Prevention of Heart Failure in Patients with Diabetes: Role of Diabetes Medications

Purpose of Review

Type 2 diabetes mellitus (DM) is a major risk factor for the development of heart failure (HF). In patients with DM, preventing HF using diabetes medications should be an imperative for primary care physicians and cardiologists alike.

Recent Findings

Prior studies with DPP-IV inhibitors, thiazolidinediones (TZDs), and GLP-1 agonists have demonstrated either a neutral effect on HF or increased HF hospitalizations. Two recent large-scale randomized controlled trials (RCTs), EMPA-REG OUTCOME and CANVAS, compared sodium glucose transporter-2 inhibitor (SGLT-2i) to placebo. Use of SGLT-2i led to a substantial reduction in HF events and hospitalizations in patients with DM, with or without history of HF.

Summary

Use of SGLT-2i therapy has been shown to reduce HF in patients with DM.

     

SGLT-2 Inhibitors and Cardiovascular Risk: An Analysis of CVD-REAL

Background

Prior studies found patients treated with sodium-glucose co-transporter-2 inhibitors (SGLT-2i) had lower rates of death and heart failure (HF). Whether the benefits of SGLT-2i vary based upon the presence of cardiovascular disease (CVD) is unknown.

Effect of SGLT-2 inhibitors on cardiovascular outcomes in heart failure patients: A meta-analysis of randomized controlled trials

BackgroundTo investigate the overall effect of sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on cardiovascular outcomes in a broad spectrum of heart failure (HF) patients, and further stratified by status of ejection fraction and diabetes mellitus.MethodsElectronic databases were searched to identify randomized controlled trials that compared SGLT-2i with placebo in patients with HF. Efficacy outcomes included the composite of cardiovascular death (CVD) or hospitalization for heart failure (HHF), individual CVD, individual HHF, and all-cause mortality (ACM).ResultsA total of 8 large trials comprising 16,460 HF patients were enrolled. Pooled data demonstrated that SGLT-2i significantly reduced the risk for primary composite outcome (CVD or HHF) by 23% (HR: 0.77, 95% CI: 0.72–0.82) in HF patients. Use of SGLT-2i was associated with a statistically significant 32% reduction in HHF (HR: 0.68, 95% CI: 0.62–0.75), a 15% reduction in CVD (HR: 0.85, 95% CI: 0.76–0.94) and a 16% reduction in ACM (HR: 0.84, 95% CI: 0.77–0.92). Sensitivity analyses using Mantel-Haenszel method displayed consistent results. Subgroup analyses demonstrated that SGLT-2i were robustly effective in HFrEF subgroup as well as in HF with absence/presence of T2DM, and displayed a strong trend to be effective in HFpEF. Safety analysis demonstrated SGLT-2i group had a lower proportion of serious adverse events than placebo group (RR 0.89, 95% CI: 0.86–0.93).ConclusionsCompared with placebo, SGLT-2 inhibitors have remarkable cardiovascular benefits in a broad range of HF patients. Beneficial effects were robust in HF patients regardless of T2DM status, and a strong trend to be effective in HFpEF.     

Effects of sodium-glucose co-transporter-2 inhibitors by background cardiovascular medications: A systematic review and meta-analysis

Aim

To explore whether the beneficial cardiovascular (CV) effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors is consistent with or without concurrent use of CV medications in patients with type 2 diabetes, heart failure (HF) or chronic kidney disease.

Methods

We searched Medline and Embase up to September 2022 for CV outcomes trials. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for HF. Secondary outcomes included the individual components of CV death, hospitalization for HF, death from any cause, major adverse CV events or renal events, volume depletion and hyperkalaemia. We pooled hazard ratios (HRs) and risk ratios alongside 95% confidence intervals (CIs).

