J Atherosclerosis Prev Treat. 2022 May-Aug;13(2):49-60 | doi:10.53590/japt.02.1033
Angelos Liontos1, Dimitrios Biros1, George Liamis2, Haralampos Milionis1
1First Department of Internal Medicine, Faculty of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina, Greece
2Second Department of Internal Medicine, Faculty of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina, Greece
Arterial hypertension (AH) is a major cardiovascular risk factor and often coexists with insulin resistance. Insulin resistance impairs glucose homeostasis and has been associated with the development of new-onset type 2 diabetes mellitus (T2D). Overactivity of renin-angiotensin system (RAS) mediated by angiotensin II adversely affects glucose homeostasis. The blockade of RAS with the use of angiotensin converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) has been associated with beneficial effects on glucose metabolism. On the other hand, calcium channel blockers (CCBs) have been reported to exert a metabolic neutral effect. By contrast, the use of diuretics and beta-blockers has been shown to have an overall negative effect on glucose metabolism. Current ESH/ESC treatment guidelines recommend the use of fixed single-pill combinations of RAS blockers with either CCBs or thiazide/thiazide-like diuretics in hypertensive patients with grade 1 AH and high cardiovascular risk, or greater. Nonetheless, considering the patient’s medical history and comorbidities, antihypertensive treatment should be carefully tailored. To this, hypertensive patients at risk of developing new-onset T2D, with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), should be preferentially treated with either monotherapy or combined treatment using agents which do not affect or worsen glucose homeostasis.
Key words: Arterial hypertension, calcium channel blocker, impaired fasting glucose, impaired glucose tolerance, renin-angiotensin-system blocker
Corresponding author: Angelos Liontos, MD, Assistant Consultant of Internal Medicine, University Hospital of Ioannina, Department of Internal Medicine, First Division of Internal Medicine, St. Niarchou Ave., Ioannina, Greece, Tel.: +30 6936626792, +30 2651099624, E-mail: firstname.lastname@example.org
Submission: 27.05.2022, Acceptance: 07.06.2022
Patients with arterial hypertension (AH) often present with impaired glucose metabolism and/or insulin resistance1,2 which is associated with an increased risk of developing type 2 diabetes mellitus (T2D)3.
Individuals with impaired glucose metabolism have been identified by the American Diabetes Association (ADA) between normoglycemia and T2D, including those with impaired fasting glucose (IFG) or impaired glucose tolerance (IFG)4. The prevalence of AH is higher among individuals with IFG or IGT compared with those with normoglycemia5-7.
Different classes of antihypertensive drugs exert various effects on glucose homeostasis8: renin-angiotensin system (RAS) blockers, including angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs), have been shown to have beneficial effects on glucose homeostasis; calcium channel blockers (CCBs) have an overall neutral effect9. By contrast, thiazides and beta-blockers have been associated with negative effects as well as the development of new-onset T2D.
Recent guidelines by ESH/ESC advocate the use of fixed singe-pill combinations of RAS blockers with CCBs or with thiazide/thiazide-like diuretics as first line therapy in hypertensive patients with grade 1 AH and high cardiovascular risk, or greater10,11. Nonetheless, treatment strategy of AH should take into consideration any adverse effects of the agents used on glucose metabolism and the incidence of new-onset T2D12.
This review discusses the available information regarding the effect of commonly used RAS blockers, CCBs and their combinations on indices of glucose homeostasis and the incidence of new-onset T2D, in non-diabetic patients with AH. The foreground question is shown by PICO statement13 in Table 1.
MATERIALS AND METHODS
A literature review was conducted focusing on the effect of antihypertensive agents and their combinations on glucose homeostasis. We studied papers discussing the effects of ARBs, ACEi or CCBs and their combinations; ARB/CCB and ACEi/CCB. Literature research was performed using PUBMED and MEDLINE, with the following Medical Subjects Headings terms (MeSH) and keywords: “antihypertensive treatment”, “combination of ARB and CCB”, “combination of ACEi and CCB”, “carbohydrate metabolism”, “glucose metabolism”, “glucose homeostasis”, “prediabetes”, “impaired fasting glucose”, “IFG”, “impaired glucose tolerance”, “IGT”, “insulin sensitivity”, “insulin resistance”, “HOMA-IR”, “new-onset T2D”. Randomized controlled trials, original papers, review articles and meta-analyses were included. The references of these articles were scrutinized for relevant articles. For articles not written in English, only the abstracts were considered. Articles with results regarding only diabetic population of patients were excluded from the analysis.
Figure 1 provides a flow diagram of the selected process and articles included in the analysis.
Figure 1. Flow diagram of the selected process and articles included in the analysis.
Comparative trials of drug combinations included in this review are summarized in Table 2.
Renin-angiotensin system (RAS) blockers
Glucose homeostasis and RAS are strongly associated. Overactivity of RAS, mediated by angiotensin II, results in insulin resistance, and eventually may lead to T2D14. Several trials have identified a beneficial effect of RAS blockers on glucose metabolism.
Angiotensin converting enzyme inhibitors, ACEi
Treatment with ACEi was associated with a lower incidence of new-onset T2D in clinical trials showing an overall favorable effect on glucose metabolism.
In HOPE (n=9,279)15 and CAPPP trials (n=10,985)16, treatment with an ACEi (ramipril vs. placebo and captopril vs. diuretic or beta-blocker, respectively), resulted in a reduction of T2D incidence (-34%, p<0.001 and 21%, p<0.01, respectively). Similar results were shown in the ALLHAT trial (n=33,357). In ALLHAT, a risk reduction of new-onset T2D was associated with lisinopril treatment vs. chlorthalidone or amlodipine treatment (-30%, p<0.001, -17%, p<0.01, respectively)17.
