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Managing hypertension in type 2 diabetes mellitus
Accepted Manuscript Managing hypertension in type 2 diabetes mellitus Samuel Horr, MD, Steven Nissen, MD, MACC
PII:
S1521-690X(16)30018-5
DOI:
10.1016/j.beem.2016.06.001
Reference:
YBEEM 1094
To appear in:
Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Horr S, Nissen S, Managing hypertension in type 2 diabetes mellitus, Best Practice & Research Clinical Endocrinology & Metabolism (2016), doi: 10.1016/j.beem.2016.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Managing hypertension in type 2 diabetes mellitus
Samuel Horr, MD
Cardiovascular Medicine Fellow, Cleveland Clinic Foundation Telephone: 216-636-2898
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Fax: 216-444-8690
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[email protected]
Steven Nissen, MD, MACC [email protected]
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Cardiovascular Medicine Department Chair, Cleveland Clinic Foundation Telephone: 216-445-6852
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Fax: 216-445-6855
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Abstract
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Hypertension is a common problem in the diabetic population with estimates suggesting a prevalence exceeding 60%. Comorbid hypertension and diabetes mellitus are associated with high rates of macrovascular and microvascular complications. These two pathologies share overlapping risk factors, importantly central obesity. Treatment of hypertension is unequivocally beneficial and improves allcause mortality, cardiovascular mortality, major cardiovascular events, and microvascular outcomes including nephropathy and retinopathy. Although controversial, current guidelines recommend a target blood pressure in the diabetic population of <140/90 mmHg, which is a similar target to that proposed for individuals without diabetes. Management of blood pressure in patients with diabetes includes both lifestyle modifications and pharmacological therapies. This article reviews the evidence for management of hypertension in patients with type 2 diabetes mellitus, and provides a recommended treatment strategy based on the available data.
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Prevalence and Importance
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Hypertension is a common medical problem in the general population, estimated to be present in 29.1% of the U.S. population over the age of 18. This proportion increases to 65% in those over the age of 601. Worldwide, hypertension is estimated to affect 40% of the population over the age of 25, equating to approximately 1 billion individuals in 20082. Globally, hypertension was estimated to be the number one risk factor accounting for 9.4 million deaths and 7% of disability-adjusted life years in 20103.
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High rates of hypertension in patients with diabetes mellitus were first recognized in 19294. Subsequent studies have shown that patients with diabetes have at least twice the rate of hypertension than those without diabetes5 . A recent systematic review found that hypertension has been reported to be present in greater than 60% of those with diabetes with rates in some studies exceeding 75%6. In the Hypertension and Diabetes Study, 39% of patients with a new diagnosis of type 2 diabetes mellitus had a pre-existing diagnosis of hypertension7. Impaired glucose metabolism has been shown to predict those that will go on to develop hypertension8; the reverse has been shown as well – patients with hypertension are approximately 2.5 times more likely to have impaired fasting glucose metabolism9. By 2040, it is estimated that there will be at least 642 million people with type 2 diabetes mellitus worldwide10.
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Elevations in blood pressure are strongly associated with an increased risk of numerous cardiovascular diseases, in a continuous fashion11. This association is further highlighted in the diabetic population, with an elevated blood pressure associated with higher rates of macrovascular and microvascular complications including myocardial infarction, stroke, congestive heart failure, retinopathy, and nephropathy12. The risk of coronary artery disease is threefold higher in patients with both diabetes and hypertension than in patients with either condition alone13. In fact, one observational study found that 8 out of 10 patients with diabetes will die of cardiovascular causes14. Pathogenesis
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While diabetic nephropathy is the most common cause of hypertension in type 1 diabetes mellitus, hypertension commonly occurs in patients with type 2 diabetes without evidence of underlying kidney disease. Central obesity is a powerful predictor of both hypertension and type 2 diabetes.
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Insulin resistance is a common defect seen in primary hypertension15 that is absent in secondary hypertension16. Insulin resistance, and thus hyperinsulinemia, can precipitate hypertension by activating the sympathetic nervous system and impairing the suppressibility of the renin-angiotensin system (RAS), promoting sodium retention. Diabetes leads to increased vascular activity and proliferation of vascular smooth muscle cells, which is thought to play a significant role in the development of hypertension17.
Benefit of Treatment
Treatment of hypertension in patients with diabetes mellitus has been shown in numerous studies to reduce rates of cardiovascular events and to slow the progression of nephropathy and retinopathy12, 1821 . A recently published meta-analysis of forty randomized controlled trials of blood pressure lowering in patients with diabetes showed that each 10 mmHg reduction in systolic blood pressure was associated with a reduction in all-cause mortality (RR 0.87 [95% CI, 0.78-0.96]), cardiovascular events,
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Blood Pressure Targets
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major coronary heart disease events, and stroke. Microvascular outcomes, including risk of albuminuria and retinopathy, were also improved with reductions in systolic blood pressure18. In the UK Prospective Diabetes Study (UKPDS), patients were randomized in an embedded two-by-two factorial design, to either tight or less-tight blood pressure control. Mean blood pressures achieved during the trial were 144/82 mmHg and 154/87 mmHg in the tight and less-tight blood pressure control groups respectively. Tighter blood pressure control resulted in statistically significant lower rates of diabetes-related deaths, strokes, and microvascular disease22. Two early randomized placebo controlled trials: SHEP (The Systolic Hypertension in the Elderly Program) and Syst-Eur (The Systolic Hypertension in Europe Trial) showed substantial decreases in cardiovascular events, mortality and stroke in patients with diabetes who had reductions in systolic blood pressure23, 24. Mean baseline systolic blood pressure levels in these two trials were >170 mmHg, with modest targets of a 20 mmHg reduction and <150 mmHg respectively. The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study is a more contemporary trial that showed a decrease in all-cause mortality of 14% and cardiovascular mortality of 18% with lower treatment goals than previous trials. The mean baseline systolic blood pressure in ADVANCE was lower than SHEP and Syst-Eur at 145 mmHg, with a reduction to 136 mmHg in the treatment arm19.