Results

We included 12 trials comprising 83 804 patients. SGLT-2 inhibitors reduced the risk of CV death or hospitalization for HF regardless of background use of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), b-blockers, diuretics, mineralocorticoid receptor antagonists (MRAs), or triple combination therapy of either an ACEI/ARB plus b-blocker plus MRA, or an ARNI plus b-blocker plus MRA (HRs ranged from 0.61 to 0.83; P > .1 for each subgroup interaction). Similarly, no subgroup differences were evident for most analyses for the secondary outcomes of CV death, hospitalization for HF, all-cause mortality, major adverse CV or renal events, hyperkalaemia and volume depletion rate.

Conclusions

The benefit of SGLT-2 inhibitors seems to be additive to background use of CV medications in a broad population of patients. These findings should be interpreted as hypothesis generating because most of the subgroups analysed were not prespecified.     

Early effects of empagliflozin on exercise tolerance in patients with heart failure: A pilot study

Background

Sodium‐glucose linked transporter 2 inhibition recently emerged as a promising therapy for reducing the risk of heart failure (HF) in patients with type 2 diabetes mellitus (T2DM). However, there is a lack of data endorsing its role in symptomatic HF patients. We sought to evaluate the short‐term effects of empagliflozin on maximal exercise capacity in these patients.

Hypothesis

We postulate tretament with empagliflozin may improve functional capacity in patients with T2DM and established HF.

Methods

Nineteen T2DM patients with symptomatic HF were prospectively included and underwent cardiopulmonary exercise testing before and 30 days after initiation of empagliflozin therapy. A mixed‐effects model for repeated measures was used.

Results

Median patient age was 72 years (interquartile range, 60–79 years); 42.1% were in New York Heart Association class III. Baseline mean (± SD) peak oxygen consumption (peak VO₂) was 10.9 ± 4.0 mL/min/kg. Peak VO₂ increased significantly at 30 days (?: +1.21 [0.66 to 1.76] mL/min/kg; P < 0.001). A significant improvement in ventilatory efficiency during exercise, 6‐minute walking distance, and quality of life, and a reduction in antigen carbohydrate 125, were also found. Estimated glomerular filtration rate and natriuretic peptides did not significantly change.

Conclusions

In this pilot study, empagliflozin was associated with 1‐month improvement in exercise capacity in T2DM patients with symptomatic HF. This beneficial effect was also found for other surrogates of severity.

     

Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL 2 Study

Background

Randomized trials demonstrated a lower risk of cardiovascular (CV) events with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in patients with type 2 diabetes (T2D) at high CV risk. Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile, but these studies focused on heart failure and death and were limited to the United States and Europe.

Type 2 diabetes increases the risk of hospital admission for heart failure and reduces the risk of in hospital mortality in Spain (2001–2015)

BackgroundTo compare trends in incidence, clinical characteristics and outcomes of heart failure (HF) hospitalizations among patients with or without type 2 diabetes (T2DM) in Spain (2001–2015).MethodsWe used national hospital discharge data to select hospital admissions for HF as primary diagnosis. Incidence, comorbidities, diagnostic and therapeutic procedures, and in hospital mortality (IHM) were analyzed.ResultsWe identified a total of 1,501,811 admissions for HF (36.87% with T2DM). Incidences were higher among those with T2DM than those without diabetes. The adjusted incidence of HF among T2DM patients was 4.93 higher than for non-diabetic subjects (IRR 4.93;95%CI 4.91–4.95). Jointpoint analysis showed that sex-age-adjusted admissions in T2DM patients with HF increased by 7.12% per year from 2001 to 2007 and stabilized afterwards. For non-diabetic patients a constant increase overtime of around 1% was found.Patients with T2DM were significantly younger than patients without diabetes (77.22 vs. 79.36 years) and had more coexisting medical conditions according to the Charlson Comorbidity Index (mean CCI 1.99 ± 0.88 vs. 1.90 ± 0.86). For the total time period, crude IHM was lower for T2DM patients than for non-diabetic people (8.35% vs, 10.57%; p < 0.05) and the association remained significant after multivariable adjustment ((OR, 0.84; 95%CI 0.83–0.86).). Female sex, older age and multiple comorbidities were significant risk factors for IHM.ConclusionsT2DM increases the risk of admission for HF by five-fold. Our study demonstrates an increase in hospitalization for HF in diabetic patients from 2001 to 2007 and stabilization afterwards. T2DM was associated with a lower IHM after hospitalization for HF.     

