Refractory and Resistant Hypertension in Patients with Type 2 Diabetes Mellitus: Different Response to Renal Denervation

Aim      To compare the antihypertensive effectivity of renal denervation in patients with diabetes mellitus (DM) and associated refractory arterial hypertension (rfAH) (treated with 5 or more classes of antihypertensive drugs, including a thiazide diuretic and a mineralocorticoid receptor antagonist) and uncontrolled resistant AH (ucAH) (treated with 3-4 drugs).

Material and methods  This interventional study with renal denervation included 18 DM patients with rfAH and 40 DM patients with ucAH; 16 and 36 of them, respectively, completed the study in 6 months. At baseline, patients were sex- and age-matched. Study methods included measurement of office blood pressure (BP; systolic/diastolic BP, SBP/DBP); outpatient BP monitoring; evaluation of kidney function (estimated glomerular filtration rate by the CKD-EPI formula); diurnal diuresis volume; diurnal urinary excretion of albumin, potassium and sodium; diurnal excretion of metanephrines and normetanephrines; and plasma levels of glucose and glycated hemoglobin, aldosterone, and active renin. Patients were instructed about maintaining compliance with their antihypertensive and hypoglycemic therapy throughout the study.

Results At baseline, patients of both groups were comparable by BP and major clinical indexes, except for higher values of nocturnal SBP variability (p<0.05) in patients with rfAH. At 6 months following renal denervation, both groups displayed significant decreases in office and average daily SBP and also in the “load” with increased mean diurnal SBP. However, the decrease in average daily SBP was almost 4 times greater in the rfAH group than in the ucAH group ( –19.9 and –5.1 mm Hg, respectively, р=0.02). Moreover, 81 % of patients in the rfAH group responded to the intervention (average daily SBP decrease ≥10 mm Hg) while the number of responders in the ucAH group was considerably smaller (42 %; p=0.02). In patients with rfAH, renal denervation was associated with a significant decrease in pulse BP and nocturnal SBP variability and with the increase in diurnal diuresis. No other alterations were noted in laboratory test results in either group.

Conclusion      DM patients with rfAH may be the best candidates for the procedure of renal denervation.

1. Rapsomaniki E, Timmis A, George J, Pujades-Rodriguez M, Shah AD, Denaxas S et al. Blood pressure and incidence of twelve cardiovascular diseases: lifetime risks, healthy lifeyears lost, and age-specific associations in 1•25 million people. The Lancet. 2014;383(9932):1899–911. DOI: 10.1016/S0140-6736(14)60685-1

2. Badin Yu.V., Fomin I.V., Belenkov Yu.N., Mareev V.Yu., Ageev F.T., Polyakov D.S. et al. EPOCHA-AH 1998–2017. Dynamics of prevalence, awareness of arterial hypertension, treatment coverage, and effective control of blood pressure in the European part of the Russian Federation. Kardiologiia. 2019;59(1S):34–42. DOI: 10.18087/cardio.2445

3. Kasiakogias A, Tsioufis C, Dimitriadis K, Konstantinidis D, Koumelli A, Leontsinis I et al. Cardiovascular morbidity of severe resistant hypertension among treated uncontrolled hypertensives: a 4-year followup study. Journal of Human Hypertension. 2018;32(7):487–93. DOI: 10.1038/s41371-018-0065-y

4. Acelajado MC, Pisoni R, Dudenbostel T, Dell’Italia LJ, Cartmill F, Zhang B et al. Refractory Hypertension: Definition, Prevalence, and Patient Characteristics. The Journal of Clinical Hypertension. 2012;14(1):7–12. DOI: 10.1111/j.1751-7176.2011.00556.x

5. Dudenbostel T, Siddiqui M, Oparil S, Calhoun DA. Refractory Hypertension: A Novel Phenotype of Antihypertensive Treatment Failure. Hypertension. 2016;67(6):1085–92. DOI: 10.1161/HYPERTENSIONAHA.116.06587

6. Aksenova A.V., Esaulova T.E., Sivakova O.A., Chazova I.E. Resistant and refractory arterial hypertension: similarities and differences, new approaches to diagnosis and treatment. Systemic Hypertension. 2018;15(3):11–3. DOI: 10.26442/2075-082X_2018.3.11-13

7. Kuzmin O.B., Buchneva N.V., Zhezha V.V., Serdyuk S.V. Uncontrolled Arterial Hypertension: Kidney, Neurohormonal Imbalance, and Approaches to Antihypertensive Drug Therapy. Kardiologiia. 2019;59(12):64–71. DOI: 10.18087/cardio.2019.12.n547

8. Velasco A, Siddiqui M, Kreps E, Kolakalapudi P, Dudenbostel T, Arora G et al. Refractory Hypertension Is not Attributable to Intravascular Fluid Retention as Determined by Intracardiac Volumes. Hypertension. 2018;72(2):343–9. DOI: 10.1161/HYPERTENSIONAHA.118.10965

