CME INDIA Presentation by Dr. Bijay Patni, HOD, Diabetes Wellness Care, Kolkata.

Based on a presentation at TS RSSDI Conference, 5th May 2024.

Resistant Hypertension - What Physicians Must Know?

What is Refractory hypertension (RfH)?

  • It is an extreme phenotype of antihypertensive treatment failure and a specific subgroup of resistant hypertension (RH).
  • The phenotype of refractory hypertension was first proposed in a retrospective analysis of patients referred to the University of Alabama at Birmingham Hypertension Clinic whose blood pressure could not be controlled on any antihypertensive regimen.
  • It is characterized by uncontrolled out-of-office blood pressure (BP) levels despite the use of at least five antihypertensive drugs including Long-acting diuretic & Mineralocorticoid receptor antagonist.
Resistant Hypertension - What Physicians Must Know?

Prevalence of RfH

  • The prevalence of RfH ranges from 0.5% to 4.3% among general treated hypertensives and between 3.6% and 51.4% of patients with resistant hypertension (RHT).
  • RfH is associated with younger age, African ancestry, obesity, hypertension-mediated organ damage, clinical cardiovascular diseases, and comorbidities such as type 2 diabetes and obstructive sleep apnea.

Prevalence of RfH in Diabetes

Resistant Hypertension - What Physicians Must Know?

Sympathetic Overactivity Hypothesis in RfH: The most accepted mechanism

  • In individuals with RfH, there is evidence of chronic sympathetic overactivity.
  • This excessive sympathetic tone leads to:
    • Increased Vasoconstriction: Sympathetic nerves release norepinephrine, causing blood vessels to constrict. This raises peripheral resistance and elevates blood pressure.
    • Enhanced Renal Sodium Retention: Sympathetic activation affects the kidneys, leading to increased sodium and water retention. This contributes to volume overload and hypertension.
    • Altered Baroreceptor Sensitivity: Baroreceptors, which detect changes in blood pressure, become less responsive in RfH. As a result, the body’s ability to regulate blood pressure is compromised.
    • End-Organ Damage: Chronic sympathetic stimulation damages blood vessels, heart tissue, and renal structures, exacerbating hypertension-mediated organ damage.

Factors that can cause pseudo-refractory hypertension include

  • The white-coat effect: Many people have higher blood pressure readings at the doctor’s office than at home. This is called the white-coat effect or white coat syndrome. It’s linked to the stress and anxiety that being at a medical appointment can produce.
  • Wrong medication dose: Hypertension isn’t classed as refractory if adjusting the dosage of a medication helps to manage it.
  • Wrong medication: Refectory hypertension is resistant to classes of medications, not specific medications. If going from one medication to another within a medication class helps manage hypertension, it is not refractory.
  • Other medications: Some medications can raise blood pressure or interfere with how blood pressure medications work.
  • Supplements: This may include prescription medications or other types of supplements. They can interfere with blood pressure medications and spike blood pressure.

Factors that can cause pseudo-refractory hypertension include

  • Skipping medications: Not taking your blood pressure medications can make it appear as if those medications aren’t working correctly. This can look like refractory hypertension, but true refractory hypertension means that blood pressure can’t be managed even when medications are taken correctly and at the highest tolerable doses.
  • Smoking: increases blood pressure because it narrows the arteries. Smokers aren’t considered to have refractory hypertension unless they quit and no changes to blood pressure occur.
  • Consuming excess sodium: High levels of sodium in your diet increase your blood pressure. Eliminating them can lower your pressure. Someone needs to be on a low sodium diet without changes to blood pressure before hypertension can be called refractory.
  • Lack of physical exercise: Exercise decreases blood pressure. Someone who isn’t getting some physical activity in their week isn’t considered to have refractory hypertension.
  • Consuming too much alcohol: Frequently consuming large amounts of alcohol raises blood pressure.

