Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

By Aly Becraft, MS and Kevin C Maki, PhD

The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial was designed to assess the effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor, canagliflozin, on renal outcomes in patients with type 2 diabetes (T2D) and chronic kidney disease.1,2 This randomized, double-blind, placebo-controlled, multicenter clinical trial included patients of at least 30 years of age with an estimated glomerular filtration rate of 30 to <90 mL per minute per 1.73 m2 of body-surface area, albuminuria, and a glycated hemoglobin level of 6.5 to 12.0%. Patients were randomized to receive a 100 mg daily dose of canagliflozin or placebo added to renin-angiotensin-aldosterone blockade. The primary outcome was a composite of end stage renal disease (ESRD), doubling of the serum creatinine level for at least 30 days, or death from renal or cardiovascular (CV) disease. Secondary outcomes were tested hierarchically in the following order:

  1. composite of CV death or hospitalization for heart failure (HF)
  2. composite of CV death, myocardial infarction (MI) or stroke
  3. hospitalization for HF
  4. composite of ESRD, doubling of the serum creatinine level or renal death
  5. CV death
  6. death from any cause
  7. composite of CV death, MI, stroke, or hospitalization for HF or for unstable angina (UA)

 

The trial design was event driven; after a planned interim analysis, the trial was stopped early due to the requisite number of primary outcome events having been achieved. The final analysis included 4401 randomized patients and a median follow up time of 2.62 years. The results for the outcomes, including the hazard ratios (HR) and 95% confidence intervals (CI), are shown in the table below.


 

 

Outcome

Canagliflozin

(n = 2202)

Placebo

(n = 2199)

HR

(95% CI)

p-value

 

Events/1000 patient-years

   

Primary composite outcome

43.2

61.2

0.70

(0.59, 0.82)

0.00001

Secondary outcomes

  CV death or hospitalization for HF

31.5

45.4

0.69

(0.57, 0.83)

<0.001

  CV death, MI or stroke

38.7

48.7

0.80

(0.67, 0.95)

0.01

  Hospitalization for HF

15.7

25.3

0.61

(0.47, 0.80)

<0.001

  ESRD, doubling of serum creatinine level or renal death

27.0

40.4

0.66

(0.53, 0.81)

<0.001

  CV death

19.0

24.4

0.78

(0.61, 1.00)

0.05*

           

 

*No significant between-group difference in the risk of CV death was observed, so the differences in all subsequent outcomes in the hierarchical testing sequence were not formally tested.

 

Conclusion: Compared to placebo, canagliflozin lowered risk of kidney failure and CV events after a median follow-up of 2.62 years, supporting efficacy as a treatment option for renal and CV protection in patients with T2D and chronic kidney disease.

References:

  1. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; Epub ahead of print.
  2. Ingelfinger JR, Rosen CJ. Clinical credence – SGLT2 inhibitors, diabetes, and chronic kidney disease. N Engl J Med. 2019; Epub ahead of print.

 

 

Photo by Akash Deep

No Additional Benefits on Cardiometabolic Risk Parameters of Reduced Red Meat or Increased Fiber Intake in an Energy-restricted Diet

No Additional Benefits on Cardiometabolic Risk Parameters of Reduced Red Meat or Increased Fiber Intake in an Energy-restricted Diet

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

To date, results from epidemiological studies have suggested that a high intake of red meat is associated with a higher risk of developing type 2 diabetes (T2D) while high fiber intake is associated with a lower risk 1-5. Furthermore, high intakes of red meat have also been suggested to be linked to increased risks of cardiovascular disease (CVD) and mortality 6,7.  One of the main approaches for reducing risk of T2D and CVD is weight loss 8-10. Research findings have also suggested that cardiometabolic risk can be improved with dietary modification independent of weight loss 11,12.