The overall favorable effect of ACEi was also reported by large meta-analyses. In a meta-analysis of 10 randomized controlled trials (RCTs, n=75,950), the use of ACEi was associated with a lower incidence of T2D vs. placebo (OR: 0.77; p<0.001)18. Similarly, in two network meta-analyses (including 224,140 and 224,832 subjects, respectively), ACEi were associated with a risk reduction of new-onset T2D vs. placebo (-22% and -18%, respectively)19,20. Another meta-analysis showed that ACEi treatment reduced the incidence of new-onset T2D (OR: 0.80, CI: [0.71, 0.91]) vs. other agents (beta-blockers, diuretics, CCBs or placebo)21.
Concerning patients with IFG or IGT, small trials evaluated the effect of ACEi on glucose homeostasis. Delapril (among ACEi) improved insulin sensitivity in hypertensive patients with IGT22,23.
Of note, in DREAM trial (n=5,269), ramipril (another ACEi member) had a neutral effect on glucose homeostasis24. Although, ramipril among patients with IFG or IGT did not reduce the incidence of new-onset T2D, it led to regression to normal glucose levels (p=0.001)21,24. However, this finding was not confirmed by the extension of DREAM trial25.
Angiotensin receptor blockers, ARBs
Large clinical trials evaluated the effect of ARB treatment on glucose homeostasis; an overall beneficial effect was shown. Various ARBs decreased the incidence of new-onset T2D in several large RCTs, while others exerted a neutral effect.
Treatment with valsartan in VALUE (n=15,245) and NAVIGATOR trials (n=9,518) resulted in a lower incidence of new-onset T2D vs. placebo (HR: 0.86; p<0.001)26 and vs. amlodipine (HR: 0.77; p<0.001)27, respectively. Losartan was also associated with a reduction of new-onset T2D vs. atenolol (HR: 0.75; p=0.001), in LIFE trial (n=9193)28.
Candesartan treatment vs. placebo showed an overall lower incidence of T2D (HR: 0.78; CI: [0.64, 0.96], p=0.02), in the CHARM-overall programme (n=7,599)29. The incidence of T2D was lower in only one arm (CHARM-Preserved) of this trial (OR: 0.60; CI: [0.41, 0.86]; p=0.005)30. In the CHARM-Added and CHARM-Alternative arms, candesartan did not show a difference on new-onset T2D (p=0.25)31,32. Similarly, a non-significant difference on new-onset T2D was observed among candesartan vs. placebo, in elderly patients in SCOPE trial (n=4,964)33.
The effect of telmisartan was assessed by 3 major trials. In the TRANSCEND (n=5926)34,35 and PRoFESS trials (n=20,332)36, telmisartan showed a trend in reducing new-onset T2D vs. placebo (20.1% vs 21.6%; HR: 0.91 CI: [0.79, 1.05]; p=0.203 and 1.2% vs 1.5%; p=0.1, respectively). In the ONTARGET trial, telmisartan vs. ramipril did not show a difference in this outcome (6.7% vs. 7.5%, HR: 1.12; CI: [0.97, 1.29]) .
However, meta-analyses of these trials showed different results. A meta-analysis of LIFE, SCOPE and VALUE trials associated treatment with ARBs with a clinically significant reduction in the occurrence of new-onset T2D (RRR: 0.80, CI: [0.74, 0.86]; p<0.0001)37. Similar results were shown in the meta-analysis of TRANSCEND and PRoFESS trials. Telmisartan reduced the risk of new-onset T2D vs. placebo by approximately 16% (OR: 0.84 CI: [0.72, 0.97]; p<0.05)38.
It has been shown that some ARBs possess peroxisome proliferator activated receptor-γ (PPAR-γ) partial activating properties and may favorably affect glucose metabolism. Several trials and meta-analyses evaluated the effects of ARBs on indices of glucose homeostasis, in patients with impaired glucose metabolism: In small trials, treatment with valsartan (although a non PPAR-γ activator) in non-diabetic hypertensive patients resulted in a reduction of fasting insulin levels and HOMA-IR39,40. On the other hand, treatment with irbesartan and telmisartan (documented with PPAR-γ activity) was associated with improvement on glucose metabolism41-43. Treatment with telmisartan, also improved HOMA-IR in several trials in non-diabetic patients44-47. In a study by Rizos et al., telmisartan improved insulin resistance indices compared with other ARBs in hypertensive pre-diabetic patients48. Moreover, the study showed that telmisartan retained its beneficial effects on glucose homeostasis even after combination with rosuvastatin (a statin associated with the development of T2D)48. Since hypertension is often accompanied with hyperlipidemia and thus antihypertensive drugs are often co-administered with statins the results of the previous study become even more relevant in clinical practice.
Of note, a meta-analysis showed that telmisartan was superior to other ARBs in improving HOMA-IR (mean difference: -0.23, CI: [-0.40 -0.06])49. Another meta-analysis of 11 RCTs with non-diabetic patients (n=59,862) compared ARBs to other classes of antihypertensive drugs. Treatment with ARBs was associated with significant reduction in the risk of new-onset T2D vs. placebo (OR: 0.83, CI: [0.78, 0.89]), beta-blockers (OR: 0.73, [0.62, 0.87]), CCBs (OR: 0.76, [0.68, 0.85]) and non-ARBs (OR: 0.57, [0.36, 0.91])50. ARBs were also associated with significant reduction in the risk of new-onset T2D, in patients with IGT (OR: 0.85, [0.78, 0.92])50.
