Management of Albuminuria: Focus on Pharmacotherapy

Transcription

1 This Clinical Resource gives subscribers additional insight related to the Recommendations published in September 2018 ~ Resource # Management of Albuminuria: Focus on Pharmacotherapy Diabetic nephropathy is the most common cause of end stage renal disease (ESRD). 1 In addition, microalbuminuria is associated with cardiovascular disease. 2 The chart below addresses questions that often arise in practice regarding prevention and management of albuminuria in type 2 diabetes, with a focus on pharmacotherapeutic interventions. Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CKD = chronic kidney disease; Cr = creatinine; CV = cardiovascular; egfr = estimated glomerular filtration rate; ESRD = End Stage Renal Disease; JNC8 = Eighth Joint National Committee; NSAIDs = nonsteroidal anti-inflammatory drugs; RAAS = renin angiotensin-aldosterone system; SGLT2 inhibitor = sodium glucose co-transporter 2; UACR = urinary albumin-to-creatinine ratio Clinical Question What causes diabetic nephropathy? Pertinent Information In diabetes, high blood glucose causes glomerular hyperfiltration and triggers inflammation, oxidative damage, fibrosis, and activation of the renin-angiotensin-aldosterone system (RAAS). Together, these effects damage the kidneys. 1 What is microalbuminuria, and what is its clinical significance? Microalbuminuria, defined as a UACR of 2 to 20 mg/mmol on random collection, or 30 to 300 mg albumin in a 24 hour urine collection (Diabetes Canada), is the earliest sign of diabetic nephropathy, and is associated with CV disease. 2,3 The diagnosis of CKD is made based on two of three UACR measurements taken over a three-month period, or an egfr <60 ml/min at three months. 3 The American Diabetes Association standards no longer use the term microalbuminuria, but do consider UCAR 30 mg/g Cr to be increased. 18 The patient can be considered to have albuminuria if two of three UACR measurements over a three- to six-month period are abnormal. 18 What is macroalbuminuria, and what is its clinical significance? Macroalbuminuria is a risk factor for cardiovascular events and progression to ESRD. 45 Diabetes Canada no longer uses the term macroalbuminuria. Overt nephropathy can be diagnosed based on a UACR >20 mg/mmol on random collection. 3 The American Diabetes Association standards no longer use the term macroalbuminuria, but do strongly recommend treatment with an ACEI or ARB for hypertension in patients with UACR 300 mg/g Cr and/or egfr <60 ml/min/1.73m 2 because in clinical trials treatment is associated with better renal and CV outcomes, including reduced risk of progression to ESRD. 18 An ACEI or ARB is also recommended for hypertensive patients with UACR 30 to 299 mg/g Cr to prevent progression to more advanced albuminuria (but not ESRD) and to reduce CV events. 18

2 (Clinical Resource #340905: Page 2 of 10) Clinical Question What drugs are effective for preventing progression of diabetic nephropathy? Continued Pertinent Information RAAS blockers Considering its pathophysiology it is not surprising that RAAS blockers have been studied to prevent progression of diabetic nephropathy. Treatment of microalbuminuria with ACEIs or ARBs has been shown to reduce the risk of development of microalbuminuria or progression from micro- to macroalbuminuria/overt nephropathy. Pertinent studies are described briefly below: ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial) enrolled patients with atherosclerosis, or diabetes with target organ damage. In ONTARGET, achieving a blood pressure of <130/80 mmhg was associated with a lower risk of microalbuminuria or macroalbuminuria, and even conversion to normoalbuminuria, vs achieving a blood pressure of <140/90 mmhg. 7 The ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension) study included almost 7,000 patients with diabetes. Patients were randomized to benazepril (Lotensin) plus amlodipine (Norvasc) or benazepril plus hydrochlorothiazide. Only benazepril/hydrochlorothiazide was associated with reduction of microalbuminuria. 9 In ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation), patients with type 2 diabetes were randomized to perindopril/indapamide (Coversyl Plus, Canada) or placebo. Active treatment was effective for preventing onset of microalbuminuria, preventing progression of microalbuminuria to macroalbuminuria, and even regression of albuminuria. 10 In the ROADMAP (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention) trial, olmesartan (Benicar) was studied to prevent microalbuminuria in normoalbuminuric diabetic patients. Microalbuminuria onset was delayed. 14 In the BENEDICT-B (Bergamo Nephrologic Diabetes Complications Trial-B) study, trandolapril (Mavik) alone was compared to verapamil/trandolapril in hypertensive diabetic patients with microalbuminuria. There was no placebo group. Both treatments were similar in regard to progression to macroalbuminuria, and regression to normoalbuminuria. Patients who regressed had higher blood pressure, better glycemic control, shorter duration of diabetes, and lower urinary albumin excretion at baseline. 15 In RENALL (Reduction of Endpoints in NIDDM with Angiotensin II Antagonist Losartan), losartan, used in addition to other antihypertensives, reduced the risk of doubling of serum creatinine in type 2 diabetes patients with macroalbuminuria and elevated serum creatinine vs placebo. It also significantly reduced the level of proteinuria and rate of renal decline. 20 In HOPE (Heart Outcomes Prevention Evaluation), ramipril reduced the risk of overt nephropathy (UACR >36 mg/mmol albumin/g Cr, or 300 mg albumin or 500 mg total protein in a 24 hour urine collection) vs placebo in patients with diabetes and CV risk, but no clinical proteinuria at baseline. 4 Irbesartan reduced the risk of progression to overt nephropathy in type 2 diabetes patients with microalbuminuria and hypertension vs placebo. 5

