Chronic kidney disease - sanofidiabete.it · Chronic kidney disease in people with ... The critical...

Chronic kidney disease

in people with Type 2 diabetes

Understanding the challenges faced and the

importance of optimising glycaemic control

SAGLB.DIA.19.12.1916 DATE OF APPROVAL: JANUARY 2020

2

Contents

Epidemiology and pathophysiology of chronic kidney disease (CKD) in people with

Type 2 diabetes mellitus (T2DM)1

2

3

The vicious cycle of glycaemic control, chronic kidney disease, hypoglycaemia

and cardiovascular disease (CVD), and its impact on patients’ outcomes

The critical role of optimal glycaemic control in the effective management of people

with CKD and T2DM

Epidemiology and pathophysiology of CKDin people with T2DM

1

4

People with T2DM have more than double the risk of

developing CKD compared with the general population1,2

*Percentage of CKD stages 1–4 among US adults aged 18 years or older using data from the 2013–2016 National Health and Nutrition Examination Survey (NHANES) and the CKD Epidemiology Collaboration equation;1 **Cross-sectional analysis using US NHANES that looked at 2,006

people from 2007–2012;2 †Based on a retrospective observational analysis using the US Optum® Clinformatics® database (January 2010–September 2017). A total of 123,169 people with CKD were identified, of whom 49.0% had lab-confirmed CKD, but had undiagnosed CKD.3

CKD, chronic kidney disease; NHANES, National Health and Nutrition Examination Survey; T2DM, Type 2 diabetes mellitus

1. Centers for Disease Control and Prevention. Chronic Kidney Disease in the United States, 2019. Available at: https://www.cdc.gov/kidneydisease/pdf/2019_National-Chronic-Kidney-Disease-Fact-Sheet.pdf [Accessed: January 2020];

2. Wu B, et al. BMJ Open Diabetes Res Care. 2016;4:e000154; 3. Bakris G, et al. Presented at the National Kidney Foundation 2019 Spring Clinical Meetings; May 8–12; Boston, MA, US. P308.

15% of adults have CKD*1

~40% of adultswith T2DM have CKD**2

1.5 in 10 adults have CKD*1

Nearly 4 in 10 adults with T2DM have CKD2

~50% of CKD

in T2DM is

undiagnosed†3

In the United States:

5

Prevalence of CKD in people

with T2DM in the United States1 Breakdown of the 38.3% by CKD stage*1

CKD affects almost 4 in 10 people with T2DM, of which half are stage 3–41

38.3%

61.7%

Stage 1

Stage 2

Stage 3a

Stage 3b

Stage 4

Stage 5

23.8%

24.5%

29.2%

14.4%

6.3%

1.8%

Cross-sectional analysis using US NHANES that looked at 2,006 people from 2007–2012.1

*Percentages of people with CKD according to stage of disease are shown.

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NHANES, National Health and Nutrition Examination Survey; T2DM, Type 2 diabetes mellitus

1. Wu B, et al. BMJ Open Diabetes Res Care. 2016;4:e000154.

50% of people with CKD are stage 3–41

Moderately to severely impaired kidney function

(i.e. eGFR <60 mL/min/1.73 m2)

Adapted from Wu B, et al. (2016)

6

Stages of CKD according to estimated glomerular filtration rate (eGFR)1,2

*eGFR calculated from serum creatine using a validated formula, preferably CKD-EPI equation.2

CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; eGFR, estimated glomerular filtration rate; ESRD, end stage renal disease

1. National Kidney Foundation. Am J Kidney Dis. 2002;39(2 Suppl 1):S1–266; 2. Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int Suppl. 2013;3:1–150.

• Staging of kidney disease generally follows the Kidney Disease Outcomes and Quality Improvement (KDOQI) CKD guidelines1,2

• eGFR is generally reduced after widespread structural damage to the kidney1,2

Stage Description eGFR (mL/min/1.73 m2)* Terms used

1

2

3a

4

5

Kidney damage with normal or ↑ GFR + other

markers of CKD (e.g. albuminuria, haematuria)

Kidney damage with mild ↓ in GFR + other

markers of CKD (e.g. albuminuria, haematuria)

Moderate to severe ↓ in GFR

Severe ↓ in GFR

Kidney failure (ESRD)

≥90

60–89

45–59

30–44

15–29

Normal

Mildly decreased

Moderately to severely decreased

Severely decreased

Kidney failure

CKD

Mildly to moderately decreased

Advanced 3b

Mild to moderate ↓ in GFR

<15

7

Diabetes is the leading cause of end-stage renal disease (ESRD) in the US1

*All people, US and territories.1

DKD, diabetic kidney disease; ESRD, end-stage renal disease; T2DM, Type 2 diabetes mellitus

1. US Renal Data System. Annual data report reference tables 2019. Available at: https://www.usrds.org/reference.aspx [Accessed: January 2020); 2. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12:2032–45; 3. Thomas MC, et al. Nat Rev Nephrol. 2016;12:73–81;

4. Arora P. Chronic Kidney Disease. Available at: https://emedicine.medscape.com/article/238798-overview#a6 [Accessed: January 2020].