ARBs vs. ACEi
Data from a retrospective cohort study (n=20,108) showed that ACEi and ARBs were associated with a similar risk of new-onset T2D during a 6-year follow-up (OR: 0.92)51, while in another retrospective study of normoglycemic patients with AH, ACEi treatment vs. ARBs resulted in a greater risk reduction of new-onset T2D (HR: 0.54, CI: [0.29, 0.99]; p=0.049)52. Similarly, in a meta-analysis (n=1,015), ACEi were superior on HOMA-IR improvement vs. ARBs in the long-term intervention subgroup of patients (mean difference: 0.41, CI: [0.06, 0.76]; p=0.022)53.
Calcium channel blockers, CCBs
CCBs are generally considered to have an overall neutral metabolic profile9. Although not initially shown, results from a re-analysis of the NAVIGATOR trial, concluded that treatment with CCB (amlodipine) was not associated with the occurrence of T2D (HR: 0.95; CI: [0.79, 1.13])54. Similarly, a meta-analysis of 10 RCTs (n=108,118) in non-diabetic patients with AH, showed that the overall risk of T2D with CCBs was not significant (RR: 0.99, CI: [0.85, 1.15])55.
Small size randomized trials evaluated the effect of treatment with CCBs in changes on indices of glucose metabolism. In these trials, amlodipine (among CCBs) exerted a neutral or a minor favorable effect8,56-60. On the other hand, manidipine (a newer CCB) through partial activation of PPAR-γ61,62 has been associated with improvement on HOMA-IR57,60,63. Manidine treatment decreased HOMA-IR vs. clinidipine and amlodipine (all, p<0.05) in obese patients60 and vs. amlodipine (-21.3%, p=0.007, vs. 8.3%, p=0.062) in patients with the metabolic syndrome63. It has been also shown that manidipine ameliorates the possible insulin resistance associated with statin therapy62, thus favoring glucose homeostasis.
CCBs vs. RAS blockers
Data analysis from large RCTs have shown a clear overall superiority of RAS blockade vs. CCBs treatment.
A meta-analysis of five clinical trials compared the efficacy of ARBs and CCBs on HOMA-IR in non-diabetic patients64. Treatment with ARBs reduced HOMA-IR (mean difference: -0.65, CI: [-0.93 -0.38]) and fasting insulin (mean difference: -2.01, CI: [-3.27 -0.74]) vs. CCBs64. In another meta-analysis CCBs were associated with a higher incidence of T2D vs. ACEi (RR: 1.23; CI: [1.01, 1.51]) and ARBs (RR: 1.27; CI: [1.14, 1.42])55.
This favorable effect of RAS blockers vs. CCBs was shown in a meta-analysis of 22 trials in primary and secondary prevention (n=145,939)65,66. Treatment with ACEi or ARBs reduced the risk of new-onset T2D (RR: 0.84; CI: [0.76, 0.93] and RR: 0.84; CI: [0.76, 0.92], respectively), whereas CCBs had a neutral effect (RR: 1.02; CI: [0.92, 1.13])65,66.
RAS blockers – CCBs combination vs. other combinations on glucose homeostasis and new-onset T2D
Several comparative trials on the effect of different ACEi/CCBs combinations vs. other antihypertensive drugs combinations assessed the effects on glucose homeostasis and the incidence of new-onset T2D.
In the ASCOT-BPLA trial (n=19,257), the incidence of new-onset T2D was lower in the amlodipine/perindopril vs. atenolol/bendroflumethiazide combination (567 vs 799 cases; HR: 0.70, CI: [0.63, 0.78]; p<0.0001)67. Similarly, the open non-randomized observational ADaPT trial (n=2,011) showed that the prevalence of new-onset T2D was higher (24.3% vs. 29.0%; p<0.05) in the group of diuretic monotherapy or combination therapy with beta-blocker vs. ACEi or ACEi/CCB combination (ramipril monotherapy or plus felodipine)68. In the STAR trial, new-onset T2D, was less frequent in trandolapril/verapamil vs. losartan plus hydrochlorothiazide (HCTZ) combination (11.0% vs. 26.6%, p=0.002)69.
Data regarding the effect of ACEi/CCB combination on indices of glucose metabolism are scarce. In the STAR trial, ACEi/CCB combination was superior to ARB plus diuretic on glucose tolerance in hypertensive patients with IGT. In this trial, trandolapril/verapamil decreased the 2-hour oral glucose tolerance test (OGTT) levels vs. losartan/HCTZ (-0.2±0.2 mmol/L; p=0.329 vs. +1.4±0.4 mmol/L; p<0.001; between groups, p<0.001)69. Although FPG and HbA1c levels were increased in both treatment arms, trandolapril/verapamil was associated with minor increases (0.24±0.23 vs. 0.76±0.22 mmol/L, p=0.087 and 0.1±0.1 vs. 0.4±0.1%, p=0.027, respectively). Furthermore, in this trial, insulin sensitivity, assessed by quantitative insulin-sensitivity check index (QUICKI), was decreased by losartan/HCTZ (0.000±0.001 vs. 0.005±0.001; p=0.016)69. Improvement on insulin sensitivity was also observed in another comparative trial (n=88) of delapril/manidipine vs. olmesartan/HCTZ combination, in obese hypertensive patients70. CCB-based combination increased insulin sensitivity (glucose infusion rate [GIR] mg/kg/min) by 3.01 mg/min/kg, (vs. baseline, p=0.038; between groups, p<0.05,) and decreased plasma insulin by 17.8 pmol/L (vs. baseline, p=0.047; between groups, p<0.05)70
A small number of trials examined the effect of ARB/CCBs vs. other combinations, mainly ARB plus thiazide diuretic (TD), on indices of glucose homeostasis and new-onset T2D.