3 (Clinical Resource #340905: Page 3 of 10) Clinical Question Drugs for preventing progression of diabetic nephropathy, continued Continued Pertinent Information In INNOVATION (Incipient to Overt: Angiotensin II Blocker, Telmisartan, Investigation on Type 2 Diabetic Nephropathy), telmisartan reduced the risk of overt nephropathy in type 2 diabetes patients with microalbuminuria, and increased rates of regression to normoalbuminuria, vs placebo. 6 Glucose-lowering agents Some agents may benefit the kidney by doing more than just improving glucose levels. For example, SGLT2 inhibitors (flozins) may reduce intraglomerular pressure and GLP-1 agonists may have an anti-inflammatory effect. 47 In the three-year EMPA-REG OUTCOME trial (a CV outcome study), empagliflozin (Jardiance) or placebo was added to standard care (e.g., ACEI or ARB [>80% of patients], statin, metformin) in patients with type 2 diabetes and CV disease. 34 At baseline, most patients had normo- or microalbuminuria, and/or egfr >60 ml/min/1.73 m 2. Empagliflozin prevented new or worsening nephropathy in about one in 16 patients. 34 Doubling of serum creatinine occurred in 1.5% of the empagliflozin patients vs 2.6% of the placebo patients (p<0.001%). 34 Progression to macroalbuminuria occurred in 11.2% of the empagliflozin patients vs 16.2% of placebo patients (p<0.001%). 34 Empagliflozin delayed need for dialysis in 1 in 333 patients. 34 In CANVAS (a CV outcome study), canagliflozin (Invokana) or placebo was added to standard care in patients with type 2 diabetes with CV disease or at high risk of CV disease. At baseline, >80% were taking a RAAS blocker. Mean egfr was 76.5 ml/min/1.73 m 2, most were normoalbuminuric. 44 Canagliflozin slowed the rate of egfr decline and reduced UACR. 44 One in 770 patients treated for one year with canagliflozin will be spared a doubling of serum creatinine, ESRD, or renal death (composite endpoint). 44 Doubling of serum creatinine was the only component that was significantly reduced. 44 New onset macroalbuminuria was also reduced. 44 In the four-year LEADER trial (a CV outcome study), liraglutide (Victoza) or placebo was added to usual care in patients with type 2 diabetes and high risk of CV disease. At baseline, >80% of patients were taking an ACEI or ARB, and few had advanced renal disease. 45 Liraglutide-treated patients had a lower incidence of nephropathy (a composite measurement of new onset macroalbuminuria or doubling of serum Cr plus egfr 45 ml/min/1.73m 2, need for renal replacement therapy, or renal disease death) in about 1 in 67 high-risk patients over four years. 33 This finding was due to prevention of new-onset persistent macroalbuminuria in about 1 in 83 patients. 45 In SUSTAIN-6 (a CV outcome study), semaglutide (Ozempic) was compared to placebo in patients with CV disease or at high risk of CV disease. At baseline, >80% of patients were taking an ACEI or ARB, only 13.4% had chronic kidney disease. 46 Semaglutide-treated patients had a lower incidence of nephropathy (a composite measurement of new onset macroalbuminuria or doubling of serum Cr plus egfr 45 ml/min/1.73m 2, need for renal replacement therapy, or renal disease death) in about 1 in 44 patients after two years. This outcome was driven by prevention of macroalbuminuria. 46 Additional studies are ongoing (see