Blood pressure treatment targets in patients with diabetes have been an area of controversy, with guidelines revised recently to reflect new recommendations. Systolic and diastolic blood pressure goals are discussed separately below.
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Systolic Blood Pressure Target
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As discussed earlier, the SHEP, UKPDS and Syst-Eur trials provided evidence that achieving a mean systolic blood pressure level of <150 mmHg improves cardiovascular and cerebrovascular outcomes, and lowers mortality in those patients with diabetes22-24. The ADVANCE trial showed that lowering systolic blood pressure from 145 mmHg to 136 mmHg improved all-cause mortality and cardiovascular mortality19.
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Until recently, no randomized trial had directly evaluated whether targeting a systolic blood pressure of <130 mmHg versus 130-140 mmHg improves clinical outcomes. Epidemiological data support the “lower is better” strategy by showing that systolic blood pressure levels >115/75mmHg in patients with diabetes are associated with increased cardiovascular events and mortality, and that a systolic blood pressure level >120 mmHg predicts long-term development of end-stage renal disease25. A competing concern exists regarding the “J-curve phenomenon”, which is a theory suggesting that lowering systolic blood pressure too far may result in adverse events – especially in the elderly and those with coronary artery disease. To address these concerns, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, which reported in 2010, was conducted. Investigators randomly assigned 4,733 patients with hypertension and diabetes to intensive therapy (targeting a systolic blood pressure of <120 mmHg) or standard therapy (targeting a systolic blood pressure of <140 mmHg). Mean achieved blood pressure was 119/64 mmHg in the intensive group and 134/71 mmHg in the standard-therapy group. There was no difference in the primary outcome, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. There was, however, a statistically significant difference in stroke rates
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between the two groups (41% risk reduction in any stroke and 37% risk reduction in nonfatal stroke with intensive therapy. The annual stroke rate, however, was quite low and thus the absolute risk reduction observed in any stroke was only 0.21%/year. At the same time, a significant increase in serious adverse events was seen in the intensive-therapy group including hypotension, arrhythmias, and bradycardia26.
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The SPRINT (Systolic Blood Pressure Intervention Trial) study reports that in a non diabetic population at high risk for cardiovascular events, targeting a systolic blood pressure of <120 mmHg, compared with <140 mmHg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensivetreatment group.27 Diastolic Blood Pressure Target
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In a post-hoc analysis of the HOT (Hypertension Optimal Treatment) trial, a target diastolic blood pressure of <80 mmHg versus <90 mmHg in 1,501 patients with diabetes improved cardiovascular events and cardiovascular mortality21. This finding, however, was in a small subgroup analysis that was not pre-specified, and consisting of only 8% of the total study population. As such, it should only be considered as hypothesis generating. The UKPDS also examined a diastolic blood pressure target of <85 mmHg; however, the comparator group was a diastolic blood pressure target of <105mmHg22. UKPDS was also a mixed study with both systolic and diastolic blood pressure goals; therefore, improvement in outcomes may be related to the improvement in the systolic blood pressure, diastolic blood pressure, or a combination of both, rendering the results difficult to interpret in isolation. Guideline Recommendations
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The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) published their fifth report (JNC V) in 199328 and sixth report (JNC VI) in 1997,29 recommending treatment targets of <130/85 mmHg. The American Diabetes Association in 200230 and JNC seventh report (JNC7) in 200331 changed their recommendations to <130/80 mmHg; however, JNC7 qualified their recommendation by noting that there were limited data to support this lower target. The European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) also made the same recommendation in 200732. In 2013, the ESC and the ESH reevaluated their guidelines and amended their recommendation to a treatment target of <140/85 based on the paucity of high quality data suggesting that lower targets were more efficacious33.
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After the publication of the ACCORD trial results in 2010, the majority of societies, including JNC8 and the ADA, adjusted their target blood pressure goals for patients with diabetes to be similar to those without diabetes, with a goal <140/90 mmHg. The ADA gives consideration for a lower target blood pressure in those patients that are at especially high risk for stroke if this can be obtained without side effects and polypharmacy given the slightly decreased stroke risk seen in ACCORD25. A diastolic goal of 80-85 mmHg is given consideration by the ESC guidelines, citing evidence from HOT and UPKSD; however, there are limitations in these studies are mentioned above. Therapeutic Strategies Lifestyle Modification
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Lifestyle modifications are essential in reducing cardiovascular risk in patients with diabetes, with or without comorbid hypertension. Weight loss, physical exercise, reduction in alcohol intake, smoking cessation, and low sodium intake are all strategies that have been proven to be effective in lowering blood pressure. These changes may also positively affect lipid and glycemic control. If blood pressure levels remains >140 mmHg systolic or >90mmHg diastolic despite lifestyle changes, pharmacological therapy should be initiated in addition to non-pharmacologic strategies25. Pharmacological agents
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Pharmacological agents are indicated in patients that cannot reach target blood pressure goals despite lifestyle modifications. In the diabetic population, achieving target blood pressure goals can be difficult and often monotherapy is not sufficient. Renin-angiotensin-system (RAS) blockers, diuretics, calciumchannel blockers, and β-blockers have all been shown in a recent meta-analysis to be useful in the treatment of hypertension in patients with diabetes20. This meta-analysis of randomized controlled trials concluded that each of the above blood pressure lowering therapy classes reduce major adverse cardiac events to similar extents in patients with or without diabetes. Monotherapy RAS- Blockers
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Renin-angiotensin system blockers, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), have long been considered first line therapy for patients with diabetes and hypertension. The ADVANCE trial randomized diabetic patients with and without hypertension to a fixed combination of perinodopril and indapamide (a thiazide diuretic) which reduced all-cause mortality by 14% and cardiovascular mortality by 18%19.
