformin and 12 needed additional repaglinide to achieve the glucose target. This resulted in a comparable decrease in fasting glucose in both groups (I-group = –2.2 ± 2.1 mmol/L and O-group –1.5 ± 0.8 mmol/L; P = 0.083). Likewise HbA1c decreased in a similar magnitude in the two groups to 5.3 ± 0.8% in the I- and 5.1 ± 0.9% in the O-group, respectively (P = 0.69). During the study period there was an average increase in body weight of 1.0 ± 2.3 kg in the I-group and a weight loss of 3.0 ± 4.4 kg in patients belonging to the O-group (P = 0.015).


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  		Table 3 Patient characteristics related to diabetes

 
Echo-Doppler and tissue Doppler imaging data
Doppler-echocardiographic and TDI data are shown in Table 4. Left ventricular systolic and diastolic dimensions (data not presented) and mitral inflow parameters did not differ between the two groups at the time of randomization. Mean LA volume index was enlarged in both groups (I-group = 31 ± 6.0 mL/m2 and 0-group = 33 ± 7.0 mL/m2). As shown in Table 4, improved glycaemic control did not significantly influence the different variables expressing compromised diastolic function in either of the two treatment groups. Thus, there was no change in É in either of the groups. E/É, a non-invasive measure of LV filling pressure, showed a trend towards a decrease in the I-group while there was an increase in the O-group (P = 0.10).


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  		Table 4 Diastolic endpoints in the total patient population and by treatment group

 
Myocardial perfusion data
Due to suboptimal image quality data were lost in a few patients in both groups as detailed in the footnote to Table 4. Myocardial blood flow index showed a numerical increase from rest to stress in the two groups (Table 4). There was a trend towards an improvement of MBFI during stress comparing baseline data with those achieved after improved glycaemic control in both groups. Following improved glycaemic control, MBVI increased numerically from rest to stress in the total population, a change apparent among patients in the I- but not in the O-group. Thus the difference between the two groups did not reach statistical significance (P = 0.10).

The possible correlation between the actual change in glycaemic control, expressed as HbA1c, and the change in E/É, as an expression of diastolic function, was investigated by regression plots without any obvious impact (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
The DADD study did not confirm the hypothesis that strict, particularly insulin based, glucose control improves diastolic function and myocardial flow reserve in patients with type 2 diabetes and early signs of diastolic dysfunction. There were indeed no significant changes in the variables used to describe these entities, except for minor trends in a favourable direction in myocardial blood volume index and lowering of E/É among patients in the insulin group compared with those on oral treatment.

The rationale behind DADD, a randomized, prospective trial, was the outcome of an observational study, performed at our hospital, of beneficial effects of improved glycaemic control on myocardial diastolic dysfunction (MDD) and capillary flow reserve in patients with type 2 diabetes.10 This study indicated that, in particular insulin-based therapy, could be of benefit. Since it was felt unethical to leave patients with established diabetes and early signs of myocardial involvement without any glucose-lowering therapy, patients were assigned to one group essentially controlled by insulin or another on oral glucose lowering drugs only. Accordingly the latter group may be seen as a substitute for a control group.

The present study population was intentionally selected as patients without a history of previous cardiovascular events or any clinical signs of coronary artery disease or congestive heart failure. Well-controlled hypertension was allowed, but none of the patients had LV hypertrophy. The obvious reason for this careful patient selection was to avoid obvious confounders when studying the impact of glucose control on early signs of myocardial dysfunction. It was necessary to screen 121 patients to find the 39 who comprised the final study population. The prevalence of diastolic dysfunction among symptom-free patients with type 2 diabetes varies in different reports. Cosson et al. reported a prevalence of 0% after exclusion of all patients with any micro- or macrovascular complications while Boyer et al., who used relatively wide criteria when diagnosing diastolic dysfunction, reported a high prevalence of 75%.27,28 Thus, variability depends on patient selection and diagnostic criteria. The present prevalence of 33%, probably relates to the use of strict diagnostic criteria. All patients had unequivocal signs of mild-to-moderate diastolic dysfunction documented by different variables, either alone or in combination, since no isolated variable has yet been accepted as the sole criterion.29,30 In the present population, LA size was enlarged in both treatment groups, a finding further confirming the presence of diastolic dysfunction in the study population.31,32 Moreover and despite careful evaluation there is still a possibility that some patients may have had sub-clinical micro- or macro-vascular engagement.

The duration of diabetes in the DADD population was rather short and their glycaemic control, although not reaching the targets recommended by Swedish and International guidelines,1 rather modestly elevated as reflected by fasting glucose and HbA1c. The target for glycaemic control in the DADD study was normalization and in the majority of patients this was achieved early during the titration period. Strict glycaemic control was maintained during the following 4 months and 77% of the patients had an HbA1c <5.5% at the end of study. In this respect, the two groups did not differ significantly from each other. Both management strategies were well tolerated and only a few patients experienced symptoms indicating hypoglycaemia. In one patient the reason was an accidental injection of a double dose of insulin. The remaining reported episodes were not verified by low blood glucose at the time of symptoms.

