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Microvascular Residual Risk THROUGH LANDMARK STUDY

8 June 2015
Hypertriglyceridemia increases risk for diabetic renal complications

The Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicenter Study showed that elevated triglycerides were associated with chronic kidney disease (CKD) independent of statin treatment in type 2 diabetes. However, there was no association between triglycerides and diabetic retinal complications.

Penno G, Solini A, Zoppini G, Fondelli C, Trevisan R, Vedovato M, Gruden G, Lamacchia O, Pontiroli AE, Arosio M, Orsi E, Pugliese G; Renal Insufficiency And Cardiovascular Events (RIACE) Study Group. Hypertriglyceridemia is independently associated with renal, but not retinal complications in subjects with type 2 diabetes: a cross-sectional analysis of the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. PLoS One 2015;10(5):e0125512.
Summary
Comments & References
STUDY SUMMARY
Objective: To evaluate whether elevated triglycerides (TG) are associated with an increased burden from microvascular complications in patients with type 2 diabetes, independent of statin treatment
Study design: Cross-sectional analysis of baseline data from the Renal Insufficiency And Cardiovascular Events (RIACE) study, an observational, prospective cohort study in subjects with type 2 diabetes.
Study population: 15,773 Caucasian subjects with type 2 diabetes (defined by the American Diabetes Association criteria), attending 19 hospital-based diabetes clinics in Italy during 2007-2008. Patients undergoing dialysis or with renal transplantation were excluded.
Methods: Subjects were divided in 4 groups based on the presence/not of elevated TG (³1.7 mmol/L); and concomitant statin therapy.

Chronic kidney disease (CKD, stages 1-5) was defined according to the presence or absence of micro or macroalbuminuria and the value of estimated glomerular filtration rate (eGFR) as calculated from serum creatinine based on the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative. Albuminuria was measured by immunonephelometry or immunoturbidimetry.1 CKD stages were defined as albuminuria alone (CKD Stages 1–2), reduced eGFR alone (CKD Stage 3, without albuminuria), or both (CKD Stage ³3 with albuminuria). Subjects assigned to CKD Stages (and GFR classes) 4 and 5 were pooled together.  

The presence of diabetic retinopathy (DR) was evaluated by fundus examination. Patients were classified into the following categories: absent DR; mild, moderate or severe non-proliferative DR, proliferative DR, or maculopathy, according to the Global Diabetic Retinopathy Project Group.2
Primary efficacity outcome: The presence of CKD or DR, as defined above
Results: The four categories of subjects are summarised in Table 1. Subjects with elevated TGs, with or without statin, had higher HbA1c, LDL cholesterol, and albuminuria, and lower HDL cholesterol (data not shown) compared with subjects with TG<1.7 mmol/L.

Table 1.Subject characteristics by category (presence/absence of elevated TG and statin treatment)

 

TG <1.7 mmol/L

TG ³1.7 mmol/L

 

On statin

No statin

On statin

No statin

N (%)

4372 (28)

6323 (40)

2325 (15)

2753 (18)

Age, yrs

67.5±8.9 *

66.0±11.1

66.0±9.0

63.8±11.3 *

Male, %

57%

57%

54%

58%

Diabetes duration, yrs

14.6±10.2 *

13.0±10.5

12.8±9.4

11.6±9.6 *

HbA1C, %

7.4±1.3

7.4±1.4

7.9±1.7

7.8±1.7

TG, mmol/L

1.13          (0.89-1.38)

1.08        (0.83-1.33)

2.23       (1.92-2.73)

2.21              (1.92-2.78)

LDL-C, mmol/L

2.56±0.80 *

2.89±0.77 *

2.70±0.96 *

3.00±0.90 *

Dyslipidemia, %

100%

67%

100%

74%

Lipid-lowering treatment, %

100%

3%

100%

14%

Fibrate, %

0.3%

2%

1%

8%

* p<0.0001 vs. each other group

Data are given as mean ± SEM except for TG which are given as median (interquartile range)

 Subjects with elevated TGs, with or without statin, had a higher prevalence of CKD, especially the albuminuric forms, but not of retinopathy, compared with subjects with TG <1.7 mmol/L (Table 2).

Table 2. Microvascular complications; n (%)

 

TG <1.7 mmol/L

TG ³1.7 mmol/L

 

On statin

No statin

On statin

No statin

CKD phenotype

 

 

 

 

None

2,830 (65)

4,276 (68)

1,178 (51)

1,591 (58)

1-2

755 (17)

1,123 (18)

494 (21)

577 (21)

³3, no albuminuria

489 (11)

550 (9)

327 (14)

307 (11)

³3, albuminuria

308 (7)

374 (6)

326 (14)

278 (10)

 

 

 

 

 

DR

 

 

 

 

No

3,322 (76)

4,995 (79)

1,754 (75)

2,205 (80)

Non advanced

595 (14)

774 (12)

288 (12)

300 (11)

Advanced

455 (10)

554 (9)

283 (12)

248 (9)

 

Logistic regression analyses showed that the presence of elevated TGs, with or without statin, was independently associated with micro and macroalbuminuria, mildly to severely reduced eGFR, and all CKD phenotypes, especially Stages 3–5 with albuminuria (Table 3). However, there was no association between elevated TGs and DR.