4 (Clinical Resource #340905: Page 4 of 10) Clinical Question Drugs for preventing progression of diabetic nephropathy, continued Pertinent Information Calcium channel blockers Calcium channel blockers are inferior to ACEI and ARBs in regard to renoprotection. 42 However, diltiazem may have benefit as an add-on. 41 A small study suggests that diltiazem added to an ACEI slows progression from micro- to macroalbuminuria, independent of blood pressure control. 41 The ACCOMPLISH (Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension) study included almost 7,000 patients with diabetes. Patients were randomized to benazepril (Lotensin) plus amlodipine (Norvasc) or benazepril plus hydrochlorothiazide. Only benazepril/hydrochlorothiazide was associated with reduction of microalbuminuria. 9 In the BENEDICT-B (Bergamo Nephrologic Diabetes Complications Trial-B) study, trandolapril (Mavik) alone was compared to verapamil/trandolapril in hypertensive diabetic patients with microalbuminuria. There was no placebo group. Both treatments were similar in regard to progression to macroalbuminuria, and regression to normoalbuminuria. Patients who regressed had higher blood pressure, better glycemic control, shorter duration of diabetes, and lower urinary albumin excretion at baseline. 15 Does treating microor macroalbuminuria prevent the hard clinical endpoints of ESRD and CV events? Continued RAAS blockers Treating macroalbuminuria with an ARB appears to reduce the risk of ESRD, but current evidence does not support a benefit on hard clinical outcomes from treating microalbuminuria. Pertinent studies are described briefly below: In RENALL (described above), losartan reduced the risk of progression to need for dialysis or kidney transplant in type 2 diabetes patients with macroalbuminuria and elevated serum creatinine. 20 In IDNT (Irbesartan Diabetic Nephropathy Trial), irbesartan reduced the risk of progression to dialysis, kidney transplant, or serum creatinine of 6 mg/dl in type 2 diabetes patients with macroalbuminuria, elevated serum creatinine, and hypertension vs amlodpine. 16 In the ACCOMPLISH study (described above) in patients with diabetes, benazepril/hydrochlorothiazide reduced microalbuminuria, but did not reduce CV events. 9 In ADVANCE (described above) perindopril/indapamide did not prevent renal death or need for renal replacement in patients with diabetes, despite its ability to prevent onset of microalbuminuria, prevent progression of microalbuminuria to macroalbuminuria, and even cause regression of albuminuria. 10 In the BENEDICT-B (described above) trandolapril and trandolapril/verapamil were similar in regard to occurrence of major CV events in hypertensive diabetic patients (there was no placebo group). Microalbuminuria patients who regressed to normoalbuminuria had fewer CV events vs those who did not regress, but patients who regressed had higher blood pressure, better glycemic control, shorter duration of diabetes, and lower urinary albumin excretion at baseline. 15 In ROADMAP (described above) CV events were increased, despite a reduction in microalbuminuria onset by

5 (Clinical Resource #340905: Page 5 of 10) Clinical Question Effect of treating albuminuria on the hard clinical endpoints of ESRD and CV events, continued Pertinent Information olmesartain. 14 In HOPE (Heart Outcomes Prevention Evaluation), ramipril reduced the risk of CV events vs placebo in patients with diabetes and CV risk, but CV benefit was independent of microalbuminuria. 4 Glucose-lowering agents In the three-year EMPA-REG OUTCOME trial in type 2 diabetes patients with CV disease, empagliflozin delayed need for dialysis in 1 in 333 patients, when added to standard care (e.g., ACEI or ARB, statin, metformin). 34 This study included patients with normo-, micro-, and macroalbuminuria at baseline. 34 Empagliflozin also showed a reduction in a composite outcome of CV death, nonfatal MI, and nonfatal stroke, as well as death from any cause. 35 In ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation), in patients randomized to intensive glucose control (A1C 6.5% or less) with gliclazide (a sulfonylurea), the NNT over five years to prevent one ESRD event was 410 in the overall population, or 41 in patients with baseline albuminuria. 37 Should RAAS blockers be combined to prevent progression of diabetic nephropathy? Continued There is no proof combination therapy slows progression of kidney disease compared to an ACEI or ARB monotherapy, but adverse effects are increased. Although combination therapy may reduce proteinuria, it can actually increase risk of CV death, renal events, hypotension, and hyperkalemia. 8,10,12,13,17,30,31 Avoid aliskiren/acei or ARB combos in patients with diabetes (contraindication) 19,32 or moderate to severe renal impairment (contraindication). 32 Pertinent studies are described briefly below: In ONTARGET (described above), the primary renal outcome was a composite of dialysis, creatinine doubling, or death. The combination of telmisartan (Micardis) plus ramipril (Altace) increased the risk of the primary outcome vs either drug alone. This was despite the combination s superiority over ramipril alone at reducing progression from microalbuminuria to macroalbuminuria. 8 The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Disease Endpoints) study set out to determine if aliskiren (Tekturna) 300 mg once daily added to an ACEI or ARB would reduce renal and CV morbidity and mortality in patients with type 2 diabetes at high event risk. The study included patients with albuminuria, microalbuminuria, or CV disease. 11 The combination did not improve renal or CV outcomes. The combination did increase the risk of hyperkalemia and hypotension in diabetes patients with renal impairment and/or CV disease (98% of participants had CKD). 12 The AVOID (Aliskiren in the Evaluation of Proteinuria in Diabetes) study was performed in hypertensive diabetic nephropathy patients. Compared to losartan alone, aliskiren plus losartan increased the risk of hyperkalemia, reduced proteinuria, and in patients with baseline blood pressure 140/90 mmhg and above, slowed the rate of renal decline (post-hoc analysis), and increased the risk of hypotension in patients with baseline blood pressure <130/80 mmhg (post-hoc analysis). 13,17 In ORIENT (Olmesartan Reducing Incidence of End Stage Renal Disease in Diabetic Nephropathy Trial), olmesartan was added to an ACEI in patients with overt nephropathy. Olmesartan reduced proteinuria, but did not reduce the