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In patients with high cardiovascular risk, RAS blockers may have an important benefit. In the diabetic sub-study of the HOPE (Heart Outcomes Prevention Evaluation) trial, 3,577 patients with elevated cardiovascular risk were randomly assigned to ramipril or placebo. Ramipril reduced major adverse cardiac events (MACE) by 25% (95% CI 12%-36%), cardiovascular death by 37% (95% CI 21%-51%) and all-cause mortality by 24% (95% CI 8%-37%)34. In the CHARM trial (Candesartan in Heart Failure – Assessment of Mortality and Morbidity) patients with chronic heart failure were randomized to candesartan or placebo. Those randomized to candesartan had reduced cardiovascular mortality and hospital admissions for heart failure. This finding held true in the pre-specified group of patients with diabetes, which consisted of approximately 2,000 individuals35. In patients with hypertension, diabetes and nephropathy, RAS blockers have been shown to reduce progression of kidney disease and to improve cardiovascular outcomes, both alone19, 36-39 and in comparison to other agents40-43, and, should thus be considered as first line agents in this population. A special caveat must be considered for the Black population. The ALLHAT (Antihypertensive and LipidLowering treatment to prevent Heart Attack Trial) study, included a pre-specified sub-group of Black patients, 46% of whom had diabetes. In this sub-group, those on lisinopril had lower reductions in blood pressure compared to those on chlorthalidone and amlodipine. Chlorthalidone was associated with decreased cardiovascular events in this population compared to lisinopril. Compared to amlodipine, lisinopril was associated with higher rates of stroke44. Another study found that Black patients required significantly higher doses of trandolapril to achieve similar blood pressure reductions to those achieved
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in non Black patients45. For use as monotherapy, RAS blockers may be inferior to thiazides and CCB; however, RAS blockers seem to be effective in this population when used in combination with a thiazide or CCB46, 47.
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The metabolic profile of RAS blockers may be more favorable than other classes of anti-hypertensive agents. One study of patients with non-insulin requiring type 2 diabetes found that treatment with captopril reduced fasting glucose and HbA1c levels48. These agents have been studied in the prevention of diabetes in those with hypertension and the results show a possible, but small, benefit49, 50. These agents are not currently recommended for this indication; however, for those with hypertension at high risk for developing diabetes, the use of a RAS blocker may be a reasonable choice. Thiazide Diuretics
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ALLHAT, published in 2002, is the largest prospective study comparing various types of antihypertensive therapies51. Thirty-six percent of the ALLHAT population of over 33,000 had a diagnosis of type 2 diabetes mellitus. Patients were randomly assigned to chlorthalidone, amlodipine, lisinopril or doxazosin. The primary outcomes of cardiovascular death and non-fatal myocardial infarctions were not different between groups. Chlorthalidone was superior to amlodipine and lisinopril in the secondary outcome of new onset heart failure and superior to lisinopril in the secondary outcome of stroke. Of note, the chlorthalidone group achieved the lowest systolic blood pressure of the three groups, which may account for these differences. The pre-specified subgroup of patients with diabetes showed similar results to the general population52.
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Some concern has been raised about the metabolic effects and complications of high-dose thiazide diuretics. In the ALLHAT population, those without diabetes were statistically more likely to develop an elevated fasting glucose than those on other treatment regimens. Small differences in glucose levels between diuretics and other treatment agents have been consistently present across numerous studies.53 Long-term follow-up (mean 6.9 years) of patients in the ALLHAT trial demonstrated that patients with baseline diabetes at the start of the trial, not surprisingly, had worse outcomes than those that developed diabetes during the course or after completion of the trial. Higher rates of incident diabetes in the chlorthalidone group persisted (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril). Those with incident diabetes on chlorthalidone had no increased risk of cardiovascular outcomes; however, those that developed incident diabetes on other treatment regimens had a statistically significant increased risk of cardiovascular events54. This finding suggests that the elevations in glucose in those on thiazides may be real, but not clinically meaningful. Given this information, thiazide diuretics remain good choice in the treatment of hypertension in patients with diabetes. Calcium Channel Blockers
ALLHAT, as mentioned above, showed no difference in primary outcomes in patients treated with chlorthalidone compared to amlodipine; however, amlodipine was associated with a higher 6-year rate of heart failure (RR 1.38, 95% CI 1.25-1.52)51. This finding of a slight increase in the risk of heart failure was also the conclusion of a large meta-analysis in 200455. Both HOT and Syst-Eur found no deleterious effects of dihydropyridine calcium channel blockers in the treatment of hypertension in patients with diabetes21, 56, 57. The diabetes subgroup of the ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) study demonstrated that a regimen with amlodipine reduced
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cardiovascular event rates and decreased stroke rates compared to an atenolol-based regimen58. The ABCD (Appropriate Blood Pressure Control in Diabetes) trial, in a secondary hypothesis, compared the effect of nisoldipine and enalapril on cardiovascular outcomes. In a small population of 470 patients, those in the nisoldipine arm had a higher incidence of myocardial infarction (RR 9.5, 95% CI 2.7-33.8).59 A similar result was reported in a study comparing fosinopril to amlodipine as a secondary outcome60. RAS blockers have been shown to be superior to both dihydropyridine and non-dihydropyridine calcium channel blockers in preventing kidney complications in those with type 2 diabetes42, 43. Given these findings, the authors of this review favor a RAS blocker (ACE inhibitor or ARB) over the use of a calcium channel blocker for monotherapy in patients with diabetes. In those intolerant of RAS blockers, or in need of combination therapy (discussed below), calcium channel blockers are reasonable. Beta-blockers
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Although UKPDS 39 demonstrated that atenolol was as effective as captopril in lowering blood pressure and preventing microvascular complications61, subsequent studies of beta-blockers as initial therapy in the general diabetic population have shown them to be inferior to other agents58. For example, the diabetes subgroup (1,195 patients) of the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study showed that losartan was more effective than atenolol at reducing cardiovascular events, cardiovascular mortality and all-cause mortality41.
