In 1999, Takeda and SmithKline developed two TZD containing drugs, pioglitazone (51) and rosiglitazone (52) which were also approved by the FDA for the management of T2D (Figure 6).[58] After capitalising the market for insulin sensitisers and becoming one of the top 25 selling brands in the United States, concerns were raised regarding rosiglitazone causing heart failure due to fluid retention and, in 2011, the European Medicines Agency recommended that it should be withdrawn from the market.[59, 60]. Here, INS is linked to type 2 diabetes mellitus.