6 (Clinical Resource #340905: Page 6 of 10) Clinical Question Combining RAAS blockers, continued Pertinent Information primary composite outcome of doubling of serum creatinine, ERSD, and death. CV death was higher in the olmesartan group. 31 What do the guidelines say about management of microalbuminuria? Annual screening with a random UACR and egfr is recommended in patients with type 2 diabetes. 3,18 ACEIs and ARBs are recommended for certain (not all) patients with diabetes: American Diabetes Association: recommended for nonpregnant adults with diabetes and hypertension and modestly elevated urinary albumin excretion ( mg/day), and strongly recommended for those with urinary excretion 300 mg/day and/or egfr <60 ml/min/1.73 m Diabetes Canada: recommended for nonpregnant adults with CKD plus hypertension or albuminuria to delay progression of CKD. 3 National Kidney Foundation: suggested for patients with UACR 30 mg/g at high risk of diabetic kidney disease or its progression. 21 What about blood pressure and glucose control? To reduce the risk or slow the progression of nephropathy, address glucose control as well as blood pressure. 3,18,21-23 Glucose control The National Kidney Foundation recommends an A1C goal of about 7% in patients without hypoglycemia risk. 21 Evidence that intensive glucose-lowering can prevent advanced renal complications is limited. 3,34 In ADVANCE, in patients randomized to intensive glucose control (A1C 6.5% or less) with gliclazide (a sulfonylurea), the NNT over five years to prevent one ESRD event was 410 in the overall population, or 41 in patients with baseline albuminuria. 37 Empagliflozin (Jardiance) and Victoza (liraglutide), although not first-line treatments, reduce CV death in high-risk patients with type 2 diabetes. 3,33,35 Empagliflozin can also delay need for dialysis in patients with type 2 diabetes and CV disease. 34 Several CV and renal outcome studies with canagliflozin or dapagliflozin are ongoing. 36 Continued Blood pressure control For patients with diabetes and hypertension, a target blood pressure of <130/80 mmhg is recommended by the National Kidney Foundation and Hypertension Canada. 23,29 The American Diabetes Association standards state this goal can be considered for some patients with diabetes, depending on the risk vs benefit to the individual. 18 For example, patients with CKD and albuminuria, or patients at high risk of CV disease, may achieve a net benefit. 18 JNC 8 recommends a

7 (Clinical Resource #340905: Page 7 of 10) Clinical Question Blood pressure and glucose control, continued How do you monitor and manage changes in renal function in patients taking ACEIs/ARBs or SGLT2 inhibitors? Pertinent Information goal of <140/90 mmhg, stating that trials have not shown that treatment to <130/80 mmhg is better for reducing renal or CV outcomes compared with a goal <140/90 mmhg. 28 The ACCORD blood pressure study suggests that achieving an average systolic blood pressure of around 119 mmhg doesn t reduce overall CV outcomes compared to an average systolic blood pressure of about 133 mmhg [Evidence level A-1]. 24 However, this lower blood pressure was associated with a reduced risk of stroke and macroalbuminuria. 24 In ONTARGET, tight blood pressure control (<130/80 mmhg) did not reduce CV events more than achieving a blood pressure of <140/90 mmhg, even though achieving a blood pressure of <130/80 mmhg was associated with a lower risk of microalbuminuria or macroalbuminuria, and even conversion to normoalbuminuria, vs achieving a blood pressure of <140/90 mmhg. 7 An ACEI or ARB is a first-line option for blood pressure control in patients with diabetes, and is recommended for patients with UACR 30 mg/g Cr by the American Diabetes Association to reduce the risk of kidney disease progression. 18 JNC8, Diabetes Canada, Hypertension Canada, and the National Kidney Foundation designate them first-line for diabetes patients with CKD. 3,23,28,29 ACEIs and ARBs have been shown to reduce CV morbidity and mortality in hypertensive patients with and without diabetes [Evidence level A-1]. 4,24,26,27 FDA and Health Canada warn about acute kidney injury after starting canagliflozin (Invokana) or dapagliflozin (Farxiga [U.S.]; Forxiga [Canada]). 38,48,49 Empagliflozin (Jardiance) and ertugliflozin (Steglatro) also carry warnings about increased serum creatinine and decreased egfr. 25,39,40,43 In over 50% of cases with canagliflozin or dapagliflozin, the problem occurred within the first month of use. 38 Risk factors: decreased blood volume; CKD; heart failure; or use of diuretics, ACEIs, ARBs, or NSAIDs. 25,38-40,43 Consider temporarily discontinuing flozins in any setting of reduced oral intake such as acute illness or fasting, or with fluid losses such as gastrointestinal illness or excessive heat exposure. 25,38-40,43 Advise patients to report reduced urination or swelling of the legs or feet. 38 Check renal function at baseline and periodically. 25,38-40,43 Some experts suggest monitoring/managing flozin renal effects similar to those of an ACEI or ARB. Heed product information regarding starting/stopping the flozin based on egfr. For information on monitoring ACEIs/ARBs, see our algorithm, Monitoring ACEIs and ARBs. Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