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Beta-blockers may also be associated with deleterious metabolic effects in those with diabetes. In the above-mentioned UKPDS paper 39, those in the atenolol group had worse glycemic control and more weight gain than those taking captopril61. Worsening glycemic control and an association with increased risk of incident diabetes has been suggested by other studies9, 62. Within the beta-blocker group, carvedilol, a combined nonselective beta and alpha-1 blocker, may have the most favorable data. In the GEMINI (Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives) trial, carvedilol was shown to have no effect on HbA1c and a favorable effect on albuminuria compared to metoprolol63. Favorable metabolic effects were found by Giugliano et al in 1997 comparing carvedilol to atenolol64. Neither study was powered to determine whether carvedilol improved ‘hard’ outcomes such as cardiovascular events or mortality. Beta-blockers may also mask symptoms of hypoglycemia in those with diabetes and patients should be warned about this potential side effect. Given these data, beta-blockers are useful as adjunctive therapy in the treatment of hypertension rather than monotherapy. Their use may be most effective in those with comorbidities such as coronary artery disease or heart failure with reduced ejection fraction33. Carvedilol may be the preferred beta-blocker based on its favorable metabolic side-effect profile. Combination Therapy
More often than not, diabetic patients are not well controlled with a single antihypertensive agent and combination therapy is required, but data comparing combination therapy are limited. The ADVANCE trial, which evaluated a combination of an ACE inhibitor and a thiazide diuretic, showed that this combination significantly reduced all-cause mortality, cardiovascular mortality, and cardiovascular events19. This regimen, however, was compared to placebo rather than to a different antihypertensive combination. The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial compared regimens of benazepril combined with either amlodipine or hydrochlorothiazide65. The diabetes subgroup analysis (n=6,946) of ACCOMPLISH showed that the combination of benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide
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at reducing MACE (8.8% versus 11.0% p =0.003)66. Of note, critics of this trial point to the use of the low-dose short acting thiazide, hydrochlorothiazide (12.5-25mg) rather than long-acting chlorthalidone, which was used in the ALLHAT trial.
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Combining an ACE inhibitor and an ARB is not recommended. ONTARGET (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) evaluated the use of telmisartan, ramipril or the combination of both in patients with vascular disease or high-risk diabetes. Telmisartan was equivalent to ramipril; however, the combination provided no additional benefit and had a higher rate of adverse events, including hypotension, syncope, and renal dysfunction. These findings remained in the diabetic subgroup analysis of >6,000 patients67. The VA NEPHRON-D (Veteran Affairs Nephropathy in Diabetes) trial showed no benefit of an ACE inhibitor and ARB combination in those with diabetic nephropathy, and also increased adverse events68.
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Aldosterone antagonists, such as spironolactone and eplerenone, are recommended as fourth-line agents in the treatment of hypertension not well controlled on combination therapy. Numerous clinical studies have shown an excellent treatment effect of aldosterone antagonists on those not well controlled on three antihypertensive agents – often labeled as resistant hypertension69-72. This finding has also been replicated in patients with diabetes mellitus73. Recommended Approach
Practice Points
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Hypertension is common in patients with diabetes and increases their risk for macrovascular and microvascular complications Screening, treatment, and reassessment of treatment efficacy of hypertension in this population is imperative Currently, the majority of guidelines recommend a goal blood pressure of <140/90 mmHg Lifestyle modifications are important and should be addressed at every visit Combination pharmacological therapy is frequently required to achieve target blood pressures RAS blockers remain a mainstay of therapy in patients with diabetes, especially those with albuminuria and/or chronic kidney disease Treatment regimens should be tailored for each patient, based on tolerability and consideration of comorbidities
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The authors of this manuscript offer a recommended approach to the treatment of hypertension in patients with diabetes as shown in Figure 1. The choice of antihypertensive drugs should be based on efficacy and tolerability. Comorbidities, such as chronic kidney disease or heart failure with reduced ejection fraction, should be taken into consideration to individualize therapy.
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Definitive randomized controlled trials are needed to determine in which patients even lower blood pressure targets may be optimal Trials are needed to compare efficacy of various antihypertensive agent combination regimens
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Empagliflozin, a selective inhibitor of sodium glucose co-transporter 2, has been recently shown to reduce blood pressure74 and improve cardiovascular outcomes75 in patients with type 2 diabetes. Further investigation into its role in treating hypertension this population is needed.
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Figure 1. Recommended strategy for managing blood pressure in patients with type 2 diabetes mellitus.
