In light of diabetes’ widespread incidence, the sector is increasingly motivated to address the associated risks for patients. With one particular landmark diabetes trial investigating renal and cardiovascular outcomes, Anna Strzelecka, SAS Doctor in Diabetes and Endocrinology, Antrim Area Hospital, Northern Health & Social Care Trust, discusses her involvement.
If not managed properly, diabetes can lead to serious complications, such as microvascular disease, including retinopathy and nephropathy, and macrovascular disease, including heart disease, stroke and peripheral vascular disease. (1)
It has been proven that patients with type 2 diabetes have a greater risk of cardiovascular (CV) death than patients without diabetes, whether or not they had experienced a previous myocardial infarction. (2, 3)
Atherosclerotic cardiovascular disease occurs 14.6 years earlier in type 2 diabetic patients when compared to the non-diabetic population, with greater severity and with more diffuse distribution. Furthermore, about two-thirds of deaths in people with diabetes mellitus are caused by CV disease: of these, around 40 per cent are from ischaemic heart disease; 15 per cent from other forms of heart disease, principally congestive heart failure; and around 10 per cent from stroke. (4)
Diabetes also remains the single most common cause of kidney failure. Almost four-in-five people with diabetes will develop kidney disease in their lifetime. 11 per cent of deaths in type 2 diabetes are caused by kidney disease. (5) 27.5 per cent of new cases needing dialysis or renal transplant are caused by type 2 diabetes. (6)
In recent years, several clinical trials showed positive effects of SGLT2 inhibitors on CV outcomes. The CANVAS study showed that patients treated with Canagliflozin had significantly lower rates of the primary CV outcome than patients receiving placebo. The results also showed a possible benefit of Canagliflozin in respect to the progression of albuminuria and the composite outcome of a sustained 40 per cent reduction in the eGFR, the need for renal-replacement therapy, or death from renal causes and further evaluation of effects of Canagliflozin on renal disease was advised. (7)
In 2014 the first patient was randomised to take part in the CREDENCE study, and in November 2015 Antrim Area Hospital was accepted as one of the study sites.
The goal of this double-blind, randomised trial was to assess whether Canagliflozin has a renal and vascular protective effect in reducing the progression of renal impairment relative to placebo in participants with type 2 diabetes mellitus (T2DM), stage 2 or 3 chronic kidney disease and macroalbuminuria, who are receiving standard of care, including a maximum tolerated labeled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker.
Composite outcome of ESKD, doubling of serum creatinine, or renal or CV death.
• CV death or hospitalisation for heart failure
• Major CV events (three-point MACE: CV death, MI, or stroke)
• Hospitalisation for heart failure
• ESKD, doubling of serum creatinine, or renal death
• CV death
• All-cause mortality
• CV death, MI, stroke, hospitalisation for heart failure, or hospitalisation for unstable angina (8)
• Age >30 years
• Type 2 diabetes mellitus with a hemoglobin A1c (HbA1c) greater than or equal to (>=) 6.5 per cent and less than or equal to (<=) 12.0 per cent with an estimated glomerular filtration rate (eGFR) of >= 30 milliliter (mL)/minute (min)/1.73meter (m)^2 and less than (<) 90 mL/min/1.73 m^2
• Participants need to be on a stable maximum tolerated labelled daily dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) for at least four weeks prior to randomisation
• Must have a urine albumin to creatinine ratio (UACR) of greater than (>) 300 milligram (mg)/gram (g) and <= 5000 mg/g
• History of diabetic ketoacidosis or type 1 diabetes mellitus
• History of hereditary glucose-galactose malabsorption or primary renal glucosuria
• Renal disease that required treatment with immunosuppressive therapy
• Known significant liver disease
• Current or history of New York Heart Association class IV heart failure
• Blood potassium level >5.5 millimole (mmol)/liter (L) during screening (8)
There were 34 countries involved, with 690 sites that randomised 4,401 participants. 118 participants were randomised in the UK, with eight in Antrim Area Hospital, making it one of the top recruiting sites in the UK.
2,202 were randomised to the Canagliflozin 100mg group, and 2,199 to the placebo group.
The trial was stopped early after a planned interim analysis reviewed by an independent data monitoring committee. Median follow-up was 2.62 years.
The relative risk of the primary outcome was 30 per cent lower in the Canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1,000 patient-years, respectively (hazard ratio, 0.70; 95 per cent confidence interval, 0.59 to 0.82; P=0.00001).
The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes, was lower by 34 per cent (hazard ratio, 0.66; 95 per cent CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32 per cent (hazard ratio, 0.68; 95 per cent CI, 0.54 to 0.86; P=0.002). The Canagliflozin group also had a lower risk of CV death, myocardial infarction, or stroke (hazard ratio, 0.80; 95 per cent CI, 0.67 to 0.95; P = 0.01) and hospitalisation for heart failure (hazard ratio, 0.61; 95 per cent CI, 0.47 to 0.80; P<0.001).
There were no significant differences in rates of amputation or fracture. (9)
It is fascinating to see such an advance in the development of oral glycaemic agents.
SGLT2 inhibitors not only proved to improve glycaemia, but have the added benefits of blood pressure and weight reduction along with CV benefits. They also reduce the risk of developing end-stage renal disease in patients with significant kidney disease and albuminuria.
In recent time ADA/EASD guidelines have been changed as well as SIGN guidelines. The NICE guideline update is awaited. It is now advised to use agents that showed CV and renal benefits earlier especially in patients with CV and renal disease.
At present SGLT2 inhibitors are licenced to be initiated only if eGFR is over 60 and can be continued at lower dose as long as eGFR remains above 45. Hopefully the licence of Canagliflozin will change in the near future and will allow the use of this agent in patients with more advanced renal disease.
2. Haffner SM, et al. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-34.
3. Erdmann E. CV events in patients with type 2 diabetes. The British journal of diabetes and vascular disease 2002;2(suppl 1):S4–8.
4. C.C Low Wang, et al. Clinical Update: CV Disease in Diabetes Mellitus: Atherosclerotic CV Disease and Heart Failure in Type 2 Diabetes Mellitus – Mechanisms, Management, and Clinical Considerations. Circulation. 2016;133:2459-2502.
5. Morrish NJ, Wang SL, Stevens LK et al (2001). Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia 44, suppl 2; s14–s21
6. Gilg J, Methven S, Casula A, Castledine C. UK Renal Registry 19th Annual Report: Chapter 1. UK RRT Adult Indicence in 2015: National and Centre-specific Analyses. Nephron 2017;137(Suppl 1): 11-44
7. Bruce Neal, et al. Canagliflozin and CV and Renal Events in Type 2 Diabetes. N Engl J Med 2017; 377:644-657
8. CREDENCE study protocol
9. Vlado Perkovic, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380:2295-2306