Incident counts of reported ESRD by primary cause of ESRD:*1

ESRD is the most recognisable consequence

of diabetic kidney disease (DKD)2

Globally, T2DM is the single leading

cause of ESRD, accounting for

~33% of all people initiating

renal replacement therapy

(dialysis, transplantation) worldwide3

Mortality in people with ESRD on dialysis

is high, 5-year survival rate for a person

with diabetes undergoing long-term

dialysis in the US is approximately 25%4

Adapted from US Renal Data System. (2019)

8

CKD

• Abnormalities of kidney structure or

function, present for >3 months, with

implications for health1

• Diagnosed by the persistent presence

of low eGFR (<60 mL/min/1.73 m2) OR

elevated urinary albumin excretion

(albumin: creatinine ratio [ACR]

>3 mg/mmol) OR both1–5

• Causes include diabetes,

hypertension, glomerulonephritis,

infection and environmental factors6

DKD

• Also known as CKD due to diabetes

or diabetic nephropathy7

• A clinical diagnosis based on

increasing albuminuria, decreased

eGFR, elevated blood pressure, and

increased morbidity and mortality

due to cardiovascular (CV)

complications7,8

Diabetic nephropathy

• Historically defined as presence of

albuminuria with retinopathy in

people with Type 1 diabetes mellitus

(T1DM)8

• Characterised pathologically by

glomerular basement membrane

thickening, endothelial damage,

mesangial expansion and nodules,

and podocytes loss8

• Only a kidney biopsy can confirm this

with certainty8

Definitions of CKD and DKD1–8

ACR, albumin: creatinine ratio; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; KDIGO, Kidney Disease: Improving Global Outcomes; T1DM, Type 1 diabetes mellitus

1. Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int Suppl. 2013;3:1–150; 2. ADA. Diabetes Care. 2019;42(Suppl 1):S1–S183; 3. Cosentino F, et al. Eur Heart J. 2020;41:255–323; 4. USRDS Annual Report 2018. Available at:

https://www.usrds.org/2018/download/v1_c01_GenPop_18_usrds.pdf [Accessed: January 2020]; 5. Hill NR, et al. PLoS One. 2016;11:e0158765; 6. Chen TK, et al. JAMA. 2019;322:1294–1304; 7. Persson F, et al. Kidney Int Suppl. 2018;8:2–7;

8. Mottl AK, et al. Diabetic kidney disease: Manifestations, evaluation, and diagnosis. Available at: https://www.uptodate.com/contents/diabetic-kidney-disease-manifestations-evaluation-and-diagnosis [Accessed: January 2020).

9

Structural changes to the glomerulus occur in people with diabetes1

CKD, chronic kidney disease

1. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12:2032–45.

Normal kidney glomerulus Diabetic kidney glomerulus

©2017 by American Society of Nephrology

Adapted from Alicic RZ, et al. (2017)

In people with diabetes, CKD induces structural changes1

10

Structural changes to the glomerulus in people with CKD and T2DM have a range

of consequences and an impact on the therapy choice1–4

Clinical consequences include decreased gluconeogenesis and reduced drug clearance1

In classical diabetic nephropathy, glomerular hyperfiltration and hypertrophy of the basement membrane occurs, followed by mesangial expansion, podocyte injury and glomerular sclerosis. This can then be followed by glomerular and tubulointerstitial fibrosis.2–4

CKD, chronic kidney disease; T2DM, Type 2 diabetes mellitus

1. Thomas MC, et al. Nat Rev Dis Primers. 2015;1:15018; 2. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12:2032–45; 3. Braunwald E. Prog Cardiovasc Dis. 2019;62:298–302; 4. Mottl AK and Tuttle KR. Diabetic kidney disease: Pathogenesis and epidemiology.

Available at: https://www.uptodate.com/contents/diabetic-kidney-disease-pathogenesis-and-epidemiology/print [Accessed: January 2020].