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Abbreviations: ACEi – Angiotension converting enzyme inhibitor, ARB – angiotensin receptor blocker, CCB – calcium channel blocker, GFR – glomerular filtration rate, RAS – renin-angiotensin system * If albuminuria or chronic kidney disease then ACEi/ARB is preferred, if black without kidney disease then can consider thiazide first line ^The preferred thiazide diuretic is chlorthalidone as this was used in the majority of the trials showing benefit % ACEi/ARB preferred as second line if thiazide diuretic initiated first ǂ Carvedilol is preferred beta-blocker due to its favorable metabolic profile compared to atenolol or metoprolol
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PII:
S1521-690X(16)30018-5
DOI:
10.1016/j.beem.2016.06.001
Reference:
YBEEM 1094
To appear in:
Best Practice & Research Clinical Endocrinology & Metabolism
Please cite this article as: Horr S, Nissen S, Managing hypertension in type 2 diabetes mellitus, Best Practice & Research Clinical Endocrinology & Metabolism (2016), doi: 10.1016/j.beem.2016.06.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Managing hypertension in type 2 diabetes mellitus
Samuel Horr, MD
Cardiovascular Medicine Fellow, Cleveland Clinic Foundation Telephone: 216-636-2898
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Fax: 216-444-8690
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[email protected]
Steven Nissen, MD, MACC [email protected]
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Cardiovascular Medicine Department Chair, Cleveland Clinic Foundation Telephone: 216-445-6852
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Fax: 216-445-6855
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Abstract
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Hypertension is a common problem in the diabetic population with estimates suggesting a prevalence exceeding 60%. Comorbid hypertension and diabetes mellitus are associated with high rates of macrovascular and microvascular complications. These two pathologies share overlapping risk factors, importantly central obesity. Treatment of hypertension is unequivocally beneficial and improves allcause mortality, cardiovascular mortality, major cardiovascular events, and microvascular outcomes including nephropathy and retinopathy. Although controversial, current guidelines recommend a target blood pressure in the diabetic population of <140/90 mmHg, which is a similar target to that proposed for individuals without diabetes. Management of blood pressure in patients with diabetes includes both lifestyle modifications and pharmacological therapies. This article reviews the evidence for management of hypertension in patients with type 2 diabetes mellitus, and provides a recommended treatment strategy based on the available data.
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Prevalence and Importance
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Hypertension is a common medical problem in the general population, estimated to be present in 29.1% of the U.S. population over the age of 18. This proportion increases to 65% in those over the age of 601. Worldwide, hypertension is estimated to affect 40% of the population over the age of 25, equating to approximately 1 billion individuals in 20082. Globally, hypertension was estimated to be the number one risk factor accounting for 9.4 million deaths and 7% of disability-adjusted life years in 20103.
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High rates of hypertension in patients with diabetes mellitus were first recognized in 19294. Subsequent studies have shown that patients with diabetes have at least twice the rate of hypertension than those without diabetes5 . A recent systematic review found that hypertension has been reported to be present in greater than 60% of those with diabetes with rates in some studies exceeding 75%6. In the Hypertension and Diabetes Study, 39% of patients with a new diagnosis of type 2 diabetes mellitus had a pre-existing diagnosis of hypertension7. Impaired glucose metabolism has been shown to predict those that will go on to develop hypertension8; the reverse has been shown as well – patients with hypertension are approximately 2.5 times more likely to have impaired fasting glucose metabolism9. By 2040, it is estimated that there will be at least 642 million people with type 2 diabetes mellitus worldwide10.
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Elevations in blood pressure are strongly associated with an increased risk of numerous cardiovascular diseases, in a continuous fashion11. This association is further highlighted in the diabetic population, with an elevated blood pressure associated with higher rates of macrovascular and microvascular complications including myocardial infarction, stroke, congestive heart failure, retinopathy, and nephropathy12. The risk of coronary artery disease is threefold higher in patients with both diabetes and hypertension than in patients with either condition alone13. In fact, one observational study found that 8 out of 10 patients with diabetes will die of cardiovascular causes14. Pathogenesis
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While diabetic nephropathy is the most common cause of hypertension in type 1 diabetes mellitus, hypertension commonly occurs in patients with type 2 diabetes without evidence of underlying kidney disease. Central obesity is a powerful predictor of both hypertension and type 2 diabetes.
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Insulin resistance is a common defect seen in primary hypertension15 that is absent in secondary hypertension16. Insulin resistance, and thus hyperinsulinemia, can precipitate hypertension by activating the sympathetic nervous system and impairing the suppressibility of the renin-angiotensin system (RAS), promoting sodium retention. Diabetes leads to increased vascular activity and proliferation of vascular smooth muscle cells, which is thought to play a significant role in the development of hypertension17.
Benefit of Treatment
Treatment of hypertension in patients with diabetes mellitus has been shown in numerous studies to reduce rates of cardiovascular events and to slow the progression of nephropathy and retinopathy12, 1821 . A recently published meta-analysis of forty randomized controlled trials of blood pressure lowering in patients with diabetes showed that each 10 mmHg reduction in systolic blood pressure was associated with a reduction in all-cause mortality (RR 0.87 [95% CI, 0.78-0.96]), cardiovascular events,
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Blood Pressure Targets
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major coronary heart disease events, and stroke. Microvascular outcomes, including risk of albuminuria and retinopathy, were also improved with reductions in systolic blood pressure18. In the UK Prospective Diabetes Study (UKPDS), patients were randomized in an embedded two-by-two factorial design, to either tight or less-tight blood pressure control. Mean blood pressures achieved during the trial were 144/82 mmHg and 154/87 mmHg in the tight and less-tight blood pressure control groups respectively. Tighter blood pressure control resulted in statistically significant lower rates of diabetes-related deaths, strokes, and microvascular disease22. Two early randomized placebo controlled trials: SHEP (The Systolic Hypertension in the Elderly Program) and Syst-Eur (The Systolic Hypertension in Europe Trial) showed substantial decreases in cardiovascular events, mortality and stroke in patients with diabetes who had reductions in systolic blood pressure23, 24. Mean baseline systolic blood pressure levels in these two trials were >170 mmHg, with modest targets of a 20 mmHg reduction and <150 mmHg respectively. The ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) study is a more contemporary trial that showed a decrease in all-cause mortality of 14% and cardiovascular mortality of 18% with lower treatment goals than previous trials. The mean baseline systolic blood pressure in ADVANCE was lower than SHEP and Syst-Eur at 145 mmHg, with a reduction to 136 mmHg in the treatment arm19.
