2018 Standards of Medical Care in Diabetes: American Diabetes

Association

Summary Recommendation Created byJill E. Allen, PharmD, BCPS

and Harold H. Katz, MD, FACP, FACE

We highlight new recommendations for treating established cardiovascular disease and managing hypertension in people with diabetes. Our clinical advisor

suggests specific ways to use the new information in practice

1

I. Introduction

In January each year, the American Diabetes Association (ADA) publishes a comprehensive resource for diabetes management. This summary outlines new recommendations from the 2018 edition for manag-ing comorbid atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes (T2DM). It also outlines new recommendations for managing hypertension in patients with diabetes. The ADA’s hypertension recommendations were also presented in a 2017 position statement on hypertension.

II. Selection of Glucose-Lowering Drugs in Patients With T2DM and ASCVD

RecommendationPatients with T2DM and established ASCVD with an inadequate response to lifestyle management and metformin should also receive a drug known to reduce major cardiovascular events (MACE) and cardio-vascular mortality (eg, empagliflozin or liraglutide). [Level of evidence: A] Canagliflozin may be considered to reduce MACE. [Level of evidence: C] Drug selection should consider drug-specific and patient factors.

Details

Cardiovascular outcome trials (CVOTs) have identified important similarities and differences among members of specific classes of glucose-lowering drugs that may help guide drug selection in patients with T2DM and established ASCVD.

· DPP-4 inhibitors generally have neutral cardiovascular effects, with the caveat that saxagliptin and possibly alogliptin may increase the risk of heart failure. · Liraglutide is currently the only GLP-1 agonist that reduces MACE and cardiovascular death; sema-glutide reduces MACE; exenatide and lixisenatide have neutral cardiovascular effects; and CVOT results are pending for dulaglutide. · Insulin glargine and insulin degludec have neutral cardiovascular effects; insulin degludec has a lower risk of serious and nocturnal hypoglycemia.· Empagliflozin is currently the only SGLT2 inhibitor that reduces MACE and cardiovascular death; canagliflozin reduces MACE but increases the risk of lower-limb amputations and bone fractures; and CVOT results are pending for dulaglutide and ertugliflozin.

Based on CVOT results, the Food and Drug Administration (FDA) has approved empagliflozin to reduce the risk of cardiovascular death and liraglutide to reduce MACE in adults with T2DM and ASCVD.

Comments

It is Important that the outcome trials to date have been conducted mostly on patients with a document-ed history of CVD or, to a lesser extent, patients considered at high-risk for CVD. In that regard, the CVOT's show that, for secondary prevention (people with a history of CVD), it makes sense to prefer liraglutide as the GLP-1 agonist of choice and empagliflozin as the SGLT-2 of choice. At this time, no data suggests that these results can be applied to primary prevention (patients with no history of CVD). Furthermore, recent concerns regarding risk of bone loss and amputation of digits has made prescribing canagliflozin more problematic for the physician.

Almost a decade after the FDA issued guidance requiring CVOTs for new glucose-lowering drugs, results of these mandated megatrials are now molding the management of ASCVD in T2DM. Completed and pending CVOTs for glucose-lowering drugs are summarized in Table 1. Ongoing CVOTs could soon change other aspects of diabetes care. For example, as shown in the table, canagliflozin, empagliflozin, liraglutide, and semaglutide reduced the progression of diabetic kidney disease in completed CVOTs.

2

But kidney disease was a secondary outcome in these studies, so large-scale confirmatory studies are needed. Expect to see results from the CREDENCE trial of canagliflozin in 2019 and the Dapa-CKD study of dapagli-flozin in 2020. Also expect to see results of studies evaluating SGLT2 inhibitors in heart failure, including the Dapa-HF study of dapagliflozin in 2019, and the EMPEROR studies of empagliflozin in 2020. Heart failure, which occurs in up to 45% of patients with T2DM, is getting increasing attention as a preventable and treatable complication of T2DM.

3

III. Hypertension Management in Patients With Diabetes

Recommendation

All patients with diabetes and hypertension should monitor their blood pressure at home. [level of evidence: B]

Details

Home blood pressure monitoring can help to detect white coat hypertension and masked hypertension, may more accurately assess ASCVD risk than office measurements, and may improve antihypertensive medication adherence.