Cardiovascular Outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: A systematic review and meta-analysis of randomized controlled trials

Background and aimsWe conducted a systematic review and meta-analysis of all the randomized controlled trials (RCTs) with SGLT-2 inhibitors (SGLT-2i) in patients with known heart failure (HF) with or without type 2 diabetes (T2DM), that have studied the outcomes of cardiovascular (CV) death, hospitalization due to HF (HHF), and composite of CV death or HHF.MethodsA systematic search in PubMed, Embase and Cochrane Library database were made up till November 20, 2020 using specific keywords. RCTs that qualified underwent a meta-analysis by applying the inverse variance-weighted averages of pooled logarithmic hazard ratio (HR) using both random- and fixed-effects model.ResultsThis meta-analysis of 9 RCTs (N = 19,741) have found a significant 26% relative risk reduction in composite of CV death or HHF (HR 0.74; 95% CI, 0.69–0.79; p < 0.001) with SGLT-2i in patients with HF. The meta-analysis of 8 RCTs (N = 16,460) also showed a significant reduction in CV death (HR 0.86; 95% CI, 0.78–0.95; p = 0.003) and HHF (HR 0.68; 95% CI, 0.62–0.74; p < 0.001) outcomes with SGLT-2i in patients with HF. Subgroup analysis stratified on baseline ejection fraction (EF) showed a similar benefit in the composite of CV death or HHF in patients with HF with reduced EF (HFrEF) or preserved EF (HFpEF).ConclusionsSGLT-2i significantly reduces the composite of CV death or HHF, CV death, and HHF in patients with HF. Although subgroup analysis suggested an insignificant P_heterogenity for these outcomes irrespective of the types of HF, however, reduction in both CV death and HHF were more pronounced in patients with HFrEF.     

Dipeptidyl peptidase-4 inhibitors do not increase the risk of cardiovascular events in type 2 diabetes: a cohort study

Aims

Two recent randomized controlled trials of type 2 diabetes mellitus (T2DM) patients with history of, or at high risk of, cardiovascular disease (CVD) showed no risk of ischemic cardiovascular events associated with dipeptidyl peptidase-4 inhibitors (DPP4i), but an increased risk of heart failure (HF) with saxagliptin. We evaluated the risk of CVD including myocardial infarction (MI), stroke, coronary revascularization, and HF associated with DPP4i in T2DM patients with and without baseline CVD as used in the community.

Methods

Using US commercial insurance claims data (2005–2012), we conducted a cohort study that included initiators of DPP4i and non-DPP4i treatments. Composite CVD endpoints including MI, stroke, coronary revascularization, and HF were defined with a hospital discharge diagnosis or procedure code. Cox proportional hazards models compared the risk of composite and individual CVD endpoints in propensity score (PS)-matched initiators of DPP4 versus non-DPP4i.

Results

We included 79,538 (18 % with baseline CVD) persons in PS-matched pairs of DPP4i and non-DPP4i initiators. The incidence rate per 1,000 person-years for composite CVD was 30.30 (95 % CI 28.24–32.51) in DPP4i and 34.76 (95 % CI 32.34–37.36) in non-DPP4i. The PS-matched hazard ratio (HR) for composite CVD was 0.87 (95 % CI 0.79–0.96) in DPP4i versus non-DPP4i. The PS-matched HR for HF was 0.81 (95 % CI 0.70–0.94) in DPP4i versus non-DPP4i. Among patients with baseline CVD, there was no increased risk of CVD or HF associated with DPP4i use.

Conclusions

Among T2DM patients, initiating DPP4i was not associated with a greater risk of CVD or HF compared to non-DPP4i initiators.     