Blood pressure treatment targets in patients with diabetes have been an area of controversy, with guidelines revised recently to reflect new recommendations. Systolic and diastolic blood pressure goals are discussed separately below.
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Systolic Blood Pressure Target
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As discussed earlier, the SHEP, UKPDS and Syst-Eur trials provided evidence that achieving a mean systolic blood pressure level of <150 mmHg improves cardiovascular and cerebrovascular outcomes, and lowers mortality in those patients with diabetes22-24. The ADVANCE trial showed that lowering systolic blood pressure from 145 mmHg to 136 mmHg improved all-cause mortality and cardiovascular mortality19.
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Until recently, no randomized trial had directly evaluated whether targeting a systolic blood pressure of <130 mmHg versus 130-140 mmHg improves clinical outcomes. Epidemiological data support the “lower is better” strategy by showing that systolic blood pressure levels >115/75mmHg in patients with diabetes are associated with increased cardiovascular events and mortality, and that a systolic blood pressure level >120 mmHg predicts long-term development of end-stage renal disease25. A competing concern exists regarding the “J-curve phenomenon”, which is a theory suggesting that lowering systolic blood pressure too far may result in adverse events – especially in the elderly and those with coronary artery disease. To address these concerns, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, which reported in 2010, was conducted. Investigators randomly assigned 4,733 patients with hypertension and diabetes to intensive therapy (targeting a systolic blood pressure of <120 mmHg) or standard therapy (targeting a systolic blood pressure of <140 mmHg). Mean achieved blood pressure was 119/64 mmHg in the intensive group and 134/71 mmHg in the standard-therapy group. There was no difference in the primary outcome, a composite of cardiovascular death, nonfatal myocardial infarction and nonfatal stroke. There was, however, a statistically significant difference in stroke rates
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between the two groups (41% risk reduction in any stroke and 37% risk reduction in nonfatal stroke with intensive therapy. The annual stroke rate, however, was quite low and thus the absolute risk reduction observed in any stroke was only 0.21%/year. At the same time, a significant increase in serious adverse events was seen in the intensive-therapy group including hypotension, arrhythmias, and bradycardia26.
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The SPRINT (Systolic Blood Pressure Intervention Trial) study reports that in a non diabetic population at high risk for cardiovascular events, targeting a systolic blood pressure of <120 mmHg, compared with <140 mmHg, resulted in lower rates of fatal and nonfatal major cardiovascular events and death from any cause, although significantly higher rates of some adverse events were observed in the intensivetreatment group.27 Diastolic Blood Pressure Target
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In a post-hoc analysis of the HOT (Hypertension Optimal Treatment) trial, a target diastolic blood pressure of <80 mmHg versus <90 mmHg in 1,501 patients with diabetes improved cardiovascular events and cardiovascular mortality21. This finding, however, was in a small subgroup analysis that was not pre-specified, and consisting of only 8% of the total study population. As such, it should only be considered as hypothesis generating. The UKPDS also examined a diastolic blood pressure target of <85 mmHg; however, the comparator group was a diastolic blood pressure target of <105mmHg22. UKPDS was also a mixed study with both systolic and diastolic blood pressure goals; therefore, improvement in outcomes may be related to the improvement in the systolic blood pressure, diastolic blood pressure, or a combination of both, rendering the results difficult to interpret in isolation. Guideline Recommendations
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The Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC) published their fifth report (JNC V) in 199328 and sixth report (JNC VI) in 1997,29 recommending treatment targets of <130/85 mmHg. The American Diabetes Association in 200230 and JNC seventh report (JNC7) in 200331 changed their recommendations to <130/80 mmHg; however, JNC7 qualified their recommendation by noting that there were limited data to support this lower target. The European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) also made the same recommendation in 200732. In 2013, the ESC and the ESH reevaluated their guidelines and amended their recommendation to a treatment target of <140/85 based on the paucity of high quality data suggesting that lower targets were more efficacious33.
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After the publication of the ACCORD trial results in 2010, the majority of societies, including JNC8 and the ADA, adjusted their target blood pressure goals for patients with diabetes to be similar to those without diabetes, with a goal <140/90 mmHg. The ADA gives consideration for a lower target blood pressure in those patients that are at especially high risk for stroke if this can be obtained without side effects and polypharmacy given the slightly decreased stroke risk seen in ACCORD25. A diastolic goal of 80-85 mmHg is given consideration by the ESC guidelines, citing evidence from HOT and UPKSD; however, there are limitations in these studies are mentioned above. Therapeutic Strategies Lifestyle Modification
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Lifestyle modifications are essential in reducing cardiovascular risk in patients with diabetes, with or without comorbid hypertension. Weight loss, physical exercise, reduction in alcohol intake, smoking cessation, and low sodium intake are all strategies that have been proven to be effective in lowering blood pressure. These changes may also positively affect lipid and glycemic control. If blood pressure levels remains >140 mmHg systolic or >90mmHg diastolic despite lifestyle changes, pharmacological therapy should be initiated in addition to non-pharmacologic strategies25. Pharmacological agents
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Pharmacological agents are indicated in patients that cannot reach target blood pressure goals despite lifestyle modifications. In the diabetic population, achieving target blood pressure goals can be difficult and often monotherapy is not sufficient. Renin-angiotensin-system (RAS) blockers, diuretics, calciumchannel blockers, and β-blockers have all been shown in a recent meta-analysis to be useful in the treatment of hypertension in patients with diabetes20. This meta-analysis of randomized controlled trials concluded that each of the above blood pressure lowering therapy classes reduce major adverse cardiac events to similar extents in patients with or without diabetes. Monotherapy RAS- Blockers
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Renin-angiotensin system blockers, such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), have long been considered first line therapy for patients with diabetes and hypertension. The ADVANCE trial randomized diabetic patients with and without hypertension to a fixed combination of perinodopril and indapamide (a thiazide diuretic) which reduced all-cause mortality by 14% and cardiovascular mortality by 18%19.