New-onset T2D was a secondary endpoint in the OLAS trial (n=120)71. In this trial, the incidence of new-onset T2D was higher in the olmesartan/HCTZ group vs. olmesartan/amlodipine group (18.3% vs. 5%, OR: 4.24)71. In the CHINA STATUS III study, (n=985) the incidence of new-onset T2D was low (0.6%, n=5) with ARB/CCB combination (valsartan/amlodipine), in a 1-year follow-up72.
Comparative trials on HOMA-IR are limited. A small trial (n=60) evaluated the effect of valsartan/amlodipine vs. valsartan/HCTZ combination on glucose metabolism indices (FPG, insulin, and HOMA-IR)73. Both treatments, resulted in no significant changes in glucose homeostasis, overall73. Of note, valsartan/amlodipine combination increased HOMA-IR by 0.1 unit (0.8[0.4-3.0] vs. 0.9[0.4-3.7]) at the end of treatment period73. On the other hand, the OLAS trial showed a clear superiority of olmesartan/amlodipine vs. olmesartan/HCTZ on metabolic parameters. HOMA-IR and fasting insulin were significantly decreased only in the olmesartan/amlodipine group (24.1 and 25.0%, respectively; both, p<0.01)71.
Results from other small trials regarding changes in HbA1c and/or FPG showed an overall favorable effect of ARB/CCBs vs. ARB/TD or ARB/beta-blocker combinations. In a trial by Shimosawa et al., an increase in HbA1c levels was observed with losartan/HCTZ vs candesartan/amlodipine (5.54±0.33% vs. 5.84 ±0.71%)74. On the other hand, Oshikawa et al. showed that losartan/HCTZ increased both HbA1c and FPG levels vs. losartan/amlodipine (p=NS)75. Similar results were also shown by several trials where both treatment comparators had overall similar neutral effects on FPG and HbA1c76-79. Combination of ARB/CCBs vs. ARB/beta-blocker also showed a neutral effect on glucose homeostasis80.
The comparison between two different ARB/CCB combinations was evaluated in the EXAMINER trial (n=52)81. Both valsartan/amlodipine vs. irbesartan/amlodipine combinations had a neutral result, as they did not exert any changes in HbA1c and FPG levels81.
In a meta-analysis (n=48,913), RAS blockers plus CCBs compared with other antihypertensive combinations, were associated with a significant decrease in FPG by 2.3 mg/dL (p=0.03) and a significant net decrease in HbA1c of 0.20% (p<0.001)82.
This review indicates that the effect of ACEi and ARBs monotherapy yields an overall favorable effect on glucose homeostasis, while treatment with CCBs appear to be neutral. RAS blockade plus CCBs combination treatment may exert also favorable effects in non-diabetic patients and seems to prevent the progression to T2D.
The incidence of new-onset T2D or the effect on other indices of glucose homeostasis of these classes of hypertensive drugs was a prespecified primary or secondary endpoint only in a few trials (Table 2)67-71. Likewise, a rather limited number of trials were designed to evaluate the effect on glycemic indices of these combinations on patients with impaired glucose homeostasis (IFG or IGT)69-71,73 (Table 2).
Despite these limitations in trial endpoints and design, it seems that ACEi/ARB plus CCBs combinations affect glucose metabolism in a positive way, mostly through their preserved separate drug action:
ACEi directly improve insulin sensitivity particularly in the skeletal muscle83 while both ACEi and ARBs increase skeletal muscle blood flow through vasodilatation, thus improving insulin sensitivity. RAS blockers (mainly telmisartan and to a much lesser degree irbesartan) exert additional favorable effects, including partial PPAR-γ agonist action and protection against the oxidative action of angiotensin II8,41-43. RAS blockers have been shown to decrease sympathetic nervous system activation, thus further contributing to improvement of insulin sensitivity9.
CCBs may improve insulin sensitivity through vasodilation in insulin-sensitive tissues and concomitant increased muscle blood flow8. These agents also decrease sympathetic nervous system activation and prevent inhibition of glucose transporters and glycogen synthase by calcium8. Additionally, it has been proposed that CCBs enhance pancreatic β-cell function and might inhibit their apoptosis55
Current guidelines for the prevention of diabetes are in favor of the use of a fixed single-pill combination of a RAS blocker with a CCB in patients with IFG or IGT. Using a thiazide diuretic (TD) or beta-blocker administration could be an alternative to CCBs in certain patient populations; beta-blocker in combination with a TD should be avoided due to its diabetogenic action12 (Figure 2).
Figure 2. Possible combinations of drugs in hypertensive patients with impaired glucose homeostasis. Blue arrow: highly recommended. Yellow arrow: might be combined, Red arrow: not recommended.
