Ace the Case: A 65-Year-Old Man with a History of Diabetes Mellitus, Hypertension, and Dyslipidemia

Clinical Review

Treatment of Hypertension in Patients With T2DM
Lifestyle Management
Lifestyle management is an important component of hypertension treatment because it lowers blood pressure, enhances the effectiveness of some antihypertensive medications, promotes other aspects of metabolic and vascular health, and generally leads to few adverse events.1 Lifestyle therapy consists of weight reduction; restricting sodium intake to 2,300 mg/day; increasing consumption of fruits, vegetables, and low-fat dairy products; avoiding excessive alcohol consumption; and increasing activity levels.2

Pharmacologic Treatment of Hypertension
Randomized clinical trials have demonstrated benefits of lowering blood pressure to <140 mm Hg systolic and <90 mm Hg diastolic in individuals with diabetes, including reduction of CVD, stroke, and diabetic kidney disease.3,4 Lowering of blood pressure with regimens based on a variety of antihypertensive agents, including ACE inhibitors, angiotensin receptor blockers (ARBs), diuretics, and calcium channel blockers, has been shown to be effective in reducing cardiovascular events.3 Our patient does not have adequate blood pressure control on his one blood pressure agent, a β-blocker. Although β-blockers may be used for the treatment of prior myocardial infarction, active angina, or heart failure, they have not been shown to reduce mortality as blood pressure-lowering agents in the absence of these conditions.5,6 According to the American Diabetes Association Guidelines, given the presence of albuminuria, our patient’s antihypertensive regimen should include an ACE inhibitor or an ARB.1 Multiple-drug therapy is often required to achieve blood pressure targets, particularly in the setting of diabetic kidney disease.3 Patients with blood pressure between 140/90 and 159/99 mm Hg may begin with a single drug. For patients with blood pressure >160/100 mm Hg, initial pharmacologic treatment with 2 antihypertensive medications is recommended to more effectively achieve adequate blood pressure control.7,8 Lifestyle modifications including weight loss, the Dietary Approaches to Stop Hypertension diet, reduction in sodium intake, and increased physical activity should accompany pharmacologic treatment. In addition, all patients with hypertension and diabetes should monitor their blood pressure at home to help identify masked or white coat hypertension, as well as to improve adherence to medications. Patients should bring their home blood pressure monitoring device with them to their provider’s office to check it for accuracy. The American Association of Clinical Endocrinologists recommends that blood pressure control be individualized, but that a target of <130/80 mm Hg is appropriate for most patients.9

Treatment of Dyslipidemia in Patients With T2DM
Lifestyle Management
Lifestyle intervention, including weight loss, increased physical activity, and medical nutritional therapy, allows some patients to reduce some CVD risk factors. Nutritional intervention should be tailored according to each patient’s age, type of diabetes, pharmacologic treatment, lipid levels, and comorbid medical conditions. Recommendations should focus on the reduction of saturated fats, cholesterol, and trans-fat intake while increasing the intake of plant stanols/sterols, n-3 fatty acids, and viscous fiber (such as in oats, legumes, and citrus).1

Statin Therapy
Patients with T2DM have an increased prevalence of lipid abnormalities that contribute to a higher risk of CVD. Several clinical trials have demonstrated the beneficial effects of pharmacologic therapy with statins on cardiovascular outcomes in patients with and without CVD.10,11 Accordingly, statins are the drugs of choice for lowering LDL cholesterol and for cardioprotection. The American Diabetes Association recommends 2 statin dosing intensities for use in clinical practice: high-intensity statin therapy will achieve an approximate 50% reduction in LDL, whereas moderate-intensity statin therapy will achieve a 30% to 50% reduction in LDL.1 For patients of all ages who have diabetes and CVD, high-intensity statin therapy should be added to lifestyle therapy.1 For patients with diabetes who are aged 40 to 75 years and who do not have CVD, moderate-intensity statin therapy should be prescribed.

Our patient is age 65 years and does not have known CVD. Like many patients with longstanding T2DM, he does have significant risk factors for CVD, including hypertension, dyslipidemia, and chronic kidney disease. The patient’s current statin therapy (pravastatin 10 mg daily) is not considered to be moderate-intensity therapy, and intensification of his lipid therapy would be recommended in this case. An increase in his pravastatin to 40 to 80 mg daily would be considered a moderate-intensity therapy. Table 1 lists the currently available medications for high- and moderate-intensity statin therapy.