8 (Clinical Resource #340905: Page 8 of 10) Levels of Evidence In accordance with our goal of providing Evidence- Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish. Level Definition Study Quality A B C Good-quality patient-oriented evidence.* Inconsistent or limited-quality patient-oriented evidence.* 1. High-quality RCT 2. SR/Meta-analysis of RCTs with consistent findings 3. All-or-none study 1. Lower-quality RCT 2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings 3. Cohort study 4. Case control study Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. *Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life). RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69: Project Leader in preparation of this clinical resource (340905): Melanie Cupp, Pharm.D., BCPS References 1. Choudhury D, Tuncel M, Levi M. Diabetic nephropathy a multifaceted target of new therapies. Discov Med 2010;10: Weir MR. Microalbuminuria and cardiovascular disease. Clin J Am Soc Nephrol 2007;2: Diabetes Canada clinical practice guidelines expert committee. Diabetes Canada 2018 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2018;42(Suppl 1):S Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO- HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355: Parving HH, Lehnert H, Brochner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345: Makino H, Haneda M, Babazono T, et al. Prevention of transition from incipient to overt nephropathy with telmisartan in patients with type 2 diabetes. Diabetes Care 2007;30: Mancia G, Schumacher H, Redon J, et al. Blood pressure targets recommended by guidelines and incidence of cardiovascular and renal events in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). Circulation 2011;124: Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372: Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010;56: de Galan BE, Perkovic V, Ninomiya T, et al. Lowering blood pressure reduces renal events in type 2 diabetes. J Am Soc Nephrol 2009;20: Parving HH, Brenner BM, McMurray JJ, et al. Aliskiren trial in type 2 diabetes using cardio-renal endpoints (ALTITUDE): rationale and study design. Nephrol Dial Transplant 2009;24: Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367: Parving HH, Persson F, Lewis JB, et al. Aliskiren combined with losartan in type 2 diabetes and nephropathy. N Engl J Med 2008;358: Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or prevention of microalbuminuria in type 2 diabetes. N Engl J Med 2011;364: Ruggenenti P, Fassi A, Ilieva A, et al. Effects of verapamil added-on trandolapril therapy in hypertensive type 2 diabetes patients with microalbuminuria: the BENEDICT-B randomized trial. J Hypertens 2011;29: Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001;345: Persson F, Lewis JB, Lewis EJ, et al. Aliskiren in combination with losartan reduces albuminuria independent of baseline blood pressure in patients with type 2 diabetes and nephropathy. Clin J Am Soc Nephrol 2011;6: American Diabetes Association. Standards of medical care in diabetes Diabetes Care 2018;41:S1-S Product information for Tekturna. Noden Pharma USA. Boston, MA November Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345: pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com

9 (Clinical Resource #340905: Page 9 of 10) 21. National Kidney Foundation. KDOQI clinical practice guideline for diabetes and CKD: 2012 update. Am J Kidney Dis 2012;60: (Accessed July 31, 2018). 22. American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care 2002;25(Suppl 1):S28-S National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease (2007). OQI/guideline_diabetes/index.htm. (Accessed July 31, 2018). 24. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362: Product information for Steglatro. Merck & Co. Whitehouse Station, NJ December 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 angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid- Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA 2002;288: Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363: James PA, Oparil S, Carter BL, et al evidencebased guideline for the management of high blood pressure in adults. report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311: Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada s 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol 2018;34: Kunz R, Friedrich C, Wolbers M, Mann JF. Metaanalysis: effect of monotherapy and combination therapy with inhibitors of the renin angiotensin system on proteinuria in renal disease. Ann Intern Med 2008;148: Imai E, Chan JC, Ito S, et al. Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study. Diabetologia 2011;54: Product monograph for Rasilez. Noden Pharma DAC. Dublin, IE. January Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375: Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375: Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373: U.S. National Institutes of Health. ClinicalTrials.gov study registry/database. (Accessed July 31, 2018). 37. Perkovic V, Heerspink HL, Chalmers J, et al. Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int 2013;83: FDA. FDA drug safety communication: FDA strengthens kidney warnings for diabetes medicine canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR). June 14, m. (Accessed August 1, 2018). 39. Product information for Jardiance. Boehringer Ingelheim Pharmaceuticals. Ridgefield, CT December Product monograph for Jardiance. Boehringer Ingelheum (Canada) Ltd. Burlington, ON L7L 5H4. April Perez-Maraver M, Carrera MJ, Micalo T, et al. Renoprotective effect of diltiazem in hypertensive type 2 diabetic patients with persistent microalbuminuria despite ACE inhibitor treatment. Diabetes Res Clin Pract 2005;70; Toto RD, Tian M, Fakouhi K, et al. Effects of calcium channel blockers on proteinuria in patients with diabetic nephropathy. J Clin Hypertens 2008;10: Product monograph for Steglatro. Merck Canada. Kirkland, QC H9H 4M7. May Perkovic V, Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS program randomized trials. Lancet Diabetes Endocrinol 2018 Jun 21. doi: /S (18) Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017;377: Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2016;375: Muskiet MHA, Tonneijck L, Smits MM, et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol 2017;13: Product monograph for Invokana. Janssen. Toronto, ON M3C 1L9. November Product monograph for Forxiga. AstraZeneca Canada. Mississauga, ON L4Y 1M4. March pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com

