Diabetic nephropathy complexities

Diabetic nephropathy complexities

Hypertension is common among patients with diabetes. Hypertension increases their risk of chronic kidney disease (CKD) onset and progression, as well as cardiovascular (CV) morbidity and mortality.1,2

More than 50% of patients with diabetes have hypertension, of whom 50% will develop some degree of renal impairment over time. A meta-analysis of 102 studies showed that patients with diabetes have a two-fold increase risk for CKD, coronary heart disease, major stroke, and mortality.1,3

In patients with diabetes, hypertension is defined as a systolic BP (SBP) ≥130mmHg or a diastolic BP (DBP) ≥80mmHg. The 2020 American Diabetes Association guideline recommends a BP target of <130/80mmHg for patients at high or very high CV risk (with atherosclerotic cardiovascular disease or 10year atherosclerotic CVD risk ≥15%), if it can be safely attained, while for those at lower risk for CVD (10-year atherosclerotic CVD risk <15%) a target of <140/90 mmHg is recommended.1,2,4

Diabetic nephropathy

Kidney damage caused by diabetes – diabetic nephropathy – is the main cause of CKD and the leading cause of end stage renal disease (ESRD) in this patient population.2,5

Although the mechanism of hypertension in diabetic nephropathy is complex and incompletely understood, it has been postulated that it may be the result of excess sodium retention, activation of the sympathetic nervous and renin-angiotensin-aldosterone systems (RAAS), endothelial cell dysfunction, and increased oxidative stress.2

The RAAS system plays a pivotal role in the regulation of BP. Apart from hypertension, the RAAS system is implicated in the pathogenesis and progression of numerous CV and renal pathologies, including structural cardiac remodelling, myocardial infarction, heart failure and CKD.6

Guidelines state that CKD can be attributed to diabetes in the presence of macroalbuminuria (>300mg/24 hr) or the presence of microalbuminuria (30mg300mg/24 hr) in the context of diabetic retinopathy or a history of diabetes exceeding 10 years.2

Inhibition of RAAS system

The inhibition of the RAAS system is the cornerstone of preventing diabetic neuropathy. The 2020 International Society of Hypertension guideline recommends RAAS-inhibitors as first-line treatment in patients with diabetes and hypertension, because they reduce albuminuria in addition to BP. Calcium channel blockers (CCBs) and diuretics (loop-diuretics if estimated glomerular filtration rate <30 ml/ min/1.73m2) can be added, state the authors of the guideline.6,7

Angiotensin receptor blockers (ARBs) and ACE inhibitors (ACEIs) are the two major RAAS inhibitors. ARBs have been in clinical use since 1995. The efficacy and safety of ARBs as a potent antihypertensive agent have been shown in numerous studies.6,8

ARBs have been shown to be more effective than other traditional agents in reducing the onset of clinical proteinuria in individuals with both Type 1 Diabetes (T1DM) and Type 2 Diabetes (T2DM) as well as incipient nephropathy.13

The aim of the Program for Irbesartan Mortality and Morbidity Evaluation was to determine whether ARBs are effective in both preventing the development of clinical proteinuria and delaying the progression of nephropathy in T2DM. It consists of two large trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Irbesartan in Patients with T2DM and Microalbuminuria (IRMA), which evaluated the renal and CV effects of irbesartan on hypertensive patients with diabetes.13

Irbesartan is one of the oldest ARBs and most effective antihypertensives. It was patented in 1990 and was approved by the American Food and Drug Administration in 1997.

In primary hypertension, irbesartan has been shown to lower BP blood over 24 hours. In many countries, including South Arica, irbesartan is approved for the treatment of nephropathy in patients with hypertension and T2DM. In the latter indication, 300mg once daily is the recommended maintenance dosage.12

According to Croom et al irbesartan is as effective as enalapril, atenolol and amlodipine in patients with mild-to-moderate hypertension, and more effective than valsartan in terms of absolute reduction in BP and response rates.9

Irbesartan produced a greater reduction in DBP at trough than once-daily losartan. The reduction in SBP achieved with irbesartan was similar or greater than that with losartan and similar to that seen with olmesartan.9

The combination of irbesartan with hydrochlorothiazide produced additive effects on BP reduction. Irbesartan also induced regression of left ventricular mass in patients with hypertension and left ventricular hypertrophy. The team concluded that irbesartan is a valuable agent in the management of patients with these indications.9

Slowing progression to diabetic nephropathy

The IRMA trial showed that fewer patients, treated with 150mg/day and 300mg/day irbesartan compared to placebo, progressed to macroalbuminuria. Hazard ratios of 0.30 was recorded in the 300mg/day group and 0.61 in the 150mg/day group.8

The IDNT trail found that patients in the irbesartan arm had a 37% lower risk of doubling the serum creatinine versus the amlodipine arm, and 33% lower than the placebo group. Development of ESRD was nominally lower with irbesartan compared with amlodipine.8

