Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug

Nesti, Lorenzo; Tricò, Domenico; Mengozzi, Alessandro; Natali, Andrea

doi:10.1186/s12933-021-01294-7

Cited by 76 publications

(72 citation statements)

References 208 publications

(238 reference statements)

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“…The observation of increased HF with thiazolidinediones prompted their withdrawal from the market, and boosted cardiovascular safety trials of newer agents, which led, quite unexpectedly, to the discovery of unprecedented cardiovascular benefits of new drugs (and even old ones [ 3 , 4 ]), especially for patients with HF. Two new classes of drugs might change the natural trajectory of the “lethal synergy” of T2D and HF, namely, glucagon-like peptide 1 receptor agonists (GLP-1Ra) and sodium–glucose cotransporter 2 inhibitors (SGLT-2i).…”

Section: Introductionmentioning

confidence: 99%

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence

Natali

Nesti

Tricò

et al. 2021

Cardiovasc Diabetol

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The impressive results of recent clinical trials with glucagon-like peptide-1 receptor agonists (GLP-1Ra) and sodium glucose transporter 2 inhibitors (SGLT-2i) in terms of cardiovascular protection prompted a huge interest in these agents for heart failure (HF) prevention and treatment. While both classes show positive effects on composite cardiovascular endpoints (i.e. 3P MACE), their actions on the cardiac function and structure, as well as on volume regulation, and their impact on HF-related events have not been systematically evaluated and compared. In this narrative review, we summarize and critically interpret the available evidence emerging from clinical studies. While chronic exposure to GLP-1Ra appears to be essentially neutral on both systolic and diastolic function, irrespective of left ventricular ejection fraction (LVEF), a beneficial impact of SGLT-2i is consistently detectable for both systolic and diastolic function parameters in subjects with diabetes with and without HF, with a gradient proportional to the severity of baseline dysfunction. SGLT-2i have a clinically significant impact in terms of HF hospitalization prevention in subjects at high and very high cardiovascular risk both with and without type 2 diabetes (T2D) or HF, while GLP-1Ra have been proven to be safe (and marginally beneficial) in subjects with T2D without HF. We suggest that the role of the kidney is crucial for the effect of SGLT-2i on the clinical outcomes not only because these drugs slow-down the time-dependent decline of kidney function and enhance the response to diuretics, but also because they attenuate the meal-related anti-natriuretic pressure (lowering postprandial hyperglycemia and hyperinsulinemia and preventing proximal sodium reabsorption), which would reduce the individual sensitivity to day-to-day variations in dietary sodium intake.

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Section: Introductionmentioning

confidence: 99%

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence

Natali

Nesti

Tricò

et al. 2021

Cardiovasc Diabetol

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“…PIO has a unique mechanism of action and several important pleiotropic effects. It has shown significant cardiovascular benefits, improvements of several components of the metabolic syndrome and beneficial effects on non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) [ 11 , 22 , 170 ]. Its possible role in other IR states is also under intense investigation, both as monotherapy and in combination with other agents [ 11 , 22 , 171 ].…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone in diabetic kidney disease: forgotten but not gone

Papaetis¹

2022

Arch Med Sci Atheroscler Dis

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Diabetic kidney disease (DKD) is described in approximately 20–40% of all diabetic patients and is associated with significant cardiovascular and all-cause mortality. The involvement of multiple metabolic, haemodynamic, inflammatory, and tubular pathways in the pathophysiology of DKD generates the need for multitargeted treatment approaches to improve its development at all levels and delay or even reverse its progression. Thiazolidinediones are potent exogenous agonists of PPAR-γ, which augment the effects of insulin on its cellular targets, mainly at the level of adipose tissue. Pioglitazone, currently the main thiazolidinedione in clinical practice, has achieved significant improvements of albuminuria in patients with type 2 diabetes. It can also interfere with most cellular pathways involved in the development and evolution of DKD. This paper explores the pathophysiological mechanisms governing its possible nephroprotective activity during a diabetic state. It also discusses its future role to ameliorate the global burden of DKD.

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“…First, together with our previous studies that do not suggest an increased risk of bladder cancer [ 30 ], ovarian cancer [ 31 ], oral cancer [ 32 ], kidney cancer [ 33 ], thyroid cancer [ 34 ], lung cancer [ 35 ] and prostate cancer [ 36 ] associated with pioglitazone use, the public health concern of an increased cancer risk associated with pioglitazone can be relieved and should not impede the clinical use of pioglitazone. Second, the potential benefits of pioglitazone on the improvement of lipid profile [ 37 ], the risk reduction of dementia [ 38 , 39 ], chronic obstructive pulmonary disease [ 40 ], non-alcoholic fatty liver disease [ 41 ], stroke [ 2 ] and cardiovascular disease [ 42 ] and the usefulness of pioglitazone in the treatment of polycystic ovarian syndrome in women [ 43 ] suggest that some patients may gain pleiotropic benefits beyond glycemic control from the appropriate use of pioglitazone.…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus: a retrospective cohort analysis

Tseng

2022

BMC Cancer

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Background Whether pioglitazone may affect breast cancer risk in female diabetes patients is not conclusive and has not been investigated in the Asian populations. Methods The reimbursement database of Taiwan’s National Health Insurance was used to enroll an unmatched cohort and a propensity score-matched cohort of ever users and never users of pioglitazone in female patients with newly diagnosed type 2 diabetes during 1999–2008. The patients were alive on January 1, 2009 and were followed up for breast cancer incidence until December 31, 2011. Cox regression was used to estimate hazard ratios for ever users and tertiles of cumulative duration of pioglitazone therapy versus never users, and for cumulative duration of pioglitazone therapy treated as a continuous variable. Three models were created for the unmatched cohort and the matched cohort, respectively: 1) without adjustment for covariates; 2) after adjustment for covariates that differed with statistical significance (P-value < 0.05) between ever users and never users; and 3) after adjustment for all covariates. Results There were 174,233 never users and 6926 ever users in the unmatched cohort; and 6926 never users and 6926 ever users in the matched cohort. After a median follow-up of 2.8 years, the numbers of incident breast cancer were 1044 in never users and 35 in ever users in the unmatched cohort and were 41 and 35, respectively, in the matched cohort. Hazard ratios suggested a null association between pioglitazone and breast cancer in all three models in either the unmatched cohort or the matched cohort. The overall hazard ratio after adjustment for all covariates was 0.758 (95% confidence interval: 0.539–1.065) in the unmatched cohort and was 0.824 (95% confidence interval: 0.524–1.296) in the matched cohort. None of the hazard ratios for the tertiles of cumulative duration of pioglitazone therapy and for the cumulative duration being treated as a continuous variable were statistically significant. Conclusions This study suggests a null association between pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus. However, because of the small breast cancer cases and the limited follow-up time, further studies are warranted to confirm our findings.

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Rethinking pioglitazone as a cardioprotective agent: a new perspective on an overlooked drug

Cited by 76 publications

References 208 publications

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence

Pioglitazone in diabetic kidney disease: forgotten but not gone

Pioglitazone and breast cancer risk in female patients with type 2 diabetes mellitus: a retrospective cohort analysis

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