ACEi; angiotensin converting enzyme inhibitor, ARB; angiotensin receptor blocker, BB; beta-blocker, CCB; calcium channel blocker, TD; thiazide diuretic
In conclusion, antihypertensive treatment should be individualized considering the patient’s history and comorbidities. In this respect, impaired glucose metabolism dictates the selection of particular drugs over others; agents with a favor and/or a neutral effect should be preferentially used to mitigate the risk of new-onset T2D. However, the overall expected benefits vs. the potential risks must always be carefully weighted for each individual patient (especially in selected patient subgroups such as those with established atherosclerotic cardiovascular disease, heart failure, uncontrolled BP etc.). As a result, when the benefits of antihypertensive treatment overweigh the risk of increased insulin resistance the patient should not be disqualified from receiving appropriate treatment with a drug associated with unfavorable glucose homeostasis.
To Hellenic Atherosclerosis Society.
This review has been supported by the Hellenic Atherosclerosis Society in the setting of a scholarship for a doctoral dissertation.
CONFLICT OF INTERESTS
AL, DM report; no conflict of interest
GL reports; personal fees from AMGEN, personal fees from NOVARTIS and personal fees from MYLAN.
HM reports; participation in educational, research and consulting activities sponsored by healthcare companies, including Amgen, Bayer, Pfizer, Servier, Viatris.
All authors declare no issues relating to journal policies.
Abbreviations: ACEi: angiotensin converting enzyme inhibitor, ADA: American Diabetes Association, AH: arterial hypertension, ARB: angiotensin receptor blocker, BB: beta-blocker, BP: blood pressure, CCB: calcium channel blocker, DBP: diastolic blood pressure, ESH: European Society of Hypertension, ESC: European Society of Cardiology, FPG: fasting plasma glucose, HbA1c: Hemoglobin A1c, HOMA-IR: homeostatic model assessment for insulin resistance, HCTZ: hydrochlorothiazide, IFG: impaired fasting glucose, IGT: impaired glucose tolerance, INS: fasting insulin, OGTT: oral glucose tolerance test, PPAR-γ: peroxisome proliferator activated receptor-γ , RAS: renin-angiotensin system, RCTs: randomized controlled trials , SBP: systolic blood pressure, T2D: type 2 diabetes mellitus, TD: thiazide diuretic, QUICKI: quantitative insulin-sensitivity check index
Abbreviations of trial names: ACCOMPLISH: Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension, ADaPT: ACEi-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes, ALLHAT: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack trial, ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm, CAMUI: Combination of antihypertensive therapy in the elderly, multicenter investigation , CAPP: Captopril Prevention Project , CHARM programme: Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity programme, CHARM-Added: Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity-Added , CHARM-Alternative: Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity-Alternative, CHARM-Preserved: Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity-preserved, DREAM: the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication , DREAM On: Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication Ongoing Follow-up, HOPE: Heart Outcomes Prevention Evaluation study, INVEST: The International Verapamil-Trandolapril Study , LIFE: Losartan Intervention For Endpoint reduction in hypertension, NAVIGATOR: Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research, ONTARGET: Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial, PRoFESS: Prevention Regimen for Effectively Avoiding Second Strokes, SCOPE: the Study on Cognition and Prognosis in the Elderly , STAR: Study of Trandolapril/Verapamil SR And Insulin Resistance , TRANSCEND: Telmisartan Randomized Assessment Study in ACEi Intolerant Subjects with Cardiovascular Disease, VALUE: Valsartan Antihypertensive Long-term Use Evaluation trial
1. Lind L, Berne C, Lithell H. Prevalence of insulin resistance in essential hypertension. J Hypertens. 1995Dec;13(12 Pt 1):1457-62.
2. Lender D, Arauz-Pacheco C, Adams-Huet B, Raskin P. Essential hypertension is associated with decreased insulin clearance and insulin resistance. Hypertension. 1997 Jan;29(1 Pt 1):111-4.
3. Gress TW, Nieto FJ, Shahar E, Wofford MR, Brancati FL. Hypertension and antihypertensive therapy as risk factors for type 2 diabetes mellitus. Atherosclerosis Risk in Communities Study. N Engl J Med. 2000 Mar;342(13):905-12.
4. American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014 Jan;37 Suppl 1:S81-90.
5. Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett PH. Insulin and hypertension: Relationship to obesity and glucose intolerance in Pima Indians. Diabetes. 1990 Nov;39(11):1430-5.
6. Stolk RP, Pols HA, Lamberts SW, Jong PTd, Hofman A, Grobbee DE. Diabetes mellitus, impaired glucose tolerance, and hyperinsulinemia in an elderly population the Rotterdam study. Am J Epidemiol. 1997 Jan;145(1):24-32.
7. Suematsu C, Hayashi T, Fujii S, Endo G, Tsumura K, Okada K, et al. Impaired fasting glucose and the risk of hypertension in Japanese men between the 1980s and the 1990s. The Osaka Health Survey. Diabetes Care. 1999 Feb;22(2):228-32.
8. Karagiannis A, Tziomalos K, Anagnostis P, Gossios TD, Florentin M, Athyros VG, et al. The effect of antihypertensive agents on insulin sensitivity, lipids and haemostasis. Curr Vasc Pharmacol. 2010 Nov;8(6):792-803.
9. Rizos CV, Elisaf MS. Antihypertensive drugs and glucose metabolism. World J Cardiol. 2014 Jul;6(7):517-30.
10. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J. 2021 Sep;42(34):3227-337.
11. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep;39(33):3021-104.
12. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41(2):255-323.
13. Thabane L, Thomas T, Ye C, Paul J. Posing the research question: not so simple. Can J Anaesth. 2009 Jan;56(1):71-9.
14. Henriksen EJ, Prasannarong M. The role of the renin-angiotensin system in the development of insulin resistance in skeletal muscle. Mol Cell Endocrinol. 2013 Sep;378(1-2):15-22.
15. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan;342(3):145-53.
16. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, Niklason A, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999 Feb;353(9153):611-6.
17. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Jama. 2002 Dec;288(23):2981-97.
18. Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 1. A meta-analysis of randomised clinical trials. Diabetes Metab. 2004 Dec;30(6):487-96.
19. Li Z, Li Y, Liu Y, Xu W, Wang Q. Comparative risk of new-onset diabetes mellitus for antihypertensive drugs: A network meta-analysis. J Clin Hypertens. 2017 Dec;19(12):1348-56.
20. Yang Y, Xu H. Comparing six antihypertensive medication classes for preventing new-onset diabetes mellitus among hypertensive patients: a network meta-analysis. J Cell Mol Med. 2017 Sep;21(9):1742-50.
21. Geng DF, Jin DM, Wu W, Liang YD, Wang JF. Angiotensin converting enzyme inhibitors for prevention of new-onset type 2 diabetes mellitus: a meta-analysis of 72,128 patients. Int J Cardiol. 2013 Sep;167(6):2605-10.
22. Sekiya M, Yamasaki Y, Tsujino T, Shiba Y, Kubota M, Kawamori R, et al. Insulin resistance in essential hypertensive patients with impaired glucose tolerance. Diabetes Res Clin Pract. 1995 Jul;29(1):49-56.
23. Weber MA. Comparison of type 1 angiotensin II receptor blockers and angiotensin converting enzyme inhibitors in the treatment of hypertension. J Hypertens Suppl. 1997 Dec;15(6):S31-6.
24. Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G, et al. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006 Oct;355(15):1551-62.
25. Investigators DO, Gerstein HC, Mohan V, Avezum A, Bergenstal RM, Chiasson JL, et al. Long-term effect of rosiglitazone and/or ramipril on the incidence of diabetes. Diabetologia. 2011 Mar;54(3):487-95.
26. McMurray JJ, Holman RR, Haffner SM, Bethel MA, Holzhauer B, Hua TA, et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med. 2010 Apr;362(16):1477-90.
27. Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004 Jun;363(9426):2022-31.
28. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet. 2002 Mar;359(9311):995-1003.
29. Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, Michelson EL, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003 Sep;362(9386):759-66.
30. Yusuf S, Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003 Sep;362(9386):777-81.
31. McMurray JJ, Ostergren J, Swedberg K, Granger CB, Held P, Michelson EL, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003 Sep;362(9386):767-71.
32. Granger CB, McMurray JJ, Yusuf S, Held P, Michelson EL, Olofsson B, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003 Sep;362(9386):772-6.
33. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003 May;21(5):875-86.
34. Telmisartan Randomised AssessmeNt Study in ACEiswcDI, Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008 Sep;372(9644):1174-83.
35. Barzilay JI, Gao P, Ryden L, Schumacher H, Probstfield J, Commerford P, et al. Effects of telmisartan on glucose levels in people at high risk for cardiovascular disease but free from diabetes: the TRANSCEND study. Diabetes care. 2011 Sep;34(9):1902-7.
36. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008 Sep;359(12):1225-37.
37. Cheung BM, Cheung GT, Lauder IJ, Lau CP, Kumana CR. Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension. J Hum Hypertens. 2006 Jan;20(1):37-43.
38. Kurtz TW, Klein U. Next generation multifunctional angiotensin receptor blockers. Hypertension research: Official journal of the Japanese Society of Hypertension. 2009 Oct;32(10):826-34.
39. Top C, Cingozbay BY, Terekeci H, Kucukardali Y, Onde ME, Danaci M. The effects of valsartan on insulin sensitivity in patients with primary hypertension. J Int Med Res. 2002 Jan-Feb;30(1):15-20.
40. Fogari R, Derosa G, Zoppi A, Rinaldi A, Lazzari P, Fogari E, et al. Comparison of the effects of valsartan and felodipine on plasma leptin and insulin sensitivity in hypertensive obese patients. Hypertension research: Official journal of the Japanese Society of Hypertension. 2005 Mar;28(3):209-14.
41. Schupp M, Janke J, Clasen R, Unger T, Kintscher U. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-gamma activity. Circulation. 2004 May;109(17):2054-7.
42. Kintscher U, Bramlage P, Paar WD, Thoenes M, Unger T. Irbesartan for the treatment of hypertension in patients with the metabolic syndrome: a sub analysis of the Treat to Target post authorization survey. Prospective observational, two armed study in 14,200 patients. Cardiovasc Diabetol. 2007 Apr;6:12.
43. Negro R, Formoso G, Hassan H. The effects of irbesartan and telmisartan on metabolic parameters and blood pressure in obese, insulin resistant, hypertensive patients. J Endocrinol Invest. 2006 Dec;29(11):957-61.
44. Nagel JM, Tietz AB, Goke B, Parhofer KG. The effect of telmisartan on glucose and lipid metabolism in nondiabetic, insulin-resistant subjects. Metabolism. 2006 Sep;55(9):1149-54.
45. Benndorf RA, Rudolph T, Appel D, Schwedhelm E, Maas R, Schulze F, et al. Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension. Metabolism. 2006 Sep;55(9):1159-64.
46. Ichikawa Y. Comparative effects of telmisartan and valsartan on insulin resistance in hypertensive patients with metabolic syndrome. Intern Med. 2007;46(17):1331-6.
