Should thiazide diuretics be used in patients with hypertension combined with diabetes mellitus? Is there evidence-based medical evidence to support this? This is an important question that clinicians often encounter. Although thiazide diuretics are consistently recommended as first-line antihypertensive drugs in national hypertension guidelines, their clinical application in China is still inadequate. The underlying reason may be clinicians’ concern about the side effects caused by thiazide diuretics such as hypokalemia, hyperuricemia, and hyperglycemia. Michael E. Ernst and Marvin M. Moser of the Department of Pharmacy Practice and Science at the University of Iowa College of Pharmacy and the Department of Family Medicine at the Carver College of Medicine, USA. A review entitled “Diuretic Use in Patients with Hypertension” was published in the New England Journal of Medicine on November 26, 2009. The article noted that thiazide diuretics are the first class of effective oral antihypertensives with an acceptable range of side effects. The upstream portion of the distal renal tubule is the main site of action of thiazides, and the initial decrease in blood pressure is attributed to a decrease in extracellular fluid and plasma volume, leading to a decrease in cardiac preload and cardiac output. Temporary increases in peripheral vascular resistance can be induced by the activation of the sympathetic nervous system and the reverse regulation of the renin-angiotensin-aldosterone system, and a thiazide diuretic combined with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) can resist this temporary increase in vascular resistance. The combination of a thiazide diuretic with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) may counteract this temporary increase in vascular resistance and may improve the antihypertensive efficacy while partially counteracting the side effects of hypokalemia, hyperuria, and hyperglycemia caused by thiazide diuretics. This is true in clinical practice, where thiazide diuretics combined with ACEI or ARB often have unexpected or even critical antihypertensive effects. In the controlled evaluation study (ADVANCE) of perindopril and damecam extended-release tablets, we found that the combination of perindopril/indapamide reduced mortality in patients with type 2 diabetes, but no such benefit was seen with intensive glycemic control to glycated hemoglobin levels less than 6.5%. Subsequent follow-up for an additional 6 years (ADVANCE-ON) showed that the risk of all-cause death and death from cardiovascular causes remained significantly lower in the active antihypertensive treatment group during the trial, with risk ratios of 0.91 (95% confidence interval [CI], 0.84-0.99; P=0.03) and 0.88 (95% CI, 0.77-0.99; P=0.04), respectively. In contrast, there was no difference in the risk of all-cause death or major macrovascular events between the intensive glycemic control and standard glycemic control groups during follow-up. Hypertension was combined in 59.8% of our type 2 diabetic patients and in 77.3% of our elderly diabetic patients. In order to improve the rate of hypertension compliance, thiazide diuretics are consistently recommended as first-line antihypertensive drugs in national hypertension guidelines. ADVANCE and ADVANCE-ON further show that even in hypertensive patients with diabetes mellitus, thiazide diuretics are still effective first-line antihypertensive drugs and their status is unshakable.