10 (Clinical Resource #340905: Page 10 of 10) Cite this document as follows: Clinical Resource, Management of Albuminuria: Focus on Pharmacotherapy. Pharmacist s Letter/Prescriber s Letter. September Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2018 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com

11 This Clinical Resource gives subscribers additional insight related to the Recommendations published in August 2018 ~ Resource # Antihypertensive Combinations Many patients need two or more antihypertensives to reach their blood pressure goal (U.S. subscribers; Canadian subscribers). 18 Emphasize lifestyle changes (e.g., reducing sodium and alcohol intake) and review for conditions (e.g., obstructive sleep apnea) and meds that can raise blood pressure. Verify adherence and the accuracy of blood pressure readings before adjusting medications. Initiating therapy with two antihypertensives is recommended in U.S. guidelines for patients who are more than 20 mmhg above their systolic goal or 10 mmhg above their diastolic goal. 1,18,19 Using two appropriately chosen antihypertensives can lower blood pressure more and help patients reach blood pressure goals sooner, with fewer side effects and at lower doses, than using a single drug. 1,18 A fixed-dose combination pill may improve adherence compared to using individual medications. 18 Certain combinations are preferred, acceptable, or not preferred based on efficacy, cardiovascular outcomes, side effects, and adherence. 1 This chart provides efficacy, cardiovascular outcomes, side effects, and single pill (i.e., fixed-dose combo) availability information for various antihypertensive combinations. Not all possible combinations are listed. The chart also provides information to assist in matching patients to a particular preferred or acceptable combination. When choosing a combination, note that most pivotal studies showing clinical benefit of treating hypertension included a thiazide. 2 Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; CCB = calcium channel blocker. a. Dihydropyridine CCBs = amlodipine, felodipine, isradipine, nicardipine, nifedipine, nisoldipine. b. Non-dihydropyridine CCBs = diltiazem and verapamil. c. The thiazides chlorthalidone and indapamide provide better 24-hour blood pressure control than hydrochlorothiazide, and were used in pivotal outcomes studies (e.g., ALLHAT, SHEP, ADVANCE). 1,3,10,15,16 d. Charts are available to compare available agents within some of the medications classes used to treat high blood pressure (e.g., ACEIs [U.S. subscribers], ARBs [U.S. subscribers; Canadian subscribers], beta-blockers [U.S. subscribers; Canadian subscribers], CCBs [U.S. subscribers; Canadian subscribers], thiazides). Combination d Single Pill Combination Availability Comments Preferred Combinations for Uncomplicated Hypertension ACEI or ARB plus Most ACEIs and ARBs available in combination ACEI/ARB reduces risk of thiazide-induced hypokalemia. 1 thiazide c with hydrochlorothiazide. ACEI/ARB ameliorates diuretic-induced activation of the reninangiotensin-aldosterone All ACEI/hydrochlorothiazide combos available system. 1 generically in U.S. Additive blood pressure reduction. 1 Continued... Olmesartan/amlodipine/ hydrochlorothiazide (U.S.)(Tribenzor) Outcomes data for ACEI/thiazide combination (e.g., reduces stroke, heart failure, mortality, diabetes complications). 3,4,7