47. Kiyici S, Guclu M, Budak F, Sigirli D, Tuncel E. Even Short-Term Telmisartan Treatment Ameliorated Insulin Resistance But Had No Influence on Serum Adiponectin and Tumor Necrosis Factor-Alpha Levels in Hypertensive Patients with Metabolic Syndrome. Metab Syndr Relat Disord. 2019 Apr;17(3):167-72.
48. Rizos CV, Milionis HJ, Kostapanos MS, Florentin M, Kostara CE, Elisaf MS, et al. Effects of rosuvastatin combined with olmesartan, irbesartan, or telmisartan on indices of glucose metabolism in Greek adults with impaired fasting glucose, hypertension, and mixed hyperlipidemia: a 24-week, randomized, open-label, prospective study. Clin Ther. 2010 Mar;32(3):492-505.
49. Wang Y, Qiao S, Han DW, Rong XR, Wang YX, Xue JJ, et al. Telmisartan Improves Insulin Resistance: A Meta-Analysis. Am J Ther. 2018 Nov/Dec;25(6):e642-e51.
50. Geng DF, Jin DM, Wu W, Xu Y, Wang JF. Angiotensin receptor blockers for prevention of new-onset type 2 diabetes: a meta-analysis of 59,862 patients. Int J Cardiol. 2012 Mar;155(2):236-42.
51. Liou YS, Chen HY, Tien L, Gu YS, Jong GP. Antihypertensive Drug Use and New-Onset Diabetes in Female Patients with Coronary Artery Disease: A Population-based Longitudinal Cohort Study. Medicine. 2015 Sep;94(36):e1495.
52. Park JY, Rha SW, Choi BG, Choi SY, Choi JW, Ryu SK, et al. Impact of Angiotensin Converting Enzyme Inhibitor versus Angiotensin Receptor Blocker on Incidence of New-Onset Diabetes Mellitus in Asians. Yonsei Med J. 2016 Jan;57(1):180-6.
53. Yao J, Fan S, Shi X, Gong X, Zhao J, Fan G. Angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers on insulin sensitivity in hypertensive patients: A meta-analysis of randomized controlled trials. PloS one [Internet]. 2021 Jul [cited 2021 Jyl 7];16(7):e0253492. Available from: https://pubmed.ncbi.nlm.nih.gov/34234365/
54. Shen L, Shah BR, Reyes EM, Thomas L, Wojdyla D, Diem P, et al. Role of diuretics, beta blockers, and statins in increasing the risk of diabetes in patients with impaired glucose tolerance: reanalysis of data from the NAVIGATOR study. Bmj. 2013 Dec;347:f6745.
55. Noto H, Goto A, Tsujimoto T, Noda M. Effect of calcium channel blockers on incidence of diabetes: a meta-analysis. Diabetes Metab Syndr Obes. 2013 Jul;6:257-61.
56. Fukao K, Shimada K, Hiki M, Kiyanagi T, Hirose K, Kume A, et al. Effects of calcium channel blockers on glucose tolerance, inflammatory state, and circulating progenitor cells in non-diabetic patients with essential hypertension: a comparative study between azelnidipine and amlodipine on glucose tolerance and endothelial function–a crossover trial (AGENT). Cardiovasc Diabetol. 2011 Sep;10:79.
57. Martinez-Martin FJ, Macias-Batista A, Comi-Diaz C, Rodriguez-Rosas H, Soriano-Perera P, Pedrianes-Martin P. Effects of manidipine and its combination with an ACE inhibitor on insulin sensitivity and metabolic, inflammatory and prothrombotic markers in hypertensive patients with metabolic syndrome: the MARCADOR study. Clin Drug Investig. 2011;31(3):201-12.
58. Fogari R, Preti P, Zoppi A, Mugellini A, Corradi L, Lazzari P, et al. Effect of valsartan addition to amlodipine on insulin sensitivity in overweight-obese hypertensive patients. Intern Med. 2008;47(21):1851-7.
59. Koh KK, Han SH, Ahn JY, Chung WJ, Lee Y, Shin EK. Amlodipine improves endothelial function and metabolic parameters in patients with hypertension. Int J Cardiol. 2009 Mar;133(1):23-31.
60. Ueshiba H, Miyachi Y. Effects of the long-acting calcium channel blockers, amlodipine, manidipine and cilnidipine on steroid hormones and insulin resistance in hypertensive obese patients. Intern Med. 2004 Jul;43(7):561-5.
61. Cavalieri L, Cremonesi G. Metabolic effects of manidipine. American journal of cardiovascular drugs: Drugs, devices, and other interventions. 2009;9(3):163-76.
62. Liberopoulos EN, Moutzouri E, Rizos CV, Barkas F, Liamis G, Elisaf MS. Effects of manidipine plus rosuvastatin versus olmesartan plus rosuvastatin on markers of insulin resistance in patients with impaired fasting glucose, hypertension, and mixed dyslipidemia. J Cardiovasc Pharmacol Ther. 2013 Mar;18(2):113-8.
63. Martinez Martin FJ. Manidipine in hypertensive patients with metabolic syndrome: the MARIMBA study. Expert Rev Cardiovasc Ther. 2009 Jul;7(7):863-9.
64. Yang Y, Wei RB, Xing Y, Tang L, Zheng XY, Wang ZC, et al. A meta-analysis of the effect of angiotensin receptor blockers and calcium channel blockers on blood pressure, glycemia and the HOMA-IR index in non-diabetic patients. Metabolism. 2013 Dec;62(12):1858-66.