Some differences in the management of refractory hypertension in patients with diabetes compared to those without diabetes

  • Stricter Blood Pressure Targets: In patients with diabetes, the target blood pressure is often set lower than in the general population. This is due to the higher risk of cardiovascular complications associated with diabetes. For example, guidelines often suggest aiming for a systolic blood pressure below 130 mmHg in diabetic patients to reduce the risk of heart disease and kidney damage.
  • Impact of Glycemic Control: Management of diabetes itself plays a critical role in controlling blood pressure. Poor glycemic control can exacerbate hypertension, so achieving and maintaining good blood sugar levels is crucial. This might involve more aggressive or tailored approaches to diabetes treatment than would be used for patients without diabetes.
  • Medication Choices: The choice of antihypertensive medications may differ. For instance, ACE inhibitors or ARBs are often preferred in diabetic patients due to their protective effects on the kidneys, which are frequently at risk in diabetes.
  • Increased Monitoring and Intervention: Diabetic patients require more frequent monitoring due to the complexities of managing two chronic conditions. This might include more regular blood pressure checks, closer dietary management, and possibly more frequent medication adjustments.
  • In managing refractory hypertension, especially in the context of diabetes, a multidisciplinary approach involving cardiologists, endocrinologists, and primary care physicians is often necessary to address the various aspects of both conditions effectively.

Diagnosis and Evaluation

Resistant Hypertension - What Physicians Must Know?

Secondary Causes and Appropriate Testing

  • Chronic kidney disease (cause and result of resistant hypertension): eGFR Urinalysis/urine albumin.
  • Obstructive sleep apnea: Polysomnography.
  • Primary hyperaldosteronism: 24-hour urine aldosterone (≥ 12 ng) 63 Suppressed plasma renin activity (< 1 ng/ml/hr) Suggested by aldosterone/renin ratio > 20.
  • Renovascular hypertension: Doppler ultrasound, CT angiogram, or MRA.
  • Pheochromocytoma: Plasma metanephrines (note: levels elevated 2-3 times in chronic kidney disease stages 4-5.
  • Coarctation of the aorta: Physical examination.
  • Other (rare) causes to consider based on clinical evaluation:
    • Cushing syndrome.
    • Thyroid dysfunction.
    • Congenital adrenal hyperplasia.
    • Acromegaly.
    • Hyperparathyroidism.
Resistant Hypertension - What Physicians Must Know?

Non-Pharmacological Interventions

  • Lifestyle Modifications: Emphasize the importance of lifestyle changes, including weight loss, increased physical activity, sodium reduction, and stress management, as adjunctive therapies to improve blood pressure control.
  • Device-Based Therapies: Consider device-based interventions, such as renal denervation or baroreflex activation therapy, in select patients with refractory hypertension who are unable to achieve target blood pressure levels with pharmacological management.
  • Procedural Interventions: In cases of resistant hypertension, evaluate the potential role of procedural interventions, including carotid body tumor resection or arteriovenous fistula creation, as complementary approaches to managing refractory hypertension.
  • Multidisciplinary Care: Promote a multidisciplinary approach, involving specialists like cardiologists, nephrologists, and endocrinologists, to address the complex interplay of diabetes and refractory hypertension effectively.

An algorithm for managing refractory hypertension in diabetes involves several critical steps that need to be tailored to the complexities of both conditions.

Step 1: Confirm Diagnosis

  • Confirm High Blood Pressure Readings: Use ambulatory blood pressure monitoring to rule out white coat hypertension.
  • Assess Medication Adherence: Confirm patient adherence to current medication regimen.
  • Rule Out Secondary Causes: Conduct appropriate tests (e.g., renal function, adrenal function).

Step 2: Lifestyle Modifications

  • Diet and Weight Management: Emphasize a low-sodium diet and maintain a healthy weight.
  • Physical Activity: Encourage regular moderate-intensity exercise.
  • Alcohol and Tobacco: Advice reduction or cessation.

Step 3: Optimize Current Treatment

  • Evaluate Current Medications: Ensure the use of maximal tolerated doses.
  • Add Mineralocorticoid Receptor Antagonists: If not already in use, consider adding to regimen.
  • Consider Other Drug Classes: Beta-blockers, alpha-blockers, or vasodilators, if not already in use.