 

  • The odds ratio (OR) for CKD increased by 7-20% for every 0.26 mmol/L increase (approximately one decile) in TGs levels.
  • The increase in OR was higher with increasing severity of albuminuria, eGFR loss and CKD phenotype, as well statin treatment.

Table 3. Odds ratio (95% CI) for association of TGs and CKD

 

CKD stages 1-2

CKD stages ³3, no albuminuria

CKD stages ³3, albuminuria

TG <1.7 mmol/L – no statin

reference

TG <1.7 mmol/L- statin

0.875                    (0.784–0.976)d

1.182                    (1.027–1.361)d

1.033                    (0.870–1.226)

TG³1.70 mmol/L—no statin

1.227                         (1.081–1.393)*

1.535                   (1.294–1.820)***

2.003                     (1.654–2.427)***

TG³1.70 mmol/L—statin

1.246                       (1.090–1.426)**

1.838                   (1.553–2.175)***

2.667                      (2.213–3.214)***

d p<0.05*p<0.01; **p=0.001; ***p<0.0001

Authors’ conclusion: TGs are associated with CKD, but not retinopathy in subjects with type 2 diabetes, independently of statin treatment. These data point to a possible role of hypertriglyceridaemia in the development of CKD.

COMMENT

The findings from this analysis of the RIACE study support elevated TGs as a contributing factor to the residual risk of diabetic renal complications in patients with type 2 diabetes, which is independent of statin treatment. The residual risk of CKD increased by 7–20% for every decile increase in TG concentrations. which is remarkably consistent with results from the REALIST-Micro study, which showed that each 0.5 mmol/L increase in TG (approximately one quintile) increased the risk of diabetic renal complications by 23%.3 Additionally, and again consistent with the REALIST-Micro study,(3) even in subjects with TG<1.7 mmol/L, statin treatment did not prevent the risk for diabetic renal complications.

 These clinical data, together with experimental studies,(4) implicate elevated TG, in the pathophysiology underlying the development of renal complications in subjects with type 2 diabetes. Deposition of TGs in renal parenchymal cells may in part result from increased glomerular uptake of circulating lipids, which subsequently undergo chemical modification, resulting in the formation of metabolites which are harmful to the kidney. However, a component of reverse causality may also contribute to the association, since there is evidence that atherogenic dyslipidaemia, defined by the combination of elevated TGs, with or without low plasma concentration of high-density lipoprotein cholesterol, is a known consequence of renal dysfunction, especially when eGFR is less than 60 ml/min/1.73m2.(5)

 As seen with the REALIST Micro-Study,3 there was no association between TGs and risk for DR. Indeed, while there is substantive evidence from two major prospective studies that fenofibrate treatment delays the progression of DR in type 2 diabetes patients with early stage disease,(6,7) in both of these studies there was no association between lipids and progression of DR. Thus, it is likely, based on current consensus of opinion and the available data that this effect is attributed to non-lipid mechanisms.(8,9)

 In conclusion, the consistency of evidence from both the RIACE and REALIST-Micro studies reaffirms the importance of a multifaceted approach, including targeting of elevated TGs, to reduce the risk of diabetic renal complications in type 2 diabetes patients. Of the available therapies, fibrates so far represent the preferred option. Targeting TGs with a fibrate might offer the possibility of reducing the residual risk of diabetic renal complications against a background of current best evidence-based treatment.  However, there may be further therapeutic possibilities on the horizon. Monoclonal antibody therapies to apolipoprotein CIII and angiopoietin-like protein 3 may offer novel approaches to targeting TGs; we await the results of clinical trials with these therapies with much interest.

References

1. Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999; 130: 461–70.

2. Wilkinson CP, Ferris FL 3rd, Klein RE et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology 2003;110: 1677–82.

3. Sacks FM, Hermans MP, Fioretto P et al. Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation 2014;129:999-1008.

4. Weinberg JM. Lipotoxicity. Kidney Int. 2006; 70: 1560–1566.

5. Keane WF, Tomassini JE, Neff DR. Lipid abnormalities in patients with chronic kidney disease: implications for the pathophysiology of atherosclerosis. J Atheroscler Thromb 2013; 20: 123–33.

6. Keech AC, Mitchell P, Summanen PA et al. FIELD study investigators. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007;370:1687–97.

7. The ACCORD Study Group and ACCORD Eye Study Group; Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. New Engl J Med 2010;363:233-44.

8. Simó R, Roy S, Behar-Cohen F, Keech A, Mitchell P, Wong TY. Fenofibrate: a new treatment for diabetic retinopathy. Molecular mechanisms and future perspectives. Curr Med Chem 2013;20:3258-66.

9. Simó R, Simó-Servat O, Hernández C. Is fenofibrate a reasonable treatment for diabetic microvascular disease? Curr Diab Rep 2015;15:24.

Key words