A.

MAKBUL AMAN M
Division of Endocrine and Metabolism Department of Internal Medicine, Faculty of
Medicine Hasanuddin University / RSUP Dr. Wahidin Sudirohusodo, Makassar
The diabetes epidemic: a global healthcare
concern

IDF Diabetes Atlas 9th Edition, 2019

 T2D, HF, and CKD are closely connected

Five times HF
T2D increased risk
A leading cause of
hospitalization in older adults3
of HF in T2D7
1 out of 2 patients will die within
63M2 5 years of diagnosis4

629M HF and CKD vicious circle:

(2045) one is associated with the other9

40% of T2D CKD 64.5% of CKD stage 1–5 patients have

patients will prevalent CVD6
develop CKD8 Prevalence of HF increases as CKD
Global
425M1 prevalence
progresses6
(2017)
13.4%5

CKD, chronic kidney disease; CVD, cardiovascular disease; HF, heart failure; T2D, Type 2 diabetes
1. International Diabetes Federation. IDF Diabetes Atlas, 8th edn. Brussels, Belgium: International Diabetes Federation; 2017; 2. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Lancet
2017;390:1211–1259; 3. Foltz-Gray D. Available at: www.aarp.org/health/doctors-hospitals/info-03-2012/hospital-admissions-older-adults.html (Accessed July 2019); 4. Taylor CJ, et al. BMJ 2019;364; DOI:
10.1136/bmj.l223; 5. Hill NR, et al. PLoS One 2016;11:e0158765; 6. US Renal Data System. USRDS Annual Report, 2018; Chapter 4. Available at: https://www.usrds.org/2018/view/v1_04.aspx (Accessed July 2019); 7.
Nichols GA, et al. Diabetes Care 2004;27:1879–1884; 8. Alicic RZ, et al. Clin J Am Soc Nephrol 2017;12:2032–2045; 9. Ronco C, et al. J Am Coll Cardiol 2008;52:1527–1539
• Diabetic kidney disease (DKD), usually occurs in patients with type 1 and type 2
diabetes mellitus (DM) without long-term adequate glycemic control.
• Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease
(ESKD), associated with increased morbidity and mortality in diabetic patients.
• DKD is defined according to the changes in renal structure and function.
• Major renal structural changes in DKD include mesangial expansion, glomerular
and tubular basement membrane thickening, and glomerular sclerosis.
 NATURAL HISTORY OF DKD
• Glomerular hyperfiltration,
occurs shortly after diagnosis in
most patients with type 1 DM.
• Hyperfiltration is due to the
relative vasodilation of renal
glomerular afferent arterioles,
leading to increased glomerular
pressure and a resultant
increase in GFR.
• Hyperfiltration is improved or
eliminated with good glycemic
control.
• Hyperfiltration also occurs in
early type 2 diabetes but its
presence is less consistent.
• Hyperfiltration predicts
albuminuria and a generally
worse prognosis in diabetic
patients.

Radica Z. Alicic, Michele T. et all, Diabetic Kidney Disease Challenges, Progress, and Possibilities, Clin J Am Soc Nephrol 12: 2032–2045, 2017
• The natural history is not always followed by
patients with progressive DKD.
• In the Diabetes Control and Complications
Trial and the follow-up Epidemiology of
Diabetes Interventions and Complications
study of participants with type 1 diabetes,
28% of the patients with an estimated GFR
<60 mL/min/1.73 m2 did not have abnormal
albuminuria.
• 5% and 30% of type 1 DKD patients develop
only transient albuminuria or never develop
albuminuria, yet still develop progressive
nephropathy.
• Similarly, a progressive decline in GFR to ESRD
in the absence of albuminuria progression
occurs in up to 50% of type 2 diabetic
patients.
• These changes in DKD patterns may be the result of widespread use of agents such as
angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers
(ARBs) that reduce proteinuria but fail to retard progression of disease in some
patients.
• Enhanced hypertension control in diabetic patients can reduce albuminuria and may
have contributed to the generalized reduction in albuminuria seen in DKD patients.
• A number of type 2 diabetic patients develop albuminuria before the onset of their
diabetes.
• In some of these individuals this reflects the presence of generalized endothelial
dysfunction rather than glomerular pathology.
• In addition, kidney disease can result directly from obesity, insulin resistance, and the
metabolic syndrome, all of which routinely precede the onset of type 2 diabetes.
• The type of kidney pathology seen in such individuals diverges in several aspects from
that of DKD.
 DIFFERENT PATHWAYS AND NETWORKS INVOLVED IN THE
INITIATION AND PROGRESSION OF DIABETIC KIDNEY DISEASE

Jonatan Barrera-Chimal, Frédéric Jaisser MD, Pathophysiologic mechanisms in diabetic

kidney disease: A focus on current and future therapeutic targets, Diabetes Obes Metab. Radica Z. Alicic, Michele T. et all, Diabetic Kidney Disease Challenges, Progress, and
2020;22:16–31 Possibilities, Clin J Am Soc Nephrol 12: 2032–2045, 2017
 DIABETIC NEPHROPATHY STAGES