Comparison of glucagons like peptide-1 receptor agonists and dipeptidyl peptide-4 inhibitors regarding cardiovascular safety and mortality in type 2 diabetes mellitus: A network meta-analysis

AimThe effects of dipeptidyl peptide-4 inhibitors (DPP-4is) and sodium-glucose cotransporter-2 inhibitors (SGLT-2is) on type 2 diabetes mellitus (T2DM) on cardiovascular events and all-cause mortality were compared.MethodsThe literature on DPP-4is and SGLT-2is treatment of T2DM was searched through Pubmed, Embase, and the web of science databases with the search deadline May 15, 2020. Network meta-analysis (NMA) was used to compare the effects of two types of inhibitors on cardiovascular events (major adverse cardiovascular events (MACE), nonfatal myocardial infarction (MI), nonfatal stroke, and cardiovascular (CV) death) and all-cause mortality in T2DM patients.ResultsA total of 15 articles were screened, including 125,796 patients. Compared with DPP-4is, SGLT-2is can significantly reduce MACE [OR: 0.86 95% CI (0.78, 0.92)], CV death [OR: 0.85 95% CI (0.71, 1.01)], nonfatal MI [OR: 0.84 95%CI (0.74, 0.95)] and all-cause mortality [OR: 0.78 95% CI (0.69, 0.89)]. For nonfatal stroke, DPP-4is and SGLT-2is have no statistically significant difference [OR: 0.99 95% CI (0.91, 1.07)].ConclusionThese data indicate that SGLT-2is is more beneficial to MACE and all-cause mortality in T2DM patients than DPP-4is.     

Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with non‐alcoholic fatty liver disease

Aim

Type 2 diabetes mellitus (T2DM) is a major complication of patients with non‐alcoholic fatty liver disease (NAFLD). The aim of this retrospective study is to determine the risk factors for development of T2DM in patients with biopsy‐proven NAFLD.

Methods

One hundred and sixty two consecutive patients with biopsy‐proven NAFLD who received a 75‐g oral glucose tolerance test were enrolled as the total cohort. Among them, we analyzed 89 patients without T2DM diagnosed by oral glucose tolerance test to estimate the cumulative rate for development of T2DM as the follow‐up cohort.

Results

Of 162 patients, the glucose tolerance pattern were DM in 45 patients (27.8%), impaired glucose tolerance in 68 (42.0%), and normal glucose tolerance in 49 (30.2%). Patients with NAFL tended to be more likely to have normal glucose tolerance than those with non‐alcoholic steatohepatitis (NASH). The serum levels of pre‐ and post‐load insulin were significantly higher in the NASH group. Of 89 patients without T2DM, 13 patients newly developed T2DM during a follow‐up period of 5.2 years. The cumulative rate of T2DM incidence was 8.8% at the end of the 5th year and 23.4% at the end of the 10th year. Multivariate analysis identified homeostasis model of assessment – insulin resistance (≥3.85, hazard ratio 40.1, P = 0.033) as an independent risk factor for development of T2DM.

Conclusions

Patients with NASH have an underlying potential of glucose intolerance. In NAFLD patients, insulin resistance is the most important risk factor for the incidence of T2DM. Appropriate therapy against insulin resistance could be needed for patients with NAFLD to prevent development of T2DM.     

Prevalence and pattern of hand soft-tissue changes in type 2 diabetes mellitus

Aims and objectives

Hand soft-tissue changes are well described in patients with T1DM, but not in T2DM patients. For this reason, this study aimed at examining the prevalence and pattern of hand soft-tissue changes in patients with T2DM.

Methods

A total of 206 consecutive patients with T2DM and 203 age-, gender- and occupation-matched healthy controls were examined by two individual observers, and then underwent the appropriate investigations.

Results

The 132 (64%) patients with T2DM included 187 hands compared with 96 (23.6%) healthy controls including 133 hands (P = 0.01 for both). Dupuytren's contracture (DC) (42 vs. 29.3%, respectively; P = 0.01), limited joint mobility (LJM) (39 vs. 28.5%, respectively; P = 0.01) and carpal tunnel syndrome (CTS) (5.3 vs. 1%, respectively; P = 0.01) were significantly higher in T2DM patients than in the controls, but not stenosing flexor tenosynovitis (FTS, ‘trigger finger’). Indeed, none of the patients or controls had FTS. In patients with T2DM, DC showed a radial shift, and was more horizontal and severe than in the controls. These hand soft-tissue changes correlated significantly with age (P = 0.0001), duration of diabetes (P = 0.001) and the presence of microangiopathy (P = 0.001).