Step 4: Advanced Pharmacologic Strategies

  • Use of Combination Therapy: Utilize combinations of drugs from different classes.
  • Consult Specialist: Consider referral to a hypertension specialist.
  • Trial of Newer Agents: Consider newer antihypertensive agents under clinical investigation if standard treatments fail.

Step 5: Continuous Monitoring and Follow-Up

  • Frequent Follow-Up: Schedule regular follow-up appointments to monitor blood pressure and adjust treatment as necessary.
  • Patient Education: Continuously educate the patient about blood pressure management and the importance of treatment adherence.

Step 6: Consider Device-Based Therapies

  • Evaluation for Renal Denervation: Patients who do not respond to pharmacologic treatment.
  • Baroreceptor Activation Therapy: Consider as a last resort if other treatments fail.

Step 7: Manage Comorbidities

  • Diabetes Management: Optimize glycemic control as it can influence blood pressure.
  • Screen for Other Cardiovascular Risks: Manage lipids, and consider antiplatelet therapy if indicated.

Conclusion and Future Considerations

Continued Research: Ongoing research efforts focused on unraveling the underlying mechanisms of refractory hypertension in diabetes, as well as the development of novel therapeutic approaches, hold promise for improving patient outcomes.

Personalized Approach: The future of refractory hypertension management in diabetes will likely involve a more personalized and targeted approach, taking into account individual patient characteristics, genetic factors, and unique pathophysiological profiles.

Patient Empowerment: Enhancing patient education and engagement will be crucial, empowering individuals with diabetes to actively participate in their care, adhere to treatment plans, and adopt lifestyle modifications to achieve better blood pressure control.

CME INDIA Learning Points

  • Since the early 1960s, the term “resistant hypertension” has been utilized to pinpoint patients facing challenging hypertension management, primarily indicating resistance to medication. Over the past five decades, it has consistently denoted the inability to regulate high blood pressure despite the administration of three or more antihypertensive drugs from different classes, including a diuretic.
  • The 2008 American Heart Association Scientific Statement expanded this definition to include patients whose blood pressure remained uncontrolled despite three medications, yet stabilized with four or more medications. While the exact number of medications is somewhat arbitrary, the purpose remains to identify individuals requiring specialized diagnostic and therapeutic attention, potentially involving referral to hypertension specialists. This standardized definition has streamlined research efforts, facilitating the identification of risk factors, underlying mechanisms, outcome assessments, and tailored treatments for this subgroup.
  • Though often used interchangeably, “refractory hypertension” has garnered less frequent usage compared to “resistant hypertension” in PubMed citations. However, recent usage of “refractory hypertension” has designated a distinct subset of patients who remain unresponsive to treatment even with maximal therapy. The differentiation between extreme cases of resistant hypertension and this novel refractory phenotype is crucial for understanding their unique risks, causes, and treatment failures.

CME INDIA Tail Piece

Resistant Hypertension - What Physicians Must Know?
Resistant Hypertension - What Physicians Must Know?

Courtesy: Management of Resistant Hypertension. Hypertension. 2018;72(5):e53-e90. American Heart Association.


  1. John M. Flack,Michael G. Buhnerkempe,Kenneth Todd Moore. Resistant Hypertension: Disease Burden and Emerging Treatment Options. Current Hypertension Reports.Published  online 16th Feb.2024.
  2. Centers for Disease Control and Prevention (CDC). Million Hearts. Estimated hypertension prevalence, treatment, and con trol among U.S. adults. March 22, 2021. https://millionhearts. hhs. gov/ data- repor ts/ hyper tensi on- preva lence. html Accessed Oct 21, 2022
  3. Desai AS, Webb DJ, Taubel J, Casey S, Cheng Y, Robbie GJ, et al. Zilebesiran, an RNA interference therapeutic agent for hypertension. N Engl J Med. 2023;389(3):228–38. https:// doi. org/10.1056/NEJMoa2208391
  4. Yeo, J.J.P., Yeo, L.S., Tan, S.S.N. et al. Prevalence of true resistant hypertension in those referred for uncontrolled hypertension in Malaysia: A comparison using different definitions. Hypertens Res 47, 352–357 (2024).

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