©2017 by American Society of Nephrology

Adapted from Alicic RZ, et al. (2017) and Thomas MC, et al. (2015)

11

Poor glycaemic control**

Hypertension**

Dyslipidaemia

Socioeconomic disadvantage

Obesity

Insulin resistance / metabolic syndrome

Episodes of acute kidney injury

Risk factors for CKD in people with diabetes1

*Intrauterine growth retardation is also a non-modifiable risk factor; **Mean, variability and maximal.1

CKD, chronic kidney disease; DKD, diabetic kidney disease

1. Thomas MC, et al. Nat Rev Dis Primers. 2015;1:15018.

Non-modifiable risk factors*1

Increasing age

Young age at onset of diabetes

Prolonged duration of diabetes

Genetic factors

Ethnicity

Family history of DKD

Gestational diabetes

Modifiable risk factors1

The vicious cycle of glycaemiccontrol, CKD, hypoglycaemiaand CVD, and its impact on patients’ outcomes

2

13

The vicious cycle of glycaemic control, CKD and hypoglycaemia has

a range of negative consequences1–15

CKD and hypoglycaemia

both increase the risk of CVD2,6–10

Hypoglycaemia is a

major obstacle to

achieving optimal

glycaemic control2,15

Poor glycaemic control increases the risk

of developing CKD and increases the

progression of renal damage11–14

CKD increases the risk

of hypoglycaemia2,15

Poor glycaemic control

increases the risk of CVD3–7

Glycaemic

control (HbA1c)

Hypoglycaemia CKD (DKD)

CVD

CKD, chronic kidney disease; CVD, cardiovascular disease; DKD, diabetic kidney disease

1. Braunwald E. Prog Cardiovasc Dis. 2019;62:298–302; 2. Alsahli M and Gerich JE. J Clin Med. 2015;4:948–64; 3. Paul SK, et al. Cardiovasc Diabetol. 2015;14:100; 4. Dokken BB. Diabetes Spectrum. 2008;21:160–165; 5. Leon BM and Maddox TM. World J Diabetes.

2015;6:1246–1258; 6. ORIGIN Trial Investigators. Eur Heart J. 2013;34:3137–44; 7. Snell-Burgeon JK and Wadwa RP. Diabetes Technol Ther. 2012;14 Suppl 1:S51–8; 8. Pecoits Filho, et al. Diabetol Metab Syndr. 2016:8;50; 9. Schiffrin EL, et al. Circulation. 2007;116:85–97; 10. Yun JS,

et al. Cardiovasc Diabetol. 2019;18:103; 11. Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243–254; 12. Stratton IM, et al. BMJ. 2000;321:405–412; 13. Alicic RZ, et al. Clin J Am Soc Nephrol. 2017;12:2032–2045; 14. Diabetes Canada. 2018. Clinical Practice Guidelines.

Available from: http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf [Accessed: January 2020]; 15. Alsahli M and Gerich JE. Mayo Clin Proc. 2014;89:1564–71.

Adapted from references below

14





Hypoglycaemia is a

major obstacle to

achieving optimal






of hypoglycaemia2,15



Glycaemic

control (HbA1c)







CVD


15

Microvascular complications increase with increasing HbA1c levels1,2

*The DCCT enrolled 1441 people, n=726 of whom (the "primary prevention" cohort) were recruited within 5 years of the onset of diabetes and had no evidence of diabetic retinopathy nor of microalbuminuria at baseline. The other n=715 subjects (the "secondary intervention"

cohort) were recruited within 15 years of the onset of diabetes and had mild-to-moderate background diabetic retinopathy with either normoalbuminuria or microalbuminuria. Subjects were randomly assigned to either intensive therapy (insulin administered either by continuous

subcutaneous insulin infusion (CSII) or by multiple daily insulin injections (MDI), with therapy guided by frequent self-monitoring of blood glucose; meticulous attention to food intake; and monthly clinic visits) or conventional therapy;1 **Composite of nephrology, amputation and

retinopathy;2 †Prospective observational study conducted in 23 clinics in England, Scotland, and Northern Ireland. 4585 UKPDS subjects, whether randomised or not to treatment, were included in analyses of incidence; of these, n=3642 were included in analyses of relative risk.2

CSII, continuous subcutaneous insulin infusion; MDI, multiple daily insulin injections; T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus

1. Skyler JS. Endocrinol Metab Clin North Am. 1996;25:243–254; 2. Stratton IM, et al. BMJ. 2000;321:405–412.

Increased HbA1c levels were a powerful predictor of nephropathy and microvascular complications in people with T1DM and T2DM1,2

16

Reducing HbA1c levels reduces the risk of nephropathy in people with T2DM1–3

ADVANCE**2UKPDS*1 ACCORD†3

Renal outcomes 30% 21% 21%

Intensive vs conventional glycaemic

control: 27.1% vs 39.0%.