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In patients with high cardiovascular risk, RAS blockers may have an important benefit. In the diabetic sub-study of the HOPE (Heart Outcomes Prevention Evaluation) trial, 3,577 patients with elevated cardiovascular risk were randomly assigned to ramipril or placebo. Ramipril reduced major adverse cardiac events (MACE) by 25% (95% CI 12%-36%), cardiovascular death by 37% (95% CI 21%-51%) and all-cause mortality by 24% (95% CI 8%-37%)34. In the CHARM trial (Candesartan in Heart Failure – Assessment of Mortality and Morbidity) patients with chronic heart failure were randomized to candesartan or placebo. Those randomized to candesartan had reduced cardiovascular mortality and hospital admissions for heart failure. This finding held true in the pre-specified group of patients with diabetes, which consisted of approximately 2,000 individuals35. In patients with hypertension, diabetes and nephropathy, RAS blockers have been shown to reduce progression of kidney disease and to improve cardiovascular outcomes, both alone19, 36-39 and in comparison to other agents40-43, and, should thus be considered as first line agents in this population. A special caveat must be considered for the Black population. The ALLHAT (Antihypertensive and LipidLowering treatment to prevent Heart Attack Trial) study, included a pre-specified sub-group of Black patients, 46% of whom had diabetes. In this sub-group, those on lisinopril had lower reductions in blood pressure compared to those on chlorthalidone and amlodipine. Chlorthalidone was associated with decreased cardiovascular events in this population compared to lisinopril. Compared to amlodipine, lisinopril was associated with higher rates of stroke44. Another study found that Black patients required significantly higher doses of trandolapril to achieve similar blood pressure reductions to those achieved
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in non Black patients45. For use as monotherapy, RAS blockers may be inferior to thiazides and CCB; however, RAS blockers seem to be effective in this population when used in combination with a thiazide or CCB46, 47.
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The metabolic profile of RAS blockers may be more favorable than other classes of anti-hypertensive agents. One study of patients with non-insulin requiring type 2 diabetes found that treatment with captopril reduced fasting glucose and HbA1c levels48. These agents have been studied in the prevention of diabetes in those with hypertension and the results show a possible, but small, benefit49, 50. These agents are not currently recommended for this indication; however, for those with hypertension at high risk for developing diabetes, the use of a RAS blocker may be a reasonable choice. Thiazide Diuretics
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ALLHAT, published in 2002, is the largest prospective study comparing various types of antihypertensive therapies51. Thirty-six percent of the ALLHAT population of over 33,000 had a diagnosis of type 2 diabetes mellitus. Patients were randomly assigned to chlorthalidone, amlodipine, lisinopril or doxazosin. The primary outcomes of cardiovascular death and non-fatal myocardial infarctions were not different between groups. Chlorthalidone was superior to amlodipine and lisinopril in the secondary outcome of new onset heart failure and superior to lisinopril in the secondary outcome of stroke. Of note, the chlorthalidone group achieved the lowest systolic blood pressure of the three groups, which may account for these differences. The pre-specified subgroup of patients with diabetes showed similar results to the general population52.
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Some concern has been raised about the metabolic effects and complications of high-dose thiazide diuretics. In the ALLHAT population, those without diabetes were statistically more likely to develop an elevated fasting glucose than those on other treatment regimens. Small differences in glucose levels between diuretics and other treatment agents have been consistently present across numerous studies.53 Long-term follow-up (mean 6.9 years) of patients in the ALLHAT trial demonstrated that patients with baseline diabetes at the start of the trial, not surprisingly, had worse outcomes than those that developed diabetes during the course or after completion of the trial. Higher rates of incident diabetes in the chlorthalidone group persisted (7.5% with chlorthalidone, 5.6% with amlodipine, and 4.3% with lisinopril). Those with incident diabetes on chlorthalidone had no increased risk of cardiovascular outcomes; however, those that developed incident diabetes on other treatment regimens had a statistically significant increased risk of cardiovascular events54. This finding suggests that the elevations in glucose in those on thiazides may be real, but not clinically meaningful. Given this information, thiazide diuretics remain good choice in the treatment of hypertension in patients with diabetes. Calcium Channel Blockers
ALLHAT, as mentioned above, showed no difference in primary outcomes in patients treated with chlorthalidone compared to amlodipine; however, amlodipine was associated with a higher 6-year rate of heart failure (RR 1.38, 95% CI 1.25-1.52)51. This finding of a slight increase in the risk of heart failure was also the conclusion of a large meta-analysis in 200455. Both HOT and Syst-Eur found no deleterious effects of dihydropyridine calcium channel blockers in the treatment of hypertension in patients with diabetes21, 56, 57. The diabetes subgroup of the ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial – Blood Pressure Lowering Arm) study demonstrated that a regimen with amlodipine reduced
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cardiovascular event rates and decreased stroke rates compared to an atenolol-based regimen58. The ABCD (Appropriate Blood Pressure Control in Diabetes) trial, in a secondary hypothesis, compared the effect of nisoldipine and enalapril on cardiovascular outcomes. In a small population of 470 patients, those in the nisoldipine arm had a higher incidence of myocardial infarction (RR 9.5, 95% CI 2.7-33.8).59 A similar result was reported in a study comparing fosinopril to amlodipine as a secondary outcome60. RAS blockers have been shown to be superior to both dihydropyridine and non-dihydropyridine calcium channel blockers in preventing kidney complications in those with type 2 diabetes42, 43. Given these findings, the authors of this review favor a RAS blocker (ACE inhibitor or ARB) over the use of a calcium channel blocker for monotherapy in patients with diabetes. In those intolerant of RAS blockers, or in need of combination therapy (discussed below), calcium channel blockers are reasonable. Beta-blockers
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Although UKPDS 39 demonstrated that atenolol was as effective as captopril in lowering blood pressure and preventing microvascular complications61, subsequent studies of beta-blockers as initial therapy in the general diabetic population have shown them to be inferior to other agents58. For example, the diabetes subgroup (1,195 patients) of the LIFE (Losartan Intervention for Endpoint Reduction in Hypertension) study showed that losartan was more effective than atenolol at reducing cardiovascular events, cardiovascular mortality and all-cause mortality41.
