Heart failure is a major health issue and a risk factor for early death and disability in type 2 diabetes. Until now, no trials of intensified multifactorial intervention in type 2 diabetes have investigated the potential beneficial effects of this treatment modality on congestive heart failure. In this post hoc analysis of outcome data from the Steno-2 randomised trial, we demonstrate that intensified multifactorial treatment in patients with type 2 diabetes mellitus, microalbuminuria and preserved baseline EF for 7.8 years reduced the hazard of developing clinical heart failure by 70% at 21.2 years of follow-up.
Twenty per cent of all patients developed heart failure, equalling the number of patients experiencing MI (20%), stroke (22%), amputation (19%) or blindness (19%)  and mortality seemed to be at least as high for patients with incident heart failure as for patients experiencing an MI. We also found that the reduction in heart failure was influenced by, but not dependent on, reduction of ischaemic heart disease risk. The results were unchanged over multiple sensitivity analyses including testing for common confounders and competing risk. Our results clearly underline the importance of applying an intensive, multifactorial approach to the management of type 2 diabetes.
In the following studies (all including patients with type 2 diabetes and micro- or macroalbuminuria), heart failure was more common than other cardiovascular complications: reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) , the Irbesartan Diabetic Nephropathy Trial (IDNT) , the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE)  and Microvascular outcomes in the Heart Outcomes Prevention Evaluation Study (MICRO-HOPE) . However, the Steno-2 study had significantly longer follow-up, thus allowing more time for atherosclerosis progression. It is unlikely that the risk reductions seen in the Steno-2 study are attributable to one single component of the multifactorial treatment regimen, but rather to the combination of polypharmacy and lifestyle intervention. The drug pattern was highly complex (ESM Figs 1, 2), but the use of ACE inhibitors, angiotensin II receptor blockers (ARBs), statins and aspirin was more frequent in the intensive-therapy group, which is probably reflected in our findings. In particular, we would anticipate the effect of more frequent use of ACE inhibitors and ARBs to be prominent.
Our findings suggest that diabetes caregivers should pay attention to early signs and symptoms of congestive heart failure including left-ventricular dysfunction and, together with cardiologists, take appropriate actions. Measuring plasma NT-proBNP might be helpful in assessing and monitoring risk of heart failure since high values or large increments were strongly associated with heart-failure outcomes and could be used to guide diabetologists to refer patients for evaluation by cardiologists. Our findings indicate that the higher risk of heart failure associated with an increase in NT-proBNP can be mitigated by intensified multifactorial intervention. However, evidence that intensive lifestyle improvement may increase NT-proBNP and the fact that NT-proBNP levels are inversely related to BMI warrants caution when interpreting our findings regarding NT-proBNP [25, 26].
Glucose-lowering drugs, as well as adjuvant therapies for diabetes comorbidities, modify the risk of developing heart failure. In 2009, increased risk of heart failure in diabetic patients treated with rosiglitazone in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial  was reported and subsequently, the use of dipeptidyl peptidase 4 (DPP-4) inhibitors also has been flagged as potentially increasing the risk of heart failure . Although the latter findings have been questioned [29, 30], the Food and Drug Administration (FDA) recently added heart-failure warnings to the Summary of medicinal Products Characteristics (SmPC) for all marketed DPP-4-inhibitors . In contrast, diabetes trials with the sodium–glucose cotransporter 2 (SGLT-2) inhibitors empagliflozin and canagliflozin have demonstrated heart-failure risk reduction [32,33,34], whereas diabetes treatment with GLP-1 receptor agonists seem to have a neutral effect on the risk of heart failure [35,36,37]. In addition, the extensive use of ACE inhibitors [24, 38], ARBs, beta blockers and statins  in type 2 diabetes may modify the risk of heart failure, although the evidence regarding the latter is weak.
This post hoc analysis has limitations: the Steno-2 study has a small sample size of 160 individuals and the type 2 diabetes study population with microalbuminuria is selected as a high-risk patient group. Therefore, the magnitude of risk reduction we demonstrate here might not be attributable to a population of lower risk. Furthermore, the sample size leads to an inherent risk of committing type 1 statistical errors due to unaccountable bias. The fact that the results presented in this paper are in accordance with previously published results regarding other manifestations of cardiovascular disease can be regarded both as a strength and as a weakness, the latter underlined by the above statement of unmeasurable bias driving the difference in outcomes between groups.
We do not have complete echocardiographic data available for the entire patient population and baseline EF was based on a calculated estimate. Therefore, whether individuals had preserved or reduced EF prior to and after hospitalisation is uncertain. However, recent evidence shows that the prognosis is independent of EF .
In the Steno-2 trial and during trial follow-up, the use of sulfonylurea drugs was frequent and even between groups (ESM Fig. 1) and the use of ACE inhibitors and beta blockers was more frequent in the intensive-therapy group (ESM Fig. 2), but the total exposure to glitazones, DPP-4 inhibitors, GLP-1 inhibitors and SGLT-2 inhibitors etc. was very limited (all <5% of patients in each group at each follow-up point). The effects on heart failure of the above-mentioned drugs that have been seen in recent large-scale clinical trials of cardiovascular outcomes occur on top of the standard of care; in most current recommendations, the standard of care resembles the treatment targets for the patients originally allocated to intensified multifactorial care in the Steno-2 trial.
The significant and meaningful risk reductions reported here should be seen as a benefit of intervention against traditional risk factors; the introduction of novel glucose-lowering drugs with pleiotropic effects, on top of improved glucose control, that reduce the risk of cardiovascular morbidity and mortality by other, not presently fully elucidated, mechanisms should lead to optimism in the field of diabetes care.
In conclusion, our study demonstrated hospitalisation for heart failure to be a frequent and fatal complication in patients with type 2 diabetes and microalbuminuria. Intensified multifactorial intervention significantly reduced the occurrence of this outcome.