Conclusion

Hand changes are more prevalent and severe in patients with T2DM, and are correlated with age, duration of diabetes and microvascular complications.     

An Exploratory Study of Dapagliflozin for the Attenuation of Albuminuria in Patients with Heart Failure and Type 2 Diabetes Mellitus (DAPPER)

Background and Aims

Sodium-dependent glucose transporter-2 (SGLT-2) inhibitors, which are anti-diabetic drugs, reportedly decrease the incidence of cardiovascular events in high-risk patients with cardiovascular diseases, and thus chronic heart failure (CHF). SGLT-2 inhibitors also decrease albuminuria in patients with type 2 diabetes mellitus (T2D). Since albuminuria is a biomarker of not only chronic kidney disease but also cardiovascular events, we hypothesized that, among T2D patients with CHF, SGLT-2 inhibitors will decrease the extent of albuminuria and also improve CHF concomitantly.

Methods

DAPPER (UMIN000025102) is a multicenter, randomized, open-labeled, parallel-group, standard treatment-controlled study, which is designed to evaluate whether dapagliflozin, one of the SGLT-2 inhibitors, decreases albuminuria in T2D patients with CHF and exerts cardioprotective effects on the failing heart. The patients are randomized to either of the dapagliflozin (5 or 10 mg, once daily orally) or control group (administration of anti-diabetic drugs administered other than SGLT 2 inhibitors). The estimated number of patients that need to be enrolled is 446 in total (223 in each group). The primary objective is the changes in the urinary albumin-to-creatinine ratio from the baseline after 2-year treatment. The key secondary objectives are (1) the safety of dapagliflozin and (2) the cardiovascular and renal efficacies of dapagliflozin.

Conclusion and Perspectives

DAPPER study investigates whether dapagliflozin decreases albuminuria and exerts beneficial effects on the failing heart in T2D patients. (UMIN000025102).

     

Eligibility for vericiguat in a real-world heart failure population according to trial,guideline and label criteria: Data from the Swedish Heart Failure Registry

Aim

We investigated the eligibility for vericiguat in a real-world heart failure (HF) population based on trial, guideline and label criteria.

Methods and results

From the Swedish HF registry, 23 573 patients with HF with reduced ejection fraction (HFrEF) enrolled between 2000 and 2018, with a HF duration ≥6 months, were considered. Eligibility for vericiguat was calculated based on criteria from (i) the Vericiguat Global Study in Subjects with Heart Failure and Reduced Ejection Fraction (VICTORIA) trial; (ii) European and American guidelines on HF; (iii) product labelling according to the Food and Drug Administration and European Medicines Agency. Estimated eligibility for vericiguat in the trial, guidelines, and label scenarios was 21.4%, 47.4%, and 47.4%, respectively. Prior HF hospitalization within 6 months was the criterion limiting eligibility the most in all scenarios (met by 49.1% of the population). In the trial scenario, other criteria meaningfully limiting eligibility were elevated N-terminal pro-B-type natriuretic peptide levels and nitrate use. In all scenarios, eligibility was higher among patients hospitalized for HF at baseline (44.3% vs. 21.4% [trial scenario] and 97.3% vs. 47.4% [guideline/label scenarios] for hospitalized vs. non-hospitalized patients). Overall, eligible patients were older, had more severe HF, more comorbidities, and consequently higher cardiovascular mortality and HF hospitalization rates compared with ineligible patients across all scenarios.

Conclusion

In a large and contemporary real-world HFrEF cohort, we estimated that 21.4% of patients would be eligible for vericiguat according to the VICTORIA trial selection criteria, 47.4% based on guidelines and labelling. Eligibility for vericiguat translated into the selection of a population at high risk of morbidity/mortality.     