RR (relative risk) (99% CI [confidence

interval]): 0.70 (0.46 to 1.07), p=0.033

Microalbuminuria(at 15 years, surrogate endpoint)

New or worsening

nephropathy

New

microalbuminuria

Intensive vs conventional glycaemic

control: 4.1% vs. 5.2%.

HR (hazard ratio) (95% CI): 0.79

(0.66 to 0.93), p=0.006

relative risk reduction relative risk reduction

*The UKPDS was an randomised controlled trial (RCT) that included people with newly-diagnosed diabetes aged 25–65 years, in the catchment areas of the 23 participating UKPDS hospitals between 1977 and 1991. People were randomised to receive conventional

(fasting plasma glucose [FPG] <15 mmol/L without symptoms of hyperglycaemia, n=1,138) or intensive treatment (FPG less than 6 mmol/L and pre-meal glucose concentrations of 4–7 mmol/L in insulin-treated people, n=2,729);1 **ADVANCE was a factorial RCT

conducted at 215 centers in 20 countries from Asia, Australasia, Europe, and North America, between June 2001 and March 2003. 11,140 people with T2DM were randomly assigned to either standard glucose control (targeted HbA1c per local guidelines, n=5,569) or

intensive glucose control (targeted HbA1c ≤6.5%, n=5,571);2 †ACCORD was a parallel group RCT conducted from January 2001 to June 2009, including people with T2DM, HbA1c levels ≥7.5% and CVD or ≥2 CVD risk factors from 77 sites in the US and Canada. This

analysis included 10,234 people (5,107 intensive [targeting HbA1c <6.0%] and 5,108 standard [targeting HbA1c 7–7.9%]). Intensive therapy was stopped before study end due to increased mortality, and people were transitioned to standard therapy.3

CVD, cardiovascular disease; FPG, fasting plasma glucose; HR, hazard ratio; RCT, randomised controlled trial; RR, relative ri sk; T2DM, Type 2 diabetes mellitus; UKPDS, UK Prospective Diabetes Study

CI, confidence interval; CVD, cardiovascular disease; HR, hazard ratio; RCT, randomised controlled trial; RR, relative risk; T2DM, Type 2 diabetes mellitus; UKPDS, UK Prospective Diabetes Study

1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53; 2. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560–72; 3. Ismail-Beigi F, et al. Lancet. 2010;376:419–30.

HbA1c reduction (%)(difference between intensive vs

standard glucose control groups)

0.9% 0.8% 1.3%

17

The presence of diabetes and CKD triples the risk of myocardial infarction (MI)

compared to diabetes without CKD*1

*Large population-based cohort study using two datasets: the Alberta Kidney Disease Network (AKDN) database and the NHANES 2003–06. Adults aged 18 years and older whose serum creatinine was measured at least once as an outpatient between 2002

and 2009 and who did not have end-stage renal disease were included. CKD defined as eGFR <60 mL/min/1.73 m² with or without proteinuria (stage 3 or 4 disease). A validated algorithm based on medical claims for diabetes treatment and hospital admission

data was used to classify people with diabetes at baseline. In sensitivity analyses, an HbA1c of >6.5% measured within 6 months of index serum creatinine, irrespective of treatment or insurance-claim data, was used to define diabetes (participants were classed

as not having diabetes if their HbA1c concentration had not been measured);1 **Includes people with and without diabetes and CKD.1

CKD, chronic kidney disease; MI, myocardial infarction

1. Tonelli M, et al, Alberta Kidney Disease Network. Lancet. 2012;380:807–14.

Population-based cohort study in Alberta, Canada (N=1,268,029)

18

Reduced eGFR increases risk for hospitalisation, CV events and death1

*Analyses were adjusted for age, sex, income, education, use or non-use of dialysis, and the presence or absence of prior coronary heart disease, prior chronic heart failure, prior ischemic stroke or transient ischemic attack, prior peripheral arterial disease, diabetes

mellitus, hypertension, dyslipidaemia, cancer, serum albumin of 3.5 g/dL or less, dementia, cirrhosis or chronic liver disease, chronic lung disease, documented proteinuria, and prior hospitalisations;1 **The study included adults (20 years of age or older) from the Kaiser