9. Dudenbostel T, Acelajado MC, Pisoni R, Li P, Oparil S, Calhoun DA. Refractory Hypertension: Evidence of Heightened Sympathetic Activity as a Cause of Antihypertensive Treatment Failure. Hypertension. 2015;66(1):126–33. DOI: 10.1161/HYPERTENSIONAHA.115.05449

10. Calhoun DA, Booth JN, Oparil S, Irvin MR, Shimbo D, Lackland DT et al. Refractory Hypertension: Determination of Prevalence, Risk Factors, and Comorbidities in a Large, Population-Based Cohort. Hypertension. 2014;63(3):451–8. DOI: 10.1161/HYPERTENSIONAHA.113.02026

11. Huggett RJ, Scott EM, Gilbey SG, Stoker JB, Mackintosh AF, Mary DASG. Impact of Type 2 Diabetes Mellitus on Sympathetic Neural Mechanisms in Hypertension. Circulation. 2003;108(25):3097–101. DOI: 10.1161/01.CIR.0000103123.66264.FE

12. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Research and Clinical Practice. 2019;157:107843. DOI: 10.1016/j.diabres.2019.107843

13. Symplicity HTN-2 Investigators, Estel MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. The Lancet. 2010;376(9756):1903–9. DOI: 10.1016/S0140-6736(10)62039-9

14. Frolova E.V., Vachev A.N., Morkovskikh N.V., Korytsev V.K. Selection of Patients with Resistant Arterial Hypertension for the Catheter-Based Renal Sympathetic Denervation. Kardiologiia. 2019;59(4):21–5. DOI: 10.18087/cardio.2019.4.10234

15. Agaeva R.A., Danilov N.M., Shelkova G.V., Sagaydak O.V., Grigin V.A., Matchin Yu.G. et al. Radiofrequency renal denervation with different device for treatment in patient with uncontrolled hypertension. Systemic Hypertension. 2018;15(4):34–8. DOI: 10.26442/2075082X.2018.4.000043

16. Savelyeva N.Yu., Zherzhova A.Yu., Е. V Mikova, Gapon L.I., Kolunin G.V., Krinochkin D.V. Radiofrequency denervation of the renal arteries in patients with resistant arterial hypertension: 3 years of observation experience. Systemic Hypertension. 2019;16(4):65–9. DOI: 10.26442/2075082X.2019.4.190596

17. Roush GC, Fagard RH, Salles GF, Pierdomenico SD, Reboldi G, Verdecchia P et al. Prognostic impact from clinic, daytime, and night-time systolic blood pressure in nine cohorts of 13 844 patients with hypertension. Journal of Hypertension. 2014;32(12):2332–40. DOI: 10.1097/HJH.0000000000000355

18. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. European Heart Journal. 2018;39(33):3021–104. DOI: 10.1093/eurheartj/ehy339

19. Messerli FH, Bangalore S, Schmieder RE. Wilder’s principle: pretreatment value determines post-treatment response. European Heart Journal. 2015;36(9):576–9. DOI: 10.1093/eurheartj/ehu467

20. Ostroumova O.D., Borisova E.V., Ostroumova T.M., Kochetkov A.I. 24 Hour Arterial Pressure Variability: Prognostic Significance, Methods of Evaluation, Effect of Antihypertensive Therapy. Kardiologiia. 2017;57(12):62–72. DOI: 10.18087/cardio.2017.12.10068

21. Mancia G, Grassi G. Mechanisms and Clinical Implications of Blood Pressure Variability. Journal of Cardiovascular Pharmacology. 2000;35(7 Suppl 4):S15–9. DOI: 10.1097/00005344- 200000004-00003

22. Gosse P, Cremer A, Pereira H, Bobrie G, Chatellier G, Chamontin B et al. Twenty-Four-Hour Blood Pressure Monitoring to Predict and Assess Impact of Renal Denervation: The DENERHTN Study (Renal Denervation for Hypertension). Hypertension. 2017;69(3):494–500. DOI: 10.1161/HYPERTENSIONAHA.116.08448

23. Kindermann I, Wedegärtner SM, Mahfoud F, Weil J, Brilakis N, Ukena J et al. Improvement in health-related quality of life after renal sympathetic denervation in real-world hypertensive patients: 12-month outcomes in the Global SYMPLICITY Registry. The Journal of Clinical Hypertension. 2017;19(9):833–9. DOI: 10.1111/ jch.13007

24. Zyubanova I.V., Mordovin V.F., Pekarskiy S.E., Ripp T.M., Falkovskaya A.Yu., Lichikaki V.A. et al. Possible mechanisms of renal denervation long-term cardiac effects. Arterial Hypertension. 2019;25(4):423–32. DOI: 10.18705/1607-419X-2019-25-4-423-432