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Heart failure (HF) is a significant public health concern characterized by notable rates of morbidity and mortality. Multimorbidity, ranging from 43% to 98% among HF patients, significantly impacts prognosis and treatment response. HF management requires a holistic approach, including guideline-directed medical therapy. Sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) is a cornerstone of HF treatment, supported by robust evidence from large-scale clinical trials across different levels of left ventricular ejection fraction. The recommendations presented in this paper have been developed by a group of cardiologists in India who convened in expert opinion meetings to discuss the utilization of ARNI in chronic HF patients with five different comorbid conditions like type 2 diabetes mellitus (T2DM), chronic kidney disease, myocardial infarction (MI), obesity, and hypertension. Key focus areas include initiation, dose titration, and management across different HF phenotypes and comorbidities. Emphasis is placed on the efficacy of ARNI irrespective of glycemic status in the T2DM population, its role in HF patients with obesity, and addressing challenges related to renal function decline and hyperkalemia. Additionally, the document highlights ARNI’s potential benefits in hypertensive and post-MI HF patients, alongside observations on the obesity paradox in HF prognosis. Overall, these recommendations aim to optimize ARNI therapy in HF patient populations with different comorbidities, addressing specific challenges and considerations to improve outcomes and quality of life.