Permanente Renal Registry whose kidney function was known and who had one or more outpatient measurements of serum creatinine, had not previously received dialysis or a kidney transplant, and were alive on the index date.1

CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; HR, hazard ratio

1. Go AS, et al. N Engl J Med. 2004;351:1296–305.

These findings highlight the clinical and public health importance of CKD that does not necessitate dialysis1

Adjusted* HR for death from any cause, CV events, and hospitalisation among 1,120,295 ambulatory adults, according to the eGFR**

Adapted from Go AS, et al. (2004)

19

Mortality is increased about 6-fold in people with diabetes and CKD*1

*A combination of impaired eGFR and albuminuria;1 **Impaired eGFR was defined as eGFR ≤60 mL/min/1.73 m2. The horizontal dashed line indicates mortality in people without diabetes

or kidney disease (the reference group). The percentages above the arrows indicate excess mortality above the reference group. Error bars indicate 95% CIs.1

CI, confidence interval; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; NHANES, National Health and Nutrition Examination Survey; T2DM, Type 2 diabetes mellitus

1. Afkarian M, et al. J Am Soc Nephrol. 2013;24:302–8.

• The increased mortality risk in people with T2DM

is largely confined to those with diabetes and

CKD1

• Without CKD, diabetes is not associated with a

large increase in mortality risk1

• The co-existence of CKD and diabetes is

associated with greater mortality than the sum

of excess risks associated with either diabetes or

CKD alone1

• Impaired eGFR and albuminuria are associated

with CV and overall mortality1

NHANES US population-based study (N=15,046)1

20

CKD (DKD)Hypoglycaemia


of hypoglycaemia2,15CKD and hypoglycaemia














Glycaemic

control (HbA1c)

CVD


Hypoglycaemia is a

major obstacle to

achieving optimal


21

The resulting analysis file contained 243,222 individuals with 2,040,206 records representing individual glucose measurements. International Classification of Diseases (ICD)-9 codes were used for hypoglycaemia diagnosis. Risk for severe hypoglycaemia

was defined as blood glucose levels of <50 mg/dL and expressed as an adjusted incidence rate ratio classified by presence or absence of CKD and diabetes. All rate ratio p-values are <0.0001. CKD defined as eGFR <60 ml/min/1.73 m2. 1

CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ICD, International Classification of Diseases

1. Moen MF, et al. Clin J Am Soc Nephrol 2009;4:1121–7.

Retrospective analysis of US veterans (N=243,222) observed for hypoglycaemia (<50 mg/dL) or death1

The presence of CKD in people with diabetes doubles the risk of severe

hypoglycaemia compared to those without CKD1

22

CKD is associated with an increased risk of hypoglycaemia overall1

The resulting analysis file contained 243,222 individuals with 2,040,206 records representing individual glucose measurements. ICD-9 codes were used for hypoglycaemia diagnosis. Risk for hypoglycaemia of varying

blood glucose severity was expressed as an adjusted incidence rate ratio classified by presence or absence of CKD and diabetes. All rate ratios p-values <0.0001. CKD defined as eGFR <60 ml/min per 1.73 m2.1

BG, blood glucose; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; ICD, International Classification of Diseases

1. Moen MF, et al. Clin J Am Soc Nephrol. 2009;4:1121–7.

Retrospective analysis of US veterans (N=243,222) observed for hypoglycaemia or death1

Hypoglycaemia risk is increased

with either diabetes or CKD, with the

risk most pronounced in the presence

of both conditions1

The risk for the most severe

hypoglycaemic events was

highest in the group with

both diabetes and CKD1

23

*Defined as a symptomatic hypoglycaemic event in which the participant required assistance of another person and there was: (i) prompt recovery after oral carbohydrate, IV glucose, or glucagon administration; and/or (ii) a documented self-measured or laboratory

plasma glucose level ≤2.0 mmol/L (≤36 mg/dL). Nocturnal severe hypoglycaemia was defined as a severe hypoglycaemic episode occurring between midnight and 06:00 a.m;1 **The ORIGIN trial was a large, randomised, 2x2 factorial trial conducted across 40 countries

and included people ≥50 years of age with impaired glucose tolerance, impaired fasting glucose or early T2DM at high CV risk (n=12,537). Subjects were randomised to glargine 100 U/mL (target FPG ≤95 mg/dL [5.3 mmol/L]) versus standard care for median 6.2 years.