12 (Clinical Resource #340808: Page 2 of 7) Combination d Single Pill Combination Availability Comments Preferred Combinations, continued ACEI or ARB plus thiazide, c continued Valsartan/amlodipine/hydrochlorothiazide (U.S.)(Exforge HCT) Consider for chronic renal insufficiency, 9,17 diabetes, 17 or history of stroke or transient ischemic attack. 7,9,17 Azilsartan/chlorthalidone (Edarbyclor) An ACE or ARB combined with amlodipine and a thiazide is associated with additional blood pressure lowering compared to combinations of two of the individual ingredients. 18 ACEI or ARB plus Benazepril/amlodipine (U.S.)(Lotrel, generics) ACEI/ARB ameliorates dihydropyridine CCB-induced edema. 1 CCB a,b,* Olmesartan/amlodipine (U.S.)(Azor, generics) ACEI/ARB counteracts dihydropyridine CCB-induced Olmesartan/amlodipine/ sympathetic stimulation (e.g., tachycardia). 1 *See comments hydrochlorothiazide (U.S.)(Tribenzor, generics) Additive blood pressure reduction with both dihydropyridine and column for Trandolapril/verapamil (Tarka, generics [U.S.]) non-dihydropyridine CCBs. 1,22,23 specifics Valsartan/amlodipine (U.S.)(Exforge, generics; also Dihydropyridine outcomes data are primarily with amlodipine. 8 distinguishing available with hydrochlorothiazide as Exforge HCT, Consider for chronic renal insufficiency, 17 diabetes, 9,17 history of between generics) stroke or transient ischemic attack, 17 and high-risk coronary artery dihydropyridine Perindopril/amlodipine (Prestalia [U.S.], Viacoram disease (ACEI plus dihydropyridine [not short-acting and nondihydropyridine [Canada]) nifedipine]). 9 Telmisartan/amlodipine (Twynsta, generics [U.S.]) Outcomes data for ACEI or ARB/thiazide combination (e.g., CCBs. reduces heart failure, myocardial infarction, mortality). 8,24 An ACEI or ARB combined with amlodipine and a thiazide is associated with additional blood pressure lowering compared to combinations of two of the individual ingredients. 18 Thiazide c, plus Olmesartan/amlodipine/ Additive blood pressure reduction. 21 CCB a,b,* hydrochlorothiazide (U.S.)(Tribenzor, generics]) VALUE study: amlodipine plus hydrochlorothiazide reduced *See comments Valsartan/amlodipine/ hydrochlorothiazide (U.S.)(Exforge HCT, generics) cardiovascular events as well as valsartan plus hydrochlorothiazide [Evidence Level A-1]. 6 column for Neither offsets the side effects of the other class (no distinction specifics between dihydropyridine and non-dihydropyridines). 1 distinguishing An ACE or ARB combined with amlodipine and a thiazide is between associated with additional blood pressure lowering compared to dihydropyridine combinations of two of individual ingredients. 18 and nondihydropyridine combination in the black patients, the elderly, or patients with Dihydropyridine CCBs plus a thiazide may be a preferred CCBs. isolated systolic hypertension due to the stroke protection with both classes compared to other antihypertensives

13 (Clinical Resource #340808: Page 3 of 7) Combination d Single Pill Combination Availability Comments Acceptable Combinations for Uncomplicated Hypertension: Consider based on patient factors (e.g., comorbidities, antihypertensive response history, contraindications/potential safety issues with preferred agents, cost). Thiazide c plus aliskiren Aliskiren/hydrochlorothiazide (Tekturna HCT [U.S.], Rasilez HCT [Canada]) Aliskiren reduces risk of thiazide-induced hypokalemia. 1 Ameliorates thiazide-induced activation of the renin-angiotensinaldosterone system. 1 Additive blood pressure reduction. 1 Reserve for patients unable to tolerate an ACEI, ARB, or other preferred antihypertensive. See our chart, ACEI, ARB, and Aliskiren Comparison. Thiazide c plus betablocker Atenolol/chlorthalidone (Tenoretic, generics) Bisoprolol/hydrochlorothiazide (U.S.) (Ziac, generics) Metoprolol tartrate/hydrochlorothiazide (U.S.)(Lopressor HCT, generics) Metoprolol succinate/hydrochlorothiazide (U.S.)(Dutoprol, generics) Nadolol/bendroflumethiazide (U.S.)(Corzide, generics) Propranolol/hydrochlorothiazide (U.S.) Pindolol/hydrochlorothiazide (Canada)(Viskazide) Beta-blockers ameliorate thiazide-induced activation of reninangiotensin-aldosterone system. 1 Additive blood pressure reduction. 1 Thiazides improve beta-blocker efficacy in African Americans. 1 Side effects (fatigue, sexual dysfunction, glucose intolerance) may be problematic. 1 Beta-blockers seem less effective than other antihypertensive classes for improving outcomes in hypertension (most data are from studies using atenolol). 5 Reserve for patients with hypertension plus another condition that would benefit from a beta-blocker (e.g., heart failure, postmyocardial infarction, angina, migraine prophylaxis). 5,9,17 See our charts, Target Doses of Meds for Systolic Heart Failure and Target Doses of Post-MI Medications, for evidence-based choices. Thiazide c plus potassium-sparing diuretic Hydrochlorothiazide/amiloride (Novamilor [Canada], generics) Hydrochlorothiazide/triamterene (Maxzide [U.S.], Dyazide [U.S.], generics) Hydrochlorothiazide/spironolactone (Aldactazide, generics) Spironolactone, amiloride, or triamterene offsets thiazide-induced hypokalemia. 1 Blood pressure reduction variable. 1 Risk of hyperkalemia in patients with creatinine clearance of 50 ml/min or less. 1 No outcomes data.

14 (Clinical Resource #340808: Page 4 of 7) Combination d Single Pill Combination Availability Comments Acceptable combinations, continued Beta-blocker plus None Additive blood pressure reduction. 1 dihydropyridine No outcomes data. 1 CCB a Reserve for patients with hypertension plus another condition that would benefit from a beta-blocker (e.g., heart failure, post-mi, angina, migraine prophylaxis). 5,9,17 See our charts, Target Doses of Meds for Systolic Heart Failure and Target Doses of Post-MI Medications, for evidence-based choices. Aliskiren plus None No outcomes data. CCB a,b Reserve aliskiren for patients who can t take an ACEI or ARB. ACEI or ARB plus beta-blocker Dihydropyridine CCB plus nondihydropyridine CCB a,b Nebivolol/valsartan (U.S.)(Byvalson) Combination provides little additional blood pressure lowering. 1 However, combination is appropriate for patients who also have systolic heart failure or post-mi. 1 See our charts, Target Doses of Meds for Systolic Heart Failure and Target Doses of Post-MI Medications, for evidence-based choices. None Additive blood pressure reduction. 19 No outcomes data. Non-dihydropyridine CCBs should be avoided in patients with reduced ejection fraction heart failure. 19 Not Preferred Combinations for Uncomplicated Hypertension ACEI plus ARB None Combination provides little additional blood pressure lowering with more adverse effects (e.g., hyperkalemia, syncope) than monotherapy and no cardiovascular outcomes benefit. 1,14,19 Not recommended per guidelines. 9,19 May have role in systolic heart failure. 1,14