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Beta-blockers may also be associated with deleterious metabolic effects in those with diabetes. In the above-mentioned UKPDS paper 39, those in the atenolol group had worse glycemic control and more weight gain than those taking captopril61. Worsening glycemic control and an association with increased risk of incident diabetes has been suggested by other studies9, 62. Within the beta-blocker group, carvedilol, a combined nonselective beta and alpha-1 blocker, may have the most favorable data. In the GEMINI (Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives) trial, carvedilol was shown to have no effect on HbA1c and a favorable effect on albuminuria compared to metoprolol63. Favorable metabolic effects were found by Giugliano et al in 1997 comparing carvedilol to atenolol64. Neither study was powered to determine whether carvedilol improved ‘hard’ outcomes such as cardiovascular events or mortality. Beta-blockers may also mask symptoms of hypoglycemia in those with diabetes and patients should be warned about this potential side effect. Given these data, beta-blockers are useful as adjunctive therapy in the treatment of hypertension rather than monotherapy. Their use may be most effective in those with comorbidities such as coronary artery disease or heart failure with reduced ejection fraction33. Carvedilol may be the preferred beta-blocker based on its favorable metabolic side-effect profile. Combination Therapy
More often than not, diabetic patients are not well controlled with a single antihypertensive agent and combination therapy is required, but data comparing combination therapy are limited. The ADVANCE trial, which evaluated a combination of an ACE inhibitor and a thiazide diuretic, showed that this combination significantly reduced all-cause mortality, cardiovascular mortality, and cardiovascular events19. This regimen, however, was compared to placebo rather than to a different antihypertensive combination. The ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial compared regimens of benazepril combined with either amlodipine or hydrochlorothiazide65. The diabetes subgroup analysis (n=6,946) of ACCOMPLISH showed that the combination of benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide
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at reducing MACE (8.8% versus 11.0% p =0.003)66. Of note, critics of this trial point to the use of the low-dose short acting thiazide, hydrochlorothiazide (12.5-25mg) rather than long-acting chlorthalidone, which was used in the ALLHAT trial.
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Combining an ACE inhibitor and an ARB is not recommended. ONTARGET (The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) evaluated the use of telmisartan, ramipril or the combination of both in patients with vascular disease or high-risk diabetes. Telmisartan was equivalent to ramipril; however, the combination provided no additional benefit and had a higher rate of adverse events, including hypotension, syncope, and renal dysfunction. These findings remained in the diabetic subgroup analysis of >6,000 patients67. The VA NEPHRON-D (Veteran Affairs Nephropathy in Diabetes) trial showed no benefit of an ACE inhibitor and ARB combination in those with diabetic nephropathy, and also increased adverse events68.
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Aldosterone antagonists, such as spironolactone and eplerenone, are recommended as fourth-line agents in the treatment of hypertension not well controlled on combination therapy. Numerous clinical studies have shown an excellent treatment effect of aldosterone antagonists on those not well controlled on three antihypertensive agents – often labeled as resistant hypertension69-72. This finding has also been replicated in patients with diabetes mellitus73. Recommended Approach
Practice Points
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Hypertension is common in patients with diabetes and increases their risk for macrovascular and microvascular complications Screening, treatment, and reassessment of treatment efficacy of hypertension in this population is imperative Currently, the majority of guidelines recommend a goal blood pressure of <140/90 mmHg Lifestyle modifications are important and should be addressed at every visit Combination pharmacological therapy is frequently required to achieve target blood pressures RAS blockers remain a mainstay of therapy in patients with diabetes, especially those with albuminuria and/or chronic kidney disease Treatment regimens should be tailored for each patient, based on tolerability and consideration of comorbidities
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The authors of this manuscript offer a recommended approach to the treatment of hypertension in patients with diabetes as shown in Figure 1. The choice of antihypertensive drugs should be based on efficacy and tolerability. Comorbidities, such as chronic kidney disease or heart failure with reduced ejection fraction, should be taken into consideration to individualize therapy.
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Definitive randomized controlled trials are needed to determine in which patients even lower blood pressure targets may be optimal Trials are needed to compare efficacy of various antihypertensive agent combination regimens
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Empagliflozin, a selective inhibitor of sodium glucose co-transporter 2, has been recently shown to reduce blood pressure74 and improve cardiovascular outcomes75 in patients with type 2 diabetes. Further investigation into its role in treating hypertension this population is needed.
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Figure 1. Recommended strategy for managing blood pressure in patients with type 2 diabetes mellitus.
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Abbreviations: ACEi – Angiotension converting enzyme inhibitor, ARB – angiotensin receptor blocker, CCB – calcium channel blocker, GFR – glomerular filtration rate, RAS – renin-angiotensin system * If albuminuria or chronic kidney disease then ACEi/ARB is preferred, if black without kidney disease then can consider thiazide first line ^The preferred thiazide diuretic is chlorthalidone as this was used in the majority of the trials showing benefit % ACEi/ARB preferred as second line if thiazide diuretic initiated first ǂ Carvedilol is preferred beta-blocker due to its favorable metabolic profile compared to atenolol or metoprolol
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