Glargine 100 U/mL was associated with a neutral effect on CV outcomes versus standard care.1

CI, confidence interval; CV, cardiovascular; FPG, fasting plasma glucose; glargine 100 U/mL, insulin glargine 100 U/mL; HR, hazard ratio; IV, intravenous; MI, myocardial infarction; T2DM, Type 2 diabetes mellitus

1. ORIGIN Investigators. Eur Heart J. 2013;34:3137–44; 2. ORIGIN Investigators. Diabetes Care. 2015;38:22–8.

The ORIGIN trial showed that severe hypoglycaemia* was associated with an

increased risk of major CV outcomes**1

In ORIGIN, 28% of participants reported non-severe hypoglycaemia and 3.8% reported severe hypoglycaemia.2

Severe events were associated with a greater risk for major CV events, mortality, CV death and arrhythmic death1

Secondary analysis of ORIGIN trial investigating associations of severe hypoglycaemia* with CV outcomes and mortality1

24








Glycaemic

control (HbA1c)

Hypoglycaemia


of hypoglycaemia2,15CKD and hypoglycaemia







CKD (DKD)

CVD


Hypoglycaemia is a

major obstacle to

achieving optimal


25

Hypoglycaemia is a critical barrier to glycaemic control and has a

negative impact on patient quality of life (QoL)1–8

*In the 4 weeks following baseline. Results shown are from a non-interventional, multi-centre, 4-week prospective-cohort survey of hypoglycaemic events conducted across 2004 sites in 24 countries from 2012 to 2013. Subjects were ≥18 years of age at the time of enrollment,

with T1DM or T2DM, treated with insulin for >12 months.1

QoL, quality of life; T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus

1. Khunti K, et al. Diabetes Res Clin Pract. 2017;130:121–129; 2. Russell-Jones D, et al. Diabetes Obes Metab. 2018;20:488–496; 3. Willis WD, et al. Expert Rev Pharmacoecon Outcomes Res. 2013;13:123–130; 4. Sakane J, et al. J Diabetes Investig. 2015;6:567–570; 5. Leiter LA, et al.

Can J Diabetes. 2005;29:00–00; 6. Fidler C, et al. J Med Econ. 2011;14:646–655; 7. Aronson R, et al. Diabetes Res Clin Pract. 2018;138:35–43; 8. Diabetes Canada. 2018; Clinical Practice Guidelines. Available from: http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf

[Accessed: January 2020].

• maintaining HbA1c levels within a

margin higher than recommended3

• reduced treatment adherence1,2,6,8

• negative impact on QoL and

physical, mental and social

functioning6,8

• decreased work productivity7

• fear of future episodes4,5

• increased cost to patient, healthcare

system and society.3,6,7

Patient actions resulting from experience of hypoglycaemia:*1–8

All of these actions

resulting from

hypoglycaemia

can impact

glycaemic control1–8

The critical role of optimal glycaemic control in theeffective management of people with CKD and T2DM

3

27

Glycaemic control is a key component of recommendations for a

multifaceted approach to treating people with CKD and T2DM1,2

*Statins not recommended in people on haemodialysis.1

ACEi, angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; GLP-1 RA, glucagon-like peptide 1 receptor agonist; LDL[-C], low-density

lipoprotein[-cholesterol]; SBP, systolic blood pressure; SGLT2, sodium-glucose cotransporter 2; T2DM, Type 2 diabetes mellitus

1. ADA. Diabetes Care. 2019;42(Suppl 1): S1–183; 2. Cosentino F, et al. Eur Heart J. Eur Heart J. 2020;41:255–323.

Management approaches to reduce or slow the progression of CKD in people with T2DM:1,2

Glucose

control1,2

Low-density

lipoprotein (LDL)

cholesterol-

lowering2

Dietary

protein1

Angiotensin-converting-enzyme

inhibitor (ACEi)/ angiotensin receptor blocker (ARB) use1,2

Sodium-glucose cotransporter 2 (SGLT2) inhibitors/ glucagon-

like peptide 1 receptor agonist (GLP-1 RA)

use1,2

Blood pressure

(BP)-lowering1,2

HbA1c targets are individualised,

but are generally ~7%

Optimise BP control to reduce risk or slow progression of CKD. Target systolic blood pressure (SBP) to 130 mmHg and >120–<130 mmHg if tolerated

Strongly recommended for those with urinary albumin-to-creatinine ratio ≥300 mg/g creatinine and/or eGFR rate <60 mL/min/1.73m2

LDL-C targets are based on CV risk level. Statins are first-choice lipid-lowering treatment in people with high LDL-C levels*

