CME INDIA Presentation by Dr. A. K. Singh, M.D (Medicine); D.M (Endocrinology)Senior Consultant Endocrinologist, G. D. Hospital & Diabetes Institute, Kolkata Ad. Editor: Williams Textbook of Endocrinology, 14th Edition (SA), 2020Executive Editor: Clinical Keys in Diabetes & Endocrinology Deputy, Editor: Clinical Diabetology, Associate Editor: World Journal of Diabetes, IJDDC (RSSDI) (139 publications; Author h-index: 37).

Based on Wadiyar Oration (ADC) @ Bengaluru on May 27, 2023.

Theme of the Presentation

Common Mistakes in Clinical Practice

Audio explanation:

Don’t prescribe two different SUs or SUs with Glinides

Audio explanation:

Audio explanation:

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• Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). (Ref-1)
• Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit. (Ref-2)

Amlodipine in DM & HTN: Where is the controversy?

• DH-CCB are excellent antihypertensive agents, and a non-randomized intervention (GISEN study, 1998) suggested that DH-CCB may be anti-proteinuric, if good BP control is achieved.
• However, randomized trials do not support this suggestion and conflicting results are available in the literature.

• Poor renal outcome with DH-CCB
  • ABCD trial (2000) – despite good BP control, nisoldipine resulted in a 3-fold greater albuminuria rate compared with enalapril.
  • IDNT (2001)- despite substantial BP reduction in the amlodipine group, proteinuria remained at baseline. By contrast, at the same BP level as the amlodipine group, the irbesartan group achieved a 33% reduction in proteinuria.
  • AASK (2003) – although amlodipine achieved better BP control than ramipril or metoprolol, proteinuria increased about 2-fold on amlodipine therapy. Also, amlodipine increased the risk of the composite endpoint of doubling of serum creatinine, ESRD, or death, compared with ramipril or metoprolol.

• Good renal outcome with DH-CCB
• INSIGHT (2000) –
  • Nifedipine GITS vs Diuretics (HCTZ+Amilozide)
  • No diff. in primary end point (CV death, non-fatal MI, stroke or HF) but nifedipine GITS shows better renal protection.
• ALLHAT (2002) –
  • Lisinopril or Amlodipine vs Chlorthalidone
  • Amlodipine fared better in declining renal function compared to lisinopril and chlorthalidone.

Audio explanation:

• This analysis suggests:
  • (1) Similar efficacy between subclasses of calcium antagonists to lower blood pressure, and
  • (2) Greater reductions in proteinuria by no dihydropyridine calcium antagonist (NDCAs) compared to (dihydropyridine calcium antagonists) DCAs in the presence or absence of diabetes.

• Based on these findings, NDCAs, alone or in combination with an ACE inhibitor or an ARB, are suggested as preferred agents to lower blood pressure in hypertensive patients with nephropathy associated with proteinuria.

Summary with DH-CCB and kidney

• These results confirm previous studies suggesting that DH-CCB are not anti-proteinuric and may actually promote proteinuria and more rapid CKD progression.
• If DH-CCB is needed for BP control, concomitant use of ARB, ACE, or BB may mitigate the vasodilatory effects of DH-CCB to cause glomerular hypertension and, apparently, promote proteinuria. This strategy may also limit RAS stimulation by DH-CCB.

What could be the mechanism?

Common belief (both positive and negative) that may not be true!

• Combination of SGLT2i and DPP4i may give better Cardio-renal outcomes compared to SGLT2i alone!
• Combination of GLP-1RA and SGLT2i may give better Cardio-renal outcomes compared to either drug!
• Night-time (Chronotherapy) vs. day-time anti-hypertensive drugs?

Audio explanation:

Night-time vs. day-time anti-hypertensive Rx: Which one is better?

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TIME STUDY Interpretation:

• Evening dosing of usual antihypertensive medication was not different from morning dosing in terms of major cardiovascular outcomes. Patients can be advised that they can take their regular antihypertensive medications at a convenient time that minimises any undesirable effects.

CME INDIA Tail Piece

Full Presentation Video Link of Dr. A. K. Singh’s Oration: Courtesy Dr. Arvinda J, Bengaluru (Dr. Aravinds Diabetes Center)

Video:

References:

1. Fried, Linda F. Emanuele, Nicholas ,Zhang, Jane H et al. Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy. N Engl J Med 2013; 369:1892-1903.DOI: 10.1056/NEJMoa1303154
2. ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008 Apr 10;358(15):1547-59. doi: 10.1056/NEJMoa0801317. Epub 2008 Mar 31. PMID: 18378520.
3. Robert W. Schrier, M.D. Additional Follow-up from the ABCD Trial in Patients with Type 2 Diabetes and Hypertension/ N Engl J Med 2000; 343:1969.DOI: 10.1056/NEJM20001228343261
4. https://www.acc.org/Latest-in-Cardiology/Clinical-Trials/2010/02/23/19/08/IDNT
5. Sica DA. The African American Study of Kidney Disease and Hypertension (AASK) trial: what more have we learned? J Clin Hypertens (Greenwich). 2003 Mar-Apr;5(2):159-67. doi: 10.1111/j.1524-6175.2003.01924.x. PMID: 12671332; PMCID: PMC8099246.
6. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(00)02527-7/fulltext
7. 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 angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002 Dec 18;288(23):2981-97. doi: 10.1001/jama.288.23.2981.
8. Bakris GL, Weir MR, Secic M, Campbell B, Weis-McNulty A. Differential effects of calcium antagonist subclasses on markers of nephropathy progression. Kidney Int. 2004 Jun;65(6):1991-2002. doi: 10.1111/j.1523-1755.2004.00620.x. PMID: 15149313.
9. Mackenzie IS, Rogers A, Poulter NR, Williams B, Brown MJ, Webb DJ, Ford I, Rorie DA, Guthrie G, Grieve JWK, Pigazzani F, Rothwell PM, Young R, McConnachie A, Struthers AD, Lang CC, MacDonald TM; TIME Study Group. Cardiovascular outcomes in adults with hypertension with evening versus morning dosing of usual antihypertensives in the UK (TIME study): a prospective, randomised, open-label, blinded-endpoint clinical trial. Lancet. 2022 Oct 22;400(10361):1417-1425. doi: 10.1016/S0140-6736(22)01786-X. Epub 2022 Oct 11. PMID: 36240838; PMCID: PMC9631239.
10. Muhammad Haisum Maqsood, Franz H. Messerli, Adam H. Skolnick, et al. Timing of Antihypertensive Drug Therapy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.Hypertension. 2023;80:1544–1554.https://doi.org/10.1161/HYPERTENSIONAHA.122.20862

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