Although study conditions, ie near normalization of glucose control in patients with type 2 diabetes with mild-to-moderate MDD as their sole manifestation of cardiac involvement, were fulfilled, the hypothesis that strict glycaemic control will improve early manifestations of myocardial dysfunction could not be verified. DADD was based on observations made by von Bibra et al.10 In this observational study, patients with type 2 diabetes, referred to a diabetic clinic due to poor metabolic control, were monitored for MDD and impaired CFR. Following 3 weeks of improved glycaemic control, in particular if insulin based, there was an improvement in myocardial diastolic function and capillary perfusion. There are several potential reasons for this discrepancy. The observational study design may have introduced bias and the reason to perform DADD was to verify previous findings in a controlled study design. Moreover the present patients were, as already stated, carefully selected to have early signs of MDD and to be devoid of concomitant confounders. Such factors were not well controlled for in the observational study. Improvement of glycaemic control differed. In DADD normalization was achieved from a starting fasting glucose about 8 mmol/L while the patients in the pilot trial were considerably less well controlled at the start of the study (fasting glucose 11–12 mmol/L decreasing to 7.4 mmol/L). An additional explanation may be that the present modest signs of myocardial diastolic involvement are more difficult to influence than the more severe state of disease observed in the pilot investigation. The time of observation also needs to be considered. In a more recent study with extended observation time of up to 52 weeks, von Bibra et al.33 once more concluded that diastolic function may be favourably influenced by improved glycaemic control. Surprisingly HbA1c did not change over time in this study although it was claimed that glucose did. Moreover, these patients were selected from a clinic when referred for enhanced insulin therapy. Thus, in contrast to the present investigation, they were not selected after careful screening with strictly defined criteria for diastolic dysfunction and they were not randomly assigned to improved glycaemic control or not and controls were those in whom blood glucose did not improve despite added therapy. In addition, one may argue that the present 4 months is a short follow-up time and that a longer period of improved glycaemic control is needed to influence myocardial function. This is, however, considered an unlikely explanation considering that the present patients were normalized early during the titration period and accordingly were strictly controlled for almost 6 months. Moreover DADD did not reveal any significant correlations between glycaemic control and myocardial improvement that may have become more apparent with time.

The present result finds support in two more recent observational studies and one controlled trial. Fang et al. observed a relation between peak systolic strain and HbA1c but not for É while Di Bonito et al. did not find any relation to metabolic variables apart from an association of É/Á with insulin resistance.34,35 In the controlled trial, Loimaala et al.36 investigated the effect of physical training during 1 year on TDI determined expressions for slightly compromised MDD in 48 male patients with type 2 diabetes but without other signs of cardiovascular disease. Although training improved glycaemic control, there was no impact on diastolic function. However, the experimental settings in this and the present study are quite different from each other. In summary, there seem to be rather divergent results regarding the effects on MDD and further trials are warranted.

Myocardial perfusion, presented in DADD as MBFI and MBVI, was not significantly influenced in any of the treatment groups, in contrast to the previous pilot study which showed a significant difference in MBVI during stress in insulin-treated patients. The present finding supports the outcome of a randomized trial, comparing nateglinide with placebo over a period of 4 months in patients with type 2 diabetes, in which normalization of glycaemic control did not improve myocardial blood flow. The patients were, like those in the present study population, free from other signs of cardiovascular disease and the difference in HbA1c between patients given nateglinide and placebo was 0.9%.37 Scognamiglio et al.38 studied the influence of postprandial glycaemia on myocardial blood flow by myocardial contrast-enhanced echocardiography. They noted that when postprandial glycaemia was decreased by an insulin analogue, myocardial blood flow defects were partially counteracted in patients with type 2 diabetes. Although encouraging, this observation, covering short time periods only, is very different from DADD. In the latter study, which covered longer periods of time the protocol did not include recordings during glycaemic peaks.

Study limitations
The lack of a placebo group may be seen as a limitation. However, considering previous observations of a potential benefit of improved glycaemic control it was not considered justified to withhold glucose lowering treatment in diabetic patients outside recommended treatment targets. Another limitation might be the small sample size. This was, as outlined, based on the pilot observation. In the I-group there was a slight improvement in E/É as an expression of diastolic dysfunction and in MBVI during stress as an expression of myocardial capillary flow reserve (Table 4). None of these changes was close to statistical significance but a statistical type II error must still be considered due to the relatively limited sample size.

Conclusions
DADD could not confirm the hypothesis that improved glycaemic control, in particular if insulin based, would reverse early signs of MDD in patients with type 2 diabetes. Thus the present findings do not support normalization of glucose control as a tool for improving myocardial function or myocardial blood flow reserve. Whether it is possible to influence more pronounced dysfunction, particularly in patients with less well-controlled diabetes, by enhanced glucose lowering therapy, remains to be established. Despite the present discouraging findings this is an important issue in view of the obvious risk for deterioration towards overt heart failure, which has a very serious prognosis in such patients.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
This study was funded by grants from AFA Insurance and by unconditional research grants from Sanofi-Aventis US.


   Acknowledgements
 
None of the providers of research funds had any role in the design and conduct of the study; collection management, analyses and interpretation of the data; and preparation, review, or approval of the manuscript. The authors are grateful to Matthias Lidin RN, Margareta Ring BMA, and Pernilla Jacobsson BMA for skilled handling of patients and data.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

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