Mechanistic Insights into Diuretic-Induced Insulin Resistance

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Abstract
He incidence of diabetes mellitus and hypertension continues to rise worldwide. The proportion of pa- tients with hypertension at risk for developing diabetes mellitus is also growing secondary to aging and increased obesity rates.1 Several guidelines recommend thiazide diuretics as either first-line or add-on antihypertensive therapy to achieve blood pressure goals.2 Concern over negative metabolic effects associated with thiazide diuret- ics, however, dates back 3 decades.3 A substantial fraction of patients with hypertension have additional cardiovascular risk factors, and many have elevated fasting glucose and are at risk for developing diabetes mellitus.4 Impaired fasting glucose itself increases the risk for cardiovascular events.5 Any medication that worsens insulin sensitivity, ie, thiazide diuretics or most -blockers will hasten the development of diabetes mellitus in those with impaired fasting glucose.6 Large observational studies demonstrate that thiazide diuretics and most -blockers increase the incidence of new-onset diabetes mellitus compared with renin-angiotensin system (RAS) blockers or calcium chan- nel blockers.7 To further support this observation, a network-based meta-analysis of hypertensive agents showed that RAS blockers were the agents least likely to be associated with the development of diabetes mellitus, whereas thiazides had a higher incidence of diabetes mellitus compared with placebo.7 The mechanism traditionally associated with this in- creased risk of diuretic-associated diabetes mellitus is a reduction in serum potassium. A meta-analysis of 59 studies involving 83 thiazide diuretic treatment arms found a significant correlation between the degree of diuretic- induced hypokalemia and an increase in plasma glucose.8 Moreover, there is evidence that prevention of hypokale- mia with K supplementation or potassium-sparing agents lessens the degree to which plasma glucose is increased consequent to diuretic therapy.8 The mechanism of this