Comments

For patients on chronic blood pressure medication, especially If blood pressure is not currently well-con-trolled, it may make sense to have the patients check blood pressure on their home monitors 2 to 3 times per week, and at different times of day. Encourage patients to bring their home monitors with them to the office visit for comparison to the office measurement. It is also important to remember that the blood pressure measured by patient's home monitor, as well as the office automatic machine measurement, can often be 5 to 10 mm Hg lower than the office manual measurement.

Patients who don’t already have a blood pressure monitor may ask for advice about buying one. The 2017 American College of Cardiology/American Heart Association/others (ACC/AHA) hypertension guide-line, which also supports out-of-office blood pressure monitoring, recommends selecting a device that has been validated according to an internationally accepted protocol, with the results published in a peer-reviewed journal. (You can read our summary of the guideline here.) The British and Irish Hyperten-sion Society maintains a list of validated home blood pressure monitors. The AHA recommends an auto-matic monitor with a cuff that wraps around the upper arm. Advise patients to measure around their upper arm and select a model with an arm cuff to fit their measurement. Warn against buying a finger or wrist device — although they may be more convenient, they are less accurate.

Recommendation

Patients with resistant hypertension should be considered for treatment with a mineralocorticoid recep-tor antagonist (ie, eplerenone, spironolactone) [level of evidence: B], and they should be referred to a certified hypertension specialist. [LOE E]

Details

By definition, a patient who continues to have blood pressure ≥140/90 despite treatment with a diuretic plus 2 other antihypertensive drugs at adequate doses has resistant hypertension. According to ADA recommendations, this should include an ACE inhibitor/angiotensin receptor blocker (ARB), plus a thia-zide-like diuretic, and a dihydropyridine calcium channel blocker. The ADA recommends 1 of these drug classes for initial antihypertensive drug therapy in diabetes. [level of evidence: A] Patients with a urinary albumin-to-creatinine ratio ≥300 mg/g creatine [level of evidence: A] or 30 to 299 mg/g creatinine should receive an ACE inhibitor or ARB as initial treatment. [Level of evidence: B] Co-administration of a miner-alocorticoid receptor antagonist with an ACE inhibitor/ARB increases the risk of hyperkalemia, necessitat-ing regular monitoring of serum creatinine and potassium.

4

Comments

For patients who are failing blood pressure treatment with ACE or ARB, it is reasonable to consider either a thiazide diuretic or a dihydropyridine calcium channel blocker as second- and third-line options, in either order. If blood pressure Is not controlled at this point, consider workup for secondary causes of hypertension, including renal artery stenosis, hyperaldosteronism, and pheochromocytoma. When considering adding a fourth agent, a mineralocorticoid inhibitor is preferred over a beta-blocker or an alpha-blocker, assuming this Is not contraindicated by an elevated baseline potassium or significant renal Insufficiency.

In patients with T2DM and resistant hypertension already receiving an ACE inhibitor/ARB plus diuretic, the risk of hyperkalemia with spironolactone was predicted by a baseline eGFR ≤45 mL/minute plus serum potassium >4.5 mEq/L. The effectiveness of spironolactone 25 to 50 mg/day as add-on therapy for resistant hypertension was recently demonstrated in the PATHWAY-2 trial. In this study, which excluded patients with an eGFR <45 mL/minute, the mean serum potassium was 4.1 (0.5) at baseline. In this patient population (almost 14% had T2DM), 2% of patients had a serum potassium level >6.0 mEq/L during treatment with spironolactone. If a mineralocorticoid receptor antagonist is used, avoid coadmin-istration of drugs and substances that increase the risk of hyperkalemia including potassium supple-ments, high-potassium foods, aliskiren, drospirenone, heparin, NSAIDs, potassium-sparing diuretics (eg, amiloride, triamterene) and trimethoprim (alone or with sulfamethoxazole [ie, Bactrim, Septra]).

