Prevention of cardiovascular disease (CVD) is one of the main objectives in the management of people with type 2 diabetes (T2DM). New glucose-lowering therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have demonstrated not only cardiovascular safety but also cardiovascular benefits. In line with emerging evidence from the cardiovascular outcome trials (CVOTs), major international guidelines advocate GLP-1RAs and SGLT-2 inhibitors with proven cardiovascular benefits as a first add-on or monotherapy in individuals with T2DM and established CVD or CVD risk factors. Based on subsequent cardiorenal outcomes and heart failure trials, the licensed indications of some SGLT-2 inhibitors have been extended beyond glycaemic management. SGLT-2 inhibitors have now been approved for the management of chronic heart failure and chronic kidney disease, both irrespective of diabetes status. This review aims to summarise the CVOTs of GLP-1RAs and SGLT-2 inhibitors from the clinician’s perspective.

The management of type 2 diabetes continues to evolve with the historical glucocentric nature of care, paving the way toward more holistic and comorbidity-based management largely due to the advent of newer medications and trial data. Clinicians need to be aware that an understanding of not only the current treatment landscape but also the future developments in care and therapy is required in order to understand the best options for the management of their patients. This article will discuss current perspectives in the pharmacological management of type 2 diabetes, largely focusing on recent trial developments and associated future trials and molecules that may impact type 2 diabetes care in the near future.

The known hallmarks of type 2 diabetes mellitus (T2DM), such as hyperglycemia, insulin resistance, visceral adiposity, inflammation, endothelial dysfunction, and oxidative stress, are known to influence the hypothalamus-pituitary-gonadal axis, leading to functional hypogonadism. Both the consequent testosterone (T) deficiency and diabetes are recognized factors influencing cardiovascular (CV) risk. In this context, T replacement therapy showed an improvement in glycemic control and metabolic, anthropometric, and body composition parameters in hypogonadal diabetic individuals. Observational and randomized studies on T replacement therapy suggested the beneficial effect of this treatment on CV risk, although inconclusive results should still be evaluated, particularly when subgroups of patients have to be considered. In this setting, the novel antidiabetic drugs have demonstrated beneficial effects on T levels, due to their positive effects on the hypothalamic–pituitary–gonadal axis, in addition to a proven CV protective action. Thus, the combined metabolic and CV effects of T replacement therapy and novel antidiabetic drugs are of great interest. In this review, we aimed to summarize the present state of the art concerning the association between T deficit and CV risk in diabetic people by analyzing the relationship between endogenous T and CV system in diabetic men. In particular, the impact of novel antidiabetic drugs on male hypogonadism, and the combined cardio-metabolic effects of T supplementation and novel antidiabetic drugs were discussed.

Obesity-related gonadal dysfunction in males has been defined recently as male obesity secondary hypogonadism (MOSH). Affected individuals present with signs and symptoms related to the sex hormone imbalance but also with a burden of metabolic risk factors and occasionally compromised fertility. In pathophysiological terms, excess body fat is associated with leptin and insulin resistance. Accelerated synthesis of leptin and hyperinsulinemia downregulate the expression of kisspeptin receptors and, consequently, the action of kisspeptin. This critical neuropeptide is known to control gonadotropin secretion. In obese males, enhanced activity of the aromatase enzyme is associated with an increase in the conversion of circulating testosterone to estrogen, further promoting a state of hypogonadism. In addition, high fat and low fiber intake alter the intestinal microbiome and the dysfunction of the gut-brain axis. Weight loss appears to be the key to readjusting the function of the hypothalamus-pituitary-gonadal axis. It can be achieved with lifestyle measures in combination with weight loss medications or bariatric surgery. The degree of weight loss appears to resolve the symptoms related to hypogonadism and improve fertility chances. However, the role of hormone replacement is also important, as testosterone replacement has been shown to reduce fat mass and increase the amount of lean body mass while also contributing to weight loss and the regulation of body mass index and waist circumference. This narrative review analyzes the evidence on developing obesity-related endocrinopathies and the available management options. Further research is required to estimate the cut-off of body mass index associated with a higher risk for hypogonadism.

The liver is known as a sexually dimorphic organ because it has both androgen and estrogen receptors and responds to sex hormones. Specifically, the unique ability of the liver to regenerate is under the control of sex hormones. In human patients, liver recovery after resection occurs more quickly in women than in men. Accumulating evidence shows that change in the amount of sex hormones occurs quickly after partial hepatectomy (PHx) and impacts the expression of genes associated with liver regeneration. Increased estrogen promotes liver regeneration by regulating liver cell proliferation and energy metabolism, whereas estrogen depletion delays liver restoration. Implantation of estrogen in male mice with PHx improves liver regeneration. In addition, a few studies report that androgen is involved in enhancing liver regeneration, but its role in this process is not fully elucidated. This review briefly describes the change of estrogen and androgen during liver regeneration after PHx and discusses their feasible relevance to liver regeneration based on the results reported so far. Therefore, this review helps to improve our understanding of the sex-related physiological difference in liver restoration and develop a sex-specific therapeutic approach for liver regeneration.