 

Willman et al. completed a 6-month, randomized controlled dietary intervention trial to assess whether lower intake of meat or higher intake of dietary fiber would have additional benefits when incorporated into an energy-restricted diet 13.  Subjects were randomized to one of three groups with all groups being instructed to reduce their caloric intakes by 400 kcal/d below their weight-maintenance requirements and exercise 3 hours/week.  The control group just decreased their caloric intake.  The “no red meat” group avoided red meat, but was able to eat turkey, fish or chicken, and subjects in the “fiber” group increased their fiber intake to at least 40 g/day.  The researchers also analyzed 9-month follow-up data from the Tuebingen Lifestyle Intervention Program (TULIP) cohort, which included subjects (n = 229) at increased risk of diabetes 14.  The intervention in TULIP consisted of increased physical activity and decreased caloric intake.

 

All participants in the 6-month trial lost weight (mean 3.3 ± 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001), with no difference among the groups.  Similarly, liver fat content decreased (P < 0.001) with no differences among the groups.  The liver fat decrease correlated with the decrease in ferritin during intervention (r2 = 0.08, P = 0.0021). This association between ferritin and liver fat changes was confirmed in TULIP (P = 0.0084).

 

Comment.  Neither the absence of dietary red meat nor the increase in fiber intake had an additional effect beyond calorie restriction and exercise on risk markers for T2D or CVD.  These results confirm that weight loss can lead to improvement in glucose metabolism, body fat composition and liver fat content and do not indicate incremental benefits for restriction of red meat intake or increasing dietary fiber intake.  Additional research is needed to assess effects of these dietary factors during weight loss maintenance.

 

References

  1. The InterAct Consortium. Association between dietary meat consumption and incident type 2 diabetes: The EPIC-InterAct study. Diabetologia 2013;56:47–59.
  2. Fretts AM, Howard BV, McKnight B, et al. Associations of processed meat and unprocessed red meat intake with incident diabetes: The Strong Heart Family Study. Am J Clin Nutr 2012;95:752–8.
  3. Lajous M, Tondeur L, Fagherazzi G, et al. Processed and unprocessed red meat consumption and incident type 2 diabetes among French women. Diabetes Care 2012;35:128–30.
  4. Pan A, Sun Q, Bernstein AM, et al. Red meat consumption and risk of type 2 diabetes: 3 cohorts of US adults and an updated meta-analysis. Am J Clin Nutr 2011;94:1088–96.
  5. Wittenbecher C, Mühlenbruch K, Kröger J, et al. Amino acids, lipid metabolites, and ferritin as potential mediators linking red meat consumption to type 2 diabetes. Am J Clin Nutr 2015;101:1241–50.
  6. Etemadi A, Sinha R, Ward MH, et al. Mortality from different causes associated with meat, heme iron, nitrates, and nitrites in the NIH-AARP Diet and Health Study: Population based cohort study. BMJ 2017;357:1957.
  7. Sun Q. Red meat consumption and mortality: Results from 2 prospective cohort studies. Arch Intern Med 2012;172:555.
  8. Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1343–50. 

  9. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393– 403. 

  10. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. J Am Coll Cardiol 2014;63:2985– 3023. 

  11. Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–90.
  12. Estruch R, Martínez-González MA, Corella D, et al. Effect of a high-fat Mediterranean diet on bodyweight and waist circumference: A prespecified secondary outcomes analysis of the PREDIMED randomised controlled trial. Lancet Diabetes Endocrinol 2016;4:666–76.
  13. Willmann C, Heni M, Linder K, et al. Potential effects of reduced red meat compared with increased fiber intake on glucose metabolism and liver fat content: a randomized and controlled dietary intervention study. Am J Clin Nutr. 2019;109:288–96.
  14. Schmid V, Wagner R, Sailer C, et al. Non-alcoholic fatty liver disease and impaired proinsulin conversion as newly identified predictors of the long-term non-response to a lifestyle intervention for diabetes prevention: Results from the TULIP study. Diabetologia 2017;60:2341– 51. 


 

Photo by Jez Timms