Dietary protein intake should be ~0.8 g/kg per day (non-dialysis-dependent people)

Consider use of an agent shown to reduce risk of CKD progression, CV events or both

28

Optimal management of your patients…

Blood pressure

monitoring

Lipid

managementCV

protection Glucose control

Balance HbA1c targets

and hypoglycaemia

All individuals with CKD should be considered at high risk for CV events and should be treated to reduce these risks1,3,4

A multidisciplinary team is important to help identify individualised targets and develop management

approaches to reduce or slow the progression of CKD in people with T2DM1–4

Management of people with T2DM and CKD: recommendations and guidelines1–4

Diet and

exercise advice

…can result in: slowed progression of CKD1,3 lower risk of CVD.1,5

CKD, chronic kidney disease; CVD, cardiovascular disease; T2DM, Type 2 diabetes mellitus

1. Diabetes Canada. 2018. Clinical Practice Guidelines. Available from: http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf [Accessed: January 2020]; 2. Betônico CC, et al. Clinics (Sao Paulo). 2016;71:47–53; 3. ADA. Diabetes Care. 2019;42(Suppl 1):S1–S183;

4. Cosentino F, et al. Eur Heart J. 2020;41:255–323; 5. Paul SK, et al. Cardiovasc Diabetol. 2015;14:100.

29

Glycaemic control has benefits for many aspects of diabetes and renal function1–12

*Intensive glycaemic control with the goal of achieving near-normoglycaemia;1,2 **Tight glucose control, targeting HbA1c (<7.0% or <53 mmol/mol).2,3

CKD, chronic kidney disease; eGFR, estimated glomerular filtration; QoL, quality of life; T1DM, Type 1 diabetes mellitus; T2DM, Type 2 diabetes mellitus

1. ADA. Diabetes Care. 2019;42(Suppl 1): S1–S183; 2. Bakris GL. Treatment of diabetic kidney disease. Available at: https://www.uptodate.com/contents/treatment-of-diabetic-kidney-disease [Accessed: January 2020]; 3. Cosentino F, et al. Eur Heart J. 2020;41:255–323;

4. Fioretto P, et al. J Am Soc Nephrol. 2006;17(Suppl 2):S86–S89; 5. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53; 6. Ziegler D, et al. Diabetologica 1991;34:822–29; 7. Ruggenenti P et al. Lancet. 2001;357:1601–8; 8. Morioka T, et al. Diabetes Care.

2001;24:909–13; 9. Wiesbauer F, et al. Transplantation. 2010;89:612–9; 10. Klebe et al. Nephrol Dial Transplant. 2007;22:2504–12; 11. Lau, et al. J Postgrad Med. 2004;50:189–93; 12. Paul SK, et al. Cardiovasc Diabetol. 2015;14:100.

Impact of glycaemic control on:

Renal functionMicro and macrovascular

complicationsClinical outcomes

• Delayed onset and progression of

albuminuria and reduced eGFR in

people with T1DM and T2DM*1,2

• Partial reversal of glomerular

hypertrophy and hyperfiltration,

important risk factors for

glomerular injury2

• Prevention of CKD, and slowed

progression of GFR decline1,2

• Decreased risk of albuminuria

development4,7

• Reduced risk for development of

renal failure5

• Decreased microvascular

complications**1–3,7

• Decreased cardiovascular

event risk12

• Reduced incidence of

autonomic neuropathy6

• The effects of glucose-lowering

therapies on CKD have helped

define HbA1c targets1

• Increased survival rate in people

undergoing haemodialysis8

• Improved chances of a

successful kidney transplant9

• Reduced costs10

• Improved patient mental QoL11

30

Treatment guidelines advocate the optimisation of glycaemic control

to reduce the risk or slow the progression of CKD1,2

CKD, chronic kidney disease; CVD, cardiovascular disease; DPP-4, dipeptidyl peptidase-4; eGFR, estimated glomerular filtration rate; GLP-1 RAs, glucagon-like peptide 1 receptor agonists; SGLT2, sodium-glucose transport protein 2

1. ADA. Diabetes Care. 2020;43(Suppl 1): S1–S212; 2. Diabetes Canada. 2018. Clinical Practice Guidelines. Available from: http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf [Accessed: January 2020].

A number of agents, including metformin, SGLT2 inhibitors, GLP-1 RAs, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones, sulphonylureas

and insulin, are suggested as potential treatments to control blood glucose.1,2

In patients with T2DM and CKD, SGLT2 inhibitors or GLP-1 RAs should be considered part of the treatment.