Recommendations for how to monitor potassium levels after starting a mineralocorticoid receptor antag-onist in patients with resistant hypertension could not be located. In heart failure, an ACC/AHA guideline recommends monitoring potassium levels at 3 days, 1 week, at least monthly for the first 3 months, and every 3 months thereafter. A new cycle of monitoring is recommended if the dose of an ACE inhibi-tor/ARB is changed. Additional monitoring is also warranted during any illness that increases the risk of renal dysfunction (e.g., dehydration).

Eplerenone may have a lower risk of gynecomastia and sexual dysfunction than spironolactone, but it may require twice-daily dosing to achieve adequate blood pressure control. Another consideration is that eplerenone product labeling contraindicates use in combination with strong cytochrome P450 3A4 inhibi-tors, and to treat hypertension in patients with T2DM and microalbuminuria.

IV. ADA Levels of Evidence:A: Clear evidence from well-conducted, generalizable randomized controlled trialsB: Supportive evidence from well-conducted cohort studiesC: Supportive evidence from poorly controlled or uncontrolled studiesE: Expert consensus or clinical experience

V. About the AuthorsDr Allen is a drug information consultant and medical writer at Pin Oak Associates, which she founded in 1995. Dr Katz is an endocrinologist at Allina Health in St Paul, MN.

5

VI. References

American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2018; 41 (January 14): S73-S85. http://care.diabetesjournals.org/content/41/Supple-ment_1/S73.full-text.pdf. Accessed January 3, 2018.

American Diabetes Association. 9. Cardiovascular disease and risk management: Standards of Medical Care in Diabetes—2018. Diabetes Care. 2018; 41 (January): S86-S104. http://care.diabetesjournals.org/content/41/Supple-ment_1/S86.full-text.pdf. Accessed January 3, 2018. American Diabetes Association. 10. Microvascular complications and foot care: Standards of medical care in diabe-tes—2018. Diabetes Care. 2018; 41 (January): S105-S118. http://care.diabetesjournals.org/content/41/Supple-ment_1/S105.full-text.pdf. Accessed January 3, 2018.

American Heart Association. Monitoring your blood pressure at home. http://www.heart.org/HEARTORG/Condi-tions/HighBloodPressure/-KnowYourNumbers/Monitoring-Your-Blood-Pressure-at-Home_UCM_301874_Article.jsp#.WlVvF1WnHX5. Accessed January 9, 2018. Ben Salem C, Badreddine A, et al. Drug-induced hyperkalemia. Drug Saf. 2014; 7 (September): 677-692.British and Irish Hypertension Society. Validated BP monitors for home use. https://bihsoc.org/bp-monitors/-for-home-use/. Accessed January 9, 2018. Cefalu WT, Kaul S, Gerstein HC, et al. Cardiovascular Outcomes Trials in Type 2 Diabetes: Where do we go from here? Reflections from a Diabetes Care editors' Expert Forum. Diabetes Care. 2018 Jan;41(1):14-31.de Boer IH, Bangalore S, et al. Diabetes and hypertension: A position statement by the American Diabetes Associa-tion. Diabetes Care. 2017; 40 (September): 1273-1284.

Inspra (eplerenone) tablets, for oral use. New York; NY: Pfizer, Inc.; May 2016. https://www.accessdata.fda.gov/drug-satfda_docs/label/2016/021437s013lbl.pdf. Accessed January 11, 2018.

Nasdaq GlobeNewswire. Highlights to be presented at Novo Nordisk's Capital Markets Day 2017. 2017; November 21. https://globenewswire.com/news-re-lease/2017/11/21/1197832/0/en/Highlights-to-be-presented-at-Novo-Nordisk-s-Capital-Markets-Day-2017.html. Accessed December 12, 2017.

Packer M. Heart failure: the most important, preventable, and treatable cardiovascular complication of type 2 diabetes. Diabetes Care. 2018; 41 (January): 11-13.

Whelton PK, Carey RM, et al. 2017 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: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hyper-tension. 2017; November 13: epub ahead of print.

Williams B, MacDonald TM, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomised, double-blind, crossover trial. Lancet. 2015; 386 (November 21); 2059-2068.

Yancy CW, Jessup M, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol. 2013; 62 (October 15): e147-239.