65. Volpe M, Patrono C. Blood pressure lowering drugs differ in their capacity to prevent type 2 diabetes. Eur Heart J. 2022 Mar;43(12):1189-90.
66. Nazarzadeh M, Bidel Z, Canoy D, Copland E, Wamil M, Majert J, et al. Blood pressure lowering and risk of new-onset type 2 diabetes: an individual participant data meta-analysis. Lancet. 2021 Nov;398(10313):1803-10.
67. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005 Sep;366(9489):895-906.
68. Zidek W, Schrader J, Luders S, Matthaei S, Hasslacher C, Hoyer J, et al. Ramipril-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes (ADaPT) study. Cardiovascular diabetology. 2012 Jan;11:1.
69. Bakris G, Molitch M, Hewkin A, Kipnes M, Sarafidis P, Fakouhi K, et al. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care. 2006 Dec;29(12):2592-7.
70. Fogari R, Derosa G, Zoppi A, Lazzari P, Corradi L, Preti P, et al. Effect of delapril/manidipine vs olmesartan/ hydrochlorothiazide combination on insulin sensitivity and fibrinogen in obese hypertensive patients. Intern Med. 2008;47(5):361-6.
71. Martinez-Martin FJ, Rodriguez-Rosas H, Peiro-Martinez I, Soriano-Perera P, Pedrianes-Martin P, Comi-Diaz C. Olmesartan/amlodipine vs olmesartan/hydrochlorothiazide in hypertensive patients with metabolic syndrome: the OLAS study. J Hum Hypertens. 2011 Jun;25(6):346-53.
72. Huo Y, Gu Y, Ma G, Guo J, Xiong L, Luo Z, et al. China STudy of valsartan/amlodipine fixed-dose combination-bAsed long-Term blood pressUre management in HypertenSive patients: a one-year registry (China STATUS III). Curr Med Res Opin. 2019 Aug;35(8):1441-9.
73. Christogiannis LG, Kostapanos MS, Tellis CC, Milionis HJ, Tselepis AD, Elisaf MS. Distinct effects of fixed combinations of valsartan with either amlodipine or hydrochlorothiazide on lipoprotein subfraction profile in patients with hypertension. J Hum Hypertens. 2013 Jan;27(1):44-50.
74. Shimosawa T, Gohchi K, Yatomi Y, Fujita T. Effectiveness of add-on low-dose diuretics in combination therapy for hypertension: Losartan/hydrochlorothiazide vs. candesartan/amlodipine. Hypertension research: Official journal of the Japanese Society of Hypertension. 2007 Sep;30(9):831-7.
75. Oshikawa J, Toya Y, Morita S, Taguri M, Hanaoka K, Hasegawa T, et al. Angiotensin receptor blocker (ARB)-diuretic versus ARB-calcium channel blocker combination therapy for hypertension uncontrolled by ARB monotherapy. Clin Exp Hypertens. 2014;36(4):244-50.
76. Nishiwaki M, Hosoai H, Ikewaki K, Ayaori M, Yamashita T, Shige H, et al. Efficacy and effects on lipid metabolism of combination treatment with losartan + hydrochlorothiazide versus losartan + amlodipine: a 48-week prospective, multicenter, randomized, open-label trial. Clin Ther. 2013 Apr;35(4):461-73.
77. Sato N, Saijo Y, Sasagawa Y, Morimoto H, Takeuchi T, Sano H, et al. Combination of antihypertensive therapy in the elderly, multicenter investigation (CAMUI) trial: results after 1 year. J Hypertens. 2013 Jun;31(6):1245-55.
78. Suh SY, Ahn T, Bae JH, Lim DS, Lee SU, Kim YK, et al. Efficacy and tolerability of amlodipine camsylate/losartan 5/100-mg versus losartan/hydrochlorothiazide 100/12.5-mg fixed-dose combination in hypertensive patients nonresponsive to losartan 100-mg monotherapy. Clin Ther. 2014 Oct;36(10):1402-11.
79. Toyoda S, Inami S, Kato T, Tsukada K, Nakamoto A, Kikegawa Y, et al. Choice of Antihypertensive Combination Therapy Based on Daily Salt Intake. Am J Med Sci. 2015 Sep;350(3):160-6.
80. Pareek A, Chandurkar NB, Sharma R, Tiwari D, Gupta BS. Efficacy and tolerability of a fixed-dose combination of metoprolol extended release/amlodipine in patients with mild-to-moderate hypertension: a randomized, parallel-group, multicentre comparison with losartan plus amlodipine. Clin Drug Investig. 2010;30(2):123-31.
81. Motozato K, Miura S, Shiga Y, Kusumoto T, Adachi S, Inoue T, et al. Efficacy and safety of two single-pill fixed-dose combinations of angiotensin II receptor blockers/calcium channel blockers in hypertensive patients (EXAMINER study). Clin Exp Hypertens. 2016;38(1):45-50.
82. Pongpanich P, Pitakpaiboonkul P, Takkavatakarn K, Praditpornsilpa K, Eiam-Ong S, Susantitaphong P. The benefits of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers combined with calcium channel blockers on metabolic, renal, and cardiovascular outcomes in hypertensive patients: a meta-analysis. Int Urol Nephrol. 2018 Dec;50(12):2261-78.
83. Jandeleit-Dahm KA, Tikellis C, Reid CM, Johnston CI, Cooper ME. Why blockade of the renin-angiotensin system reduces the incidence of new-onset diabetes. J Hypertens. 2005 Mar;23(3):463-73.