Lewis et al investigated whether irbesartan or amlodipine, a CCB, or placebo can slow the progression of nephropathy in patients with T2DM independently of its capacity to lower the BP. They found that irbesartan was associated with a 23% lower risk of ESRD compared to amlodipine and placebo. Serum creatinine concentration increased slower in the irbesartan group compared to the amlodipine (21%) and placebo (24%) groups. The authors concluded that irbesartan is effective in protecting against the progression of nephropathy due to T2DM and that protection was independent of the reduction in BP.10

Ros-Ruiz et al evaluated the effects of ultrahigh doses (600mg/per day) of irbesartan on proteinuria and renal function in patients with T2DM. Follow-up was three years. The team found that SBP and DBP decreased significantly at the end of follow-up. Serum creatinine increased by only 0.17mg/dl and proteinuria markedly decreased (59.2%). Some 25% of patients had normal albuminuria at the end of the follow-up period. Lipid profiles significantly improved. They concluded that treatment with ultra-high doses of irbesartan was highly effective and safe in reducing proteinuria and slowing progression to ESRD.11

References

1. Ciobanu DM, Kilfiger H, Apan B et al. Resistant hypertension in type 2 diabetes: prevalence and patients characteristics. Clujul Med, 2015. 2. Van Buuren PN and Toto R. Hypertension in

Diabetic Nephropathy: Epidemiology, Mechanisms and Management. Adv Chronic Kidney Dis, 2012. 3. Armario P, Blanch P, Castellanos P et al. Resistant hypertension in Diabetes. Journal of Endocrinology and

Diabetes, 2020. 4. American Diabetes Association (2020).

Cardiovascular disease and risk management: standards of medical care in diabetes-2020. Diabetes

Hypertension is about twice as prevalent in patients with diabetes compared to the general population

Benefits of early initiation of irbesartan

Palmer et al compared the effectiveness of early initiation at microalbuminuria, versus late initiation at overt nephropathy, of irbesartan 300mg/daily in patients with T2DM and renal disease. These strategies were compared with control, which consisted of antihypertensive therapy with standard medications (excluding ACE inhibitors, ARBs, dihydropyridine and CCBs). According to the authors, early irbesartan treatment improves life expectancy and reduces treatment costs in hypertensive patients with T2DM and microalbuminuria. Later initiation of irbesartan in overt nephropathy is also superior to standard care. Irbesartan should be started earlier and continued long term, concluded the authors.13

Hypertension is about twice as prevalent in patients with diabetes compared to the general population

Conclusions

Hypertension is common in patients with diabetes, increasing their risk of CVDs and renal dysfunction. Inhibition of the RAAS system has been shown to reduce these patients’ risk of progressing to CKD. ARBs are recommended as first-line therapy for patients at risk of CKD. Treatment of irbesartan has been shown to slow down progression to ESRD.

References

1. Ciobanu DM, Kilfiger H, Apan B et al. Resistant hypertension in type 2 diabetes: prevalence and patients characteristics. Clujul Med, 2015.

2. Van Buuren PN and Toto R. Hypertension in Diabetic Nephropathy: Epidemiology, Mechanisms and Management. Adv Chronic Kidney Dis, 2012.

3. Armario P, Blanch P, Castellanos P et al. Resistant hypertension in Diabetes. Journal of Endocrinology and Diabetes, 2020.

4. American Diabetes Association (2020). Cardiovascular disease and risk management: standards of medical care in diabetes-2020. DiabetesCare, 2020.

5. Giorgini F, Vora J, Fenici P et al. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovascular Diabetology, 2020.

6. Forni V, Wuerzner G, Pruijm M et al. Long-term use and tolerability of irbesartan for control of hypertension. Integrated Blood Pressure Control, 2011.

7. Unger T, Borgia C, Charchar F et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension, 2020.

8. Leoncini G, Viazzi F, de Cosmo S et al. Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations. Journal of Nephrology, 2020.

9. Croom KF, Curran MP, Goa KL et al. Irbesartan: a review of its use in hypertension and in the management of diabetic nephropathy. NEJM, 2004.

10. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. NEJM, 2001.

11. Ros-Ruiz SR, Lara PA, Fernandes JC et al. High doses of irbesartan offer long-term kidney protection in cases of established diabetic nephropathy. Nefrologia, 2012.

12. Seedat YK, Rayner BL and Veriava Y. South African hypertension practice guideline 2014 Hypertension guideline working group: Cardiovasc J Afr, 2014.

13. Palmer AJ, Annemans L, Roze S et al. Costeffectiveness of early irbesartan treatment versus control (standard antihypertensive medications excluding ACE inhibitors, other angiotensin-2 receptor antagonists, and dihydropyridine calcium channel blockers) or late irbesartan treatment in patients with type 2 diabetes, hypertension, and renal disease. Diabetes Care, 2004. SF

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World Kidney Day 12 March