High-intensity Statin Therapy

 

Moderate-intensity Statin Therapy

 

Atorvastatin 40-80 mg daily

 

Atorvastatin 10-20 mg daily

 

Rosuvastatin 20-80 mg daily

 

Rosuvastatin 5-10 mg daily

 

 

 

Simvastatin 20-40 mg daily

 

 

 

Pravastatin 40-80 mg daily

 

 

 

Lovastatin 40 mg daily

 

 

 

Fluvastatin XL 80 mg daily

 

 

 

Pitavastatin 2-4 mg daily

 

Table 1: Currently available statin medications and dosages that meet the definition of moderate- and high-intensity therapy.

In younger patients (age <40 years) with additional risk factors for CVD, consider using moderate-intensity statin therapy; lifestyle therapy is also recommended by the American Diabetes Association.1 LDL cholesterol levels should be assessed 4 to 12 weeks after initiation of statin therapy, after any change in dose, and on an individual basis to monitor for medication adherence and efficacy.

Therapy With PCKSK9 Inhibitors
In placebo-controlled trials evaluating the addition of the PCSK9 inhibitors evolocumab and alirocumab to statin therapy in participants who were at high risk for atherosclerotic cardiovascular disease (ASCVD), an average reduction in LDL cholesterol ranging from 36% to 59% was demonstrated.1 These agents have been approved for patients with ASCVD or familial hypercholesterolemia who are receiving maximally tolerated statin therapy but require additional lowering of LDL cholesterol.12, 13 The effects of PCSK9 inhibition on ASCVD outcomes were investigated in the Further Cardiovascular Outcomes Research with PCSK9 Inhibitors in Subjects with ELEVATED Risk (FOURIER) trial, which enrolled 27,564 patients with prior ASCVD and an additional high-risk feature who were receiving their maximally tolerated statin therapy but still had an LDL >70 mg/dL.14 During the median follow-up of 2.2 years, the composite outcome of death from CVD, myocardial infarction, stroke, hospitalization for angina or revascularization occurred in 11.3% vs. 9.8% of the placebo and evolocumab groups, respectively, representing a 15% relative risk reduction.14 Our patient was tolerating his low dose statin and it is unlikely that after intensification he would meet the criteria for initiation of a PCSK9 inhibitor. However, it is important for practicing clinicians to be aware of this class of medication for possible use in a smaller subset of patients.

Treatment of Hypertriglyceridemia
Hypertriglyceridemia should be addressed with dietary and lifestyle changes, including abstinence from alcohol.15 Severe hypertriglyceridemia (>1000 mg/dL) warrants pharmacologic therapy with fibric acid derivatives and/or fish oil to reduce the risk of acute pancreatitis. In patients with fasting triglyceride levels >500 mg/dL, clinicians should evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce the risk of pancreatitis. Glycemic control may also improve plasma lipid levels, particularly in patients with very high triglyceride levels and poor glycemic control. As seen in our patient, the most common pattern of dyslipidemia in patients with T2DM is low HDL cholesterol and hypertriglyceridemia. However, the evidence for the use of drugs that target these lipid factions and reduce cardiovascular events is less robust than that for statin therapy.16 In a large clinical trial of patients with T2DM and hypertriglyceridemia, treatment with a fenofibrate failed to reduce overall cardiovascular outcomes.17 Combination therapy (statin and fenofibrate) is associated with an increased risk for abnormal transaminase levels, myositis, and rhabdomyolysis. The risk of rhabdomyolysis is more common with higher doses of statins and renal insufficiency and appears to be higher when statins are combined with gemfibrozil compared to fenofibrate.18 Therefore, in patients with triglycerides >150 and <500 mg/dL, clinicians should intensify lifestyle therapy and optimize glycemic control.

Glycemic Control
Our patient should have emphasis placed on diet and lifestyle modification for weight reduction and to reduce his A1C to <7%. Enhanced glycemic control and cardiovascular risk reduction can also be achieved with the addition of liraglutide based on the LEADER Trial.19 The EMPA-REG trial demonstrated that empagliflozin reduced the rate of CV events and slowed the progression of kidney disease among patients with T2DM and high CV risk.20 However, empagliflozin should not be initiated in patients with an eGFR <45 mL/min/1.73 m2.21

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Question
If the patient’s blood pressure remains above goal after initiation of an ACE inhibitor, the addition of which of the following medications would be the next best choice?
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Correct answer: A

Rationale: Lowering of blood pressure with regimens based on a variety of antihypertensive agents, including ACE inhibitors, ARBs, thiazide diuretics, and calcium channel blockers, has been shown to be effective in reducing cardiovascular events.

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