Fasting glucose levels and incident diabetes mellitus in older nondiabetic adults randomized to receive 3 different classes of antihypertensive treatment: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

Arch Intern Med. 2006 Nov 13;166(20):2191-201. doi: 10.1001/archinte.166.20.2191.


Background: Elevated blood glucose levels are reported with thiazide-type diuretic treatment of hypertension. The significance of this finding is uncertain. Our objectives were to compare the effect of first-step antihypertensive drug therapy with thiazide-type diuretic, calcium-channel blocker, or angiotensin-converting enzyme inhibitor on fasting glucose (FG) levels and to determine cardiovascular and renal disease risks associated with elevated FG levels and incident diabetes mellitus (DM) in 3 treatment groups.

Methods: We performed post hoc subgroup analyses from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) among nondiabetic participants who were randomized to receive treatment with chlorthalidone (n = 8419), amlodipine (n = 4958), or lisinopril (n = 5034) and observed for a mean of 4.9 years.

Results: Mean FG levels increased during follow-up in all treatment groups. At year 2, those randomized to the chlorthalidone group had the greatest increase (+8.5 mg/dL [0.47 mmol/L] vs +5.5 mg/dL [0.31 mmol/L] for amlodipine and +3.5 mg/dL [0.19 mmol/L] for lisinopril). The odds ratios for developing DM with lisinopril (0.55 [95% confidence interval, 0.43-0.70]) or amlodipine (0.73 [95% confidence interval, 0.58-0.91]) vs chlorthalidone at 2 years were significantly lower than 1.0 (P<.01). There was no significant association of FG level change at 2 years with subsequent coronary heart disease, stroke, cardiovascular disease, total mortality, or end-stage renal disease. There was no significant association of incident DM at 2 years with clinical outcomes, except for coronary heart disease (risk ratio, 1.64; P = .006), but the risk ratio was lower and nonsignificant in the chlorthalidone group (risk ratio, 1.46; P = .14).

Conclusions: Fasting glucose levels increase in older adults with hypertension regardless of treatment type. For those taking chlorthalidone vs other medications, the risk of developing FG levels higher than 125 mg/dL (6.9 mmol/L) is modestly greater, but there is no conclusive or consistent evidence that this diuretic-associated increase in DM risk increases the risk of clinical events.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amlodipine / therapeutic use
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / therapeutic use*
  • Blood Glucose / analysis
  • Blood Glucose / drug effects*
  • Calcium Channel Blockers / therapeutic use
  • Chi-Square Distribution
  • Chlorthalidone / adverse effects
  • Chlorthalidone / therapeutic use*
  • Diabetes Mellitus / blood*
  • Diabetes Mellitus / chemically induced*
  • Diabetes Mellitus / epidemiology
  • Female
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Hyperlipidemias / drug therapy
  • Hypertension / blood
  • Hypertension / drug therapy*
  • Incidence
  • Lisinopril / therapeutic use
  • Male
  • Middle Aged
  • Myocardial Infarction / prevention & control
  • Proportional Hazards Models
  • Sodium Chloride Symporter Inhibitors / adverse effects
  • Sodium Chloride Symporter Inhibitors / therapeutic use*
  • Treatment Outcome


  • Angiotensin-Converting Enzyme Inhibitors
  • Antihypertensive Agents
  • Blood Glucose
  • Calcium Channel Blockers
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Sodium Chloride Symporter Inhibitors
  • Amlodipine
  • Lisinopril
  • Chlorthalidone