Glucose-lowering medication(s) must be selected carefully, considering a number of

drug- and patient-specific factors, including:

• limitations to certain treatments when eGFR is diminished (check the prescribing information)

• the renal effects of each treatment

• the need to mitigate high risks of CKD progression, CVD, and hypoglycemia.1

Hypoglycemia is more common as progressively lower HbA1c levels are targeted,

and people with CKD are at an increased risk of hypoglycemia2

ADA and Diabetes Canada Clinical Practice Guidelines state that:1,2

Longer-acting basal analogs may convey a lower hypoglycemia risk compared with shorter-acting insulins when used in combination

with oral agents1

Long-acting insulin analogues should be considered over NPH insulin to reduce the risk of nocturnal and symptomatic hypoglycemia2

31








Glycaemiccontrol (HbA1c)


CVD



Hypoglycaemia is a major obstacle to achieving optimal


Poor glycaemic control increases the risk of developing CKD and increases the


Poor glycaemic control increases the risk of CVD3–7

CKD increases the riskof hypoglycaemia2,15


32

Effective control of CKD and

hypoglycaemia may reduce the risk of CVD2,6,7

Lower hypoglycaemiaincidence during initial insulin treatment may help to improve future

glycaemic control5

Early and effective glycaemiccontrol reduces the risk of developing CKD1,3

Effective glycaemic control can reduce the risk of CVD6,7

Effective and careful management of antidiabetic treatment is key to reducing

hypoglycaemia risk in people with CKD and T2DM4

A number of opportunities exist for intervention, thereby interrupting

the vicious cycle and improving clinical outcomes1–7

CVD, cardiovascular disease; CKD, chronic kidney disease; DKD, diabetic kidney disease; T2DM, Type 2 diabetes mellitus

1. Braunwald E. Prog Cardiovasc Dis. 2019;62:298–302; 2. Alsahli M and Gerich JE. J Clin Med. 2015;4:948–64; 3. Nordwall M, et al. Diabetes Care. 2015;38:308–15; 4. Alsahli M and Gerich JE. Mayo Clin Proc. 2014;89:1564–71; 5. Harris S, et al. Presented at the 79th Scientific

Sessions of the American Diabetes Association 2019; June 7–11; San Francisco, CA, US. 1095-P; 6. Diabetes Canada. 2018. Clinical Practice Guidelines. Available from: http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf [Accessed: November 2019]; 7. ADA.

Diabetes Care. 2019;42(Suppl 1): S1–S183.

CVD

CKD (DKD)Hypoglycaemia

Glycaemiccontrol (HbA1c)


33

CKD is a common complication of diabetes: CKD affects almost 4 in 10 people with T2DM, ~50% of whom

have advanced disease2

Optimised treatment with balance between HbA1c control

and hypoglycaemia risk1–8

*Reduction in HbA1c levels refers to the difference in HbA1c levels between intensive glycaemic control and standard glycaemic control arms. Renal outcomes include new microalbuminuria and new or worsening nephropathy.4–6

CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; T2DM, Type 2 diabetes mellitus

1. Moen MF, et al. Clin J Am Soc Nephrol. 2009;4:1121–7; 2. Wu B, et al. BMJ Open Diabetes Res Care. 2016;4:e000154; 3. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53; 4. ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560–72;

5. Ismail-Beigi F, et al; Lancet. 2010;376:419–30; 6. Afkarian M, et al. J Am Soc Nephrol. 2013;24:302–8; 7. Diabetes Canada. 2018. Clinical Practice Guidelines. Available from: http://guidelines.diabetes.ca/docs/CPG-2018-full-EN.pdf [Accessed: January 2020];

8. ADA. Diabetes Care. 2019;42(Suppl 1): S1–S183.

The presence of CKD in people with diabetes doubles the risk of severe hypoglycaemia compared to

those without CKD1

Optimising glycaemic control plays an important role in the management of CKD; a 0.8–1.3% reduction in

HbA1c levels can cause up to a 30% relative reduction in renal outcomes*3–5

Mortality is increased about 6-fold in people with diabetes and CKD, compared to individuals without

diabetes or CKD6

Guidelines recommend a comprehensive, multifaceted approach to treatment, with intensive glycaemic

control to slow the deterioration of renal function and reduce CVD risk for people with T2DM7,8

34

References

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https://www.uptodate.com/contents/diabetic-kidney-disease-pathogenesis-and-epidemiology/print


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• Ruggenenti P et al. Lancet. 2001;357:1601–8.

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