Thiazide diuretics, Potassium, and the Development of Diabetes

A Quantitative Review

Hypertension2006_219

Backgrounds

• Thiazide diuretics are recommended as a 1st choice for HTN by current national clinical practice guidelines and results from the ALLHAT*. *Antyhypertensive and

Lipid Lowering treatment to prevent Heart Attack Trial

• But 4-year incidence of new-onset diabetes was significantly higher in thiazide group(11.6%) than either in Ca channel blocker group(9.8%) or ARB group(8.1%). (P<0.05)

By the way---ALLHAT---(1)

• Antihypertensive and Lipid Lowering treatment to prevent Heart Attack Trial

• Consists of antihypertensive therapy and lipid lowering treatment

By the way---ALLHAT---(2)

By the way---ALLHAT---(3)

potassium value was significantly dropped in the thiazide group

By the way---ALLHAT---(4)

Blood glucose in thiazide group was significantly elevated.

This study

• Provides a review of intervention studies that included data on the relation between thiazide-induced hypokalemia and glucose intolerance

• Aimes to evaluate clinical trials – that used thiazide diuretics– that reported metabolic effects on potassium an

d glucose

Methods

• 3 medical literature sourse– The Abridged Index Medicus 1966.1-2004.6– Cochrane Controlled Trial Database– Journal of Hypertension, Journal of Human Hy

pertension, Hypertension, American Journal of Hypertension, Journal of Clinical Hypertension and Blood Pressure

• Search terms: “diuretics, thiazide”, “hydrochlorothiazide”, or “chlorthalidone”

Methods• Limited to adult, human, subject published in English using the

terms “controlled clinical trial” or “randomized controlled trial”• Inclusion criteria of the study

– Trials that mentioned Pts with HTN 8wks and study arms with Pt 10≧ ≧– Trials that use thiazide-type diuretics as a single agent or as a primary i

nitial therapy– Trials that mesures both potassium and glucose

• Exclusion criteria of the study– Trials that used combinations of antihypertensive agents– Trials that did not attempt to separate results by the type of diuretic or

drug

Methods

• collected data are;– Trial design, size, duration– Type of thiazide drug, initial dose, dose titratio

nregimen, use of potassium supplements or potassium sparing agents

– Metabolic effects on potassium and glucose

Data Analyses

• Key data: Average change in potassium and glucose

• calcurated as;– Difference in final value in thiazide group and t

hat in placebo group (placebo comparator trials)

– Difference in final value and baseline value (baseline comparator trials; no placebo group)

Data Analyses

• An unweighed Pearson correlation, the nonparametric Spearman correlation, Pearson correlation weighed according to sample size

• 2 additional subanalyses– Trials using >50mg of hydrochlorothiazide wer

e excluded– Trials using any potassium supplements and/or

potassium sparing agents are compared

ResultsFigure 1.

Results

Results

Results

Results

Discussion• This review revealed a significant inverse relationship betwee

n K and glucose ; lower K associated with higher glucose• Many other recent clinical trials support this data• In one study, the highest fasting blood glucose occurred wot

h potassium concentrations <3.9mmol/L • But results from this study must be used carefully because

this study has some limitations (; varied study design, Pt type, way of comparison…..).

• Test for causality for the effect of thiazide-induced hypokalemia on glucose intolerance must come from a rondomized trial

Perspectives

• This study suggests that treatment of thiazide-induced hypokalemia could lessen glucose intolirance and possibly the development of diabetes

Perspectives

• As discussed above, it seemes reasonable to target K ≧4mmol/L among all Pts taking thiazide.

• It can be acomplished by using potassium-sparing diuretics and/or oral potassium supplementation. It seems good to add ACEi or ARB to thiazide because many Pts are taking 2 or more antihypertensive agents as well as because it is showen that this combination can prevent hypokalemia.