Glycated albumin and the risk of chronic kidney disease in subjects with Type 2 Diabetes: A study in North Indian Population

Aim

Glycated albumin (GA) suggested being alternative glycemic marker than haemoglobin A1C (HbA1c) in patients with chronic kidney diseases (CKD). We investigated the association between GA and the progression of diabetic nephropathy (DN) in T2DM subjects.

[HDL‐C/apoA‐I]: A multivessel cardiometabolic risk marker in women with T2DM

Aims

Although women have higher high‐density lipoprotein cholesterol (HDL‐C) than have men, their HDL particles are also prone to become small, dense, and dysfunctional in case of type 2 diabetes mellitus (T2DM). To assess the vascular risk related to HDLs of different sizes/densities without direct measurement, we adjusted HDL‐C to its main apolipoprotein (apoA‐I) as [HDL‐C/apoA‐I]. This ratio estimates HDL sizes and provides indices as to their number, cholesterol load, and density.

Methods

We stratified 280 Caucasian T2DM women according to [HDL‐C/apoA‐I] quartiles (Q) to determine how they are segregated according to cardiometabolic risk, β‐cell function, glycaemic control, and vascular complications. Five parameters were derived from combined determination of HDL‐C and apoA‐I: HDL size, HDL number, cholesterol load per particle (pP), apoA‐I pP, and HDL density.

Results

An adverse cardiometabolic profile characterized QI and QII patients whose HDLs were denser and depleted in apoA‐I, whereas QIII patients had HDLs with characteristics closer to those of controls. QIV patients had HDLs of supernormal size/composition and a more favourable phenotype in terms of fat distribution; insulin sensitivity (64% vs 41%), metabolic syndrome, and β‐cell function (32% vs 23%); exogenous insulin (44 vs 89 U·d^?1); and glycaemic control (glycated haemoglobin, 56 vs 61 mmol·mol^?1), associated with lower prevalence of microvascular/macrovascular complications: all‐cause microangiopathy 47% vs 61%; retinopathy 22% vs 34%; all‐cause macroangiopathy 19% vs 31%; and coronary artery disease 6% vs 24% (P < .05).

Conclusion

[HDL‐C/apoA‐I] can stratify T2DM women according to metabolic phenotype, macrovascular and coronary damage, β‐cell function, microangiopathic risk, and retinopathy. This ratio is a versatile and readily available marker of cardiometabolic status and vascular complications in T2DM women.     

Use of sodium-glucose co-transporter-2 inhibitors in patients with type 2 diabetes mellitus and multiple cardiovascular risk factors: An Asian perspective and expert recommendations

Diabetes mellitus in Asia accounts for more than half of the global prevalence. There is a high prevalence of cardiovascular disease (CVD) in the region among people with type 2 diabetes mellitus (T2DM) and it is often associated with multiple risk factors including hypertension, renal disease and obesity. The early onset of T2DM and the eventual long disease duration portends an increasing proportion of the population to premature CVD. In addition to lowering blood glucose, sodium-glucose co-transporter-2 (SGLT-2) inhibitors exert favourable effects on multiple risk factors (including blood pressure, body weight and renal function) and provide an opportunity to reduce the risk of CVD in patients with T2DM. In this article, we consolidated the existing literature on SGLT-2 inhibitor use in Asian patients with T2DM and established contemporary guidance for clinicians. We extensively reviewed recommendations from international and regional guidelines, published data from clinical trials in the Asian population (dapagliflozin, canagliflozin, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin), CVD outcomes trials (EMPAREG-OUTCOME, CANVAS and DECLARE-TIMI 58) and real-world evidence studies (CVD-REAL, EASEL, CVD-REAL 2 and OBSERVE-4D). A series of clinical recommendations on the use of SGLT-2 inhibitors in Asian patients with T2DM was deliberated among experts with multiple rounds of review and voting. Based on the available evidence, we conclude that SGLT-2 inhibitors represent an evidence-based therapeutic option for the primary prevention of heart failure hospitalization and secondary prevention of CVD in patients with T2DM, and should be considered early on in the treatment algorithm for patients with multiple risk factors, or those with established CVD.