STAGE PERIOD OF TIME FEATURES

I Hypertrophy and After diagnosis of No signs of nephropathy in blood and urine

hypertension diabetes mellitus Increased GFR
up to 2 years Increased renal plasma flow (RPF)
II Histological changes of > 2 years Initial morphological lesions (changes in
the kidney without basal membrane thickness, expansion of the
clinical manifestation mesangium)

III Starting nephropathy 5-15 years Starting microalbuminuria

Normal GFR
Hypertension (50%)
Well-established glomerular abnormalities
IV Clinical manifested 10-25 years Overt nephropathy
nephropathy Persistent proteinuria
Fall of GFR
Fall of RPF
Hypertension (approx. 60%)
V End-stage renal 15-30 years GFR < 10 ml/min
disease Hypertension (approx. 90%)
13
Classification of CKD Based on GFR and
Albuminuria Categories: “Heat Map”

Kidney Disease: Improving Global

Outcomes (KDIGO) CKD Work Group.
Kidney Int Suppls. 2013;3:1-150.
DKD usually manifests a clinical syndrome including :
• Persistent albuminuria,
• Increased blood pressure,
• Sustained reduction in glomerular filtration rate (GFR),
• Increased cardiovascular events and cardiovascular event-associated
mortality.
MANAGEMENT OF DKD

✓Glucose control,
✓Blood pressure control,
✓Lipid profiles control,
✓Modification of lifesty
 GLUCOSE CONTROL
• Recommend using HbA1c to monitor glycemic control in patients with diabetes
and CKD
• Glycemic Control The ADA recommends a target HbA1c of < 7%.
• KDIGO 2020 recommend an individualized HbA1c target ranging from 6,5% to
8,0% in patiens with diabetes and ckd not treated with dialisys
• The United Kingdom Prospective Diabetes Study (UKPDS) revealed a 25% risk
reduction in the composite microvascular complication endpoint in the groups
that underwent intensive control of blood sugar compared to patients receiving
what was standard control.
• A smaller trial in Japanese type 2 patients, the Kumamoto trial, revealed a 60%
reduction of albuminuria >300 mg/day with intensive glycemic control in type 2
diabetes.
 BLOOD PRESSURE CONTROL
• Reduction of BP has been reduce the incidence of major
cardiovascular events and to delay the progression of DKD.
• The optimal range of BP control in hypertensive patients
with diabetes has been an area of controversy.
• The ADA currently recommends that most patients with
diabetes should have an average seated BP of <140/90
mm Hg.
• KDIGO guidelines for BP control, which were last updated
in 2021, also recommend reduction of BP < 120 mm Hg for
systolic when tolerated.
 KDIGO

• Non-diabetic adults with CKD:

≤140 mmHg systolic and ≤90 mmHg diastolic if normoalbuminuric
≤130 mmHg systolic and ≤80 mmHg diastolic if micro or macroalbuminuric

• Diabetic adults with non dialysis-dependent CKD:

≤140 mmHg systolic and ≤90 mmHg diastolic if normoalbuminuric
≤130 mmHg systolic and ≤80 mmHg diastolic if micro or macroalbuminuric

• Kidney transplant recipients:

≤130 mmHg systolic and ≤80 mmHg diastolic

• Elderly people with CKD:

probably ≤140 mmHg systolic and ≤90 mmHg diastolic, but set targets after
consideration of co-morbidities

KDIGO Blood Pressure Work Group. Kidney Int Suppl 2012

 MONITORING OF SERUM CREATININE AND
POTASSIUM DURING ACEI OR ARB TREATMENT

KDIGO,2020
 LIPID CONTROL
• ADA recommends the use of lifestyle modification in all patients with diabetes,
• The Study of Heart and Renal Protection (SHARP) examined the effects of dual
treatment with simvastatin and ezetimibe in CKD and dialysis patients, including
those with diabetes showed that the combination of simvastatin and ezetimibe led
to a significant reduction in major atherosclerotic cardiovascular events but did not
appear to reduce the progression of CKD.
• Gemfibrozil and fenofibrate are also used frequently in DKD patients.
• The Diabetes Atherosclerosis Intervention Study and the Fenofibrate Intervention
and Event Lowering in Diabetes (FIELD) Study reported a decrease in albuminuria and
its regression toward normo albuminuria with the use of fenofibrate.
• Gemfibrozil therefore should not be given combined with statins.
• Gemfibrozil when combined with statins increases the risk of increased
transaminases and rhabdomyolysis.
 DIETARY PROTEIN RESTRICTION

• A number of studies showed that moderate protein restriction

reduced the progression of established DKD in terms of GFR
decline, albuminuria, and occurrence of ESRD in both type 1 and
type 2