15 (Clinical Resource #340808: Page 5 of 7) Combination d Single Pill Combination Availability Comments Not Preferred Combinations, continued Aliskiren plus ARB or ACEI None Combination provides little additional blood pressure lowering with more adverse effects than monotherapy, and no cardiovascular outcomes data in hypertesion. 1,14 Aliskiren added to ACEI or ARB in patients with diabetes plus renal impairment and/or cardiovascular disease increased risk of hyperkalemia and hypotension. 11 o Avoid combo in patients with diabetes or moderate to severe renal impairment. 12,13 Consider a preferred ACEI or ARB combo first. Nondihydropyridine CCB b plus betablocker Methyldopa plus beta-blocker Clonidine plus beta-blocker None Risk of heart block and bradycardia. 1 None Risk of heart block and bradycardia. 1 Abrupt discontinuation can cause hypertensive crisis. 1 None Risk of heart block and bradycardia. 1 Abrupt discontinuation can cause hypertensive crisis. 1 Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

16 (Clinical Resource #340808: Page 6 of 7) Levels of Evidence In accordance with our goal of providing Evidence- Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish. Level Definition Study Quality A B C Good-quality patient-oriented evidence.* Inconsistent or limited-quality patient-oriented evidence.* 1. High-quality RCT 2. SR/Meta-analysis of RCTs with consistent findings 3. All-or-none study 1. Lower-quality RCT 2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings 3. Cohort study 4. Case control study Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. *Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life). RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69: Project Leader in preparation of this clinical resource (340808): Beth Bryant, Pharm.D., BCPS, Assistant Editor References 1. Gradman AH, Basile JN, Carter BL, et al. Combination therapy in hypertension. J Am Soc Hypertens 2010;4: James PA, Oparil S, Carter BL, et al evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014;311: Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370: Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008;358: Clinical Resource, Atenolol for Hypertension. Pharmacist's Letter/Prescriber's Letter. January Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363: PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001;358: Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359: Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada s 2018 guidelines for diagnosis, risk assessment, prevention, and treatment of hypertension in adults and children. Can J Cardiol 2018;34: Chobanian AV. Does it matter how hypertension is controlled? N Engl J Med 2008;359: Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med 2012;367: Product information for Tekturna. Noden Pharma USA. Boston, MA November Product monograph for Rasilez. Noden Pharma DAC. Dublin 2, Ireland. January Clinical Resource, ACEI, ARB, and Aliskiren Comparison. Pharmacist s Letter/Prescriber s Letter. March Radevski IV, Valtchanova ZP, Candy GP, et al. Comparison of indapamide and low-dose hydrochlorothiazide monotherapy in black patients with mild to moderate hypertension. S Afr Med J 2002;92: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA 1991;265: Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich) 2014;16: Lopatowska P, Mlodawska E, Tomaszuk-Kazberuk A, et al. Adhering to principles of clinical pharmacology the correct fixed combinations of antihypertensive drugs. Expert Rev Clin Pharmacol 2018:11: pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com

17 (Clinical Resource #340808: Page 7 of 7) 19. Whelton PK, Carey RM, Aronow WS, et al ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC /NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;71:e Piepoli MF, Hoes AW, Agewall S, et al European guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37: Rimoldi SF, Messerli FH, Chavez P, et al. Efficacy and safety of calcium channel blocker/diuretics combination therapy in hypertensive patients: a meta analysis. J Clin Hypertens (Greenwich) 2015;17: Product information for Lotrel. Novartis Pharmaceuticals. East Hanover, NJ July Product information for Tarka. AbbVie. North Chicago, IL June Kim-Mitsuyama S, Ogawa H, Matsui K, et al. An angiotensin II receptor blocker-calcium channel blocker combination prevents cardiovascular events in elderly high-risk hypertensive patients with chronic kidney disease better than high-dose angiotensin II receptor blockade alone. Kidney Int 2013;83: Cite this document as follows: Clinical Resource, Antihypertensive Combinations. Pharmacist s Letter/Prescriber s Letter. August Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA ~ TEL (209) ~ FAX (209) Copyright 2018 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to pharmacist.therapeuticresearch.com ~ prescriber.therapeuticresearch.com ~ pharmacytech.therapeuticresearch.com ~ nursesletter.therapeuticresearch.com