New non-sulfonylurea insulin secretagogues

Current treatments for non-insulin dependent diabetes mellitus (NIDDM) remain far from ideal. The universal finding of islet dysfunction characterised by the absence of first phase insulin secretion, even prior to the level of hyperglycaemia diagnostic of NIDDM, challenges the rationale for treatments that only enhance insulin action. To date, however, the sulfonylureas are the only insulin secretagogues available and even the most rapid acting of these fail to restore early insulin release in response to meals. Four novel non-sulfonylurea insulin secretagogues are in advanced clinical development: A-4166, KAD-1229, BTS 67 582 and repaglinide. These promising new agents control prandial hyperglycaemia by augmenting the early insulin response to meals. Preclinical and early clinical data suggest that their potencies vary considerably, as do their pharmacokinetics and, importantly, their pharmacodynamics. The two shortest-acting compounds, A-4166 and KAD-1229, will be developed to be taken prior to each main meal, while the slower, longer duration agents, repaglinide and BTS 67 582, may be developed to be taken twice daily. With a sufficiently rapid onset and short duration of action, the new non-sulfonylurea insulin secretagogues may improve or even restore the impairment of early insulin secretion without inducing the prolonged hyperinsulinaemia characteristic of sulfonylureas. Treatment with these new agents will immediately improve prandial glucose control and with continued treatment these agents are expected to improve the overall metabolic state. Furthermore, a short-acting secretagogue will have minimal propensity to elicit prolonged or delayed hypoglycaemia and it is expected that by minimising chronic hyperinsulinaemia the weight gain that accompanies sulfonylurea treatment will be avoided. In summary, the new non-sulfonylurea insulin secretagogues will make an important contribution to the limited and inadequate armamentarium currently available for the treatment of NIDDM, and their use in combination with insulin sensitising agents may provide, for the first time, an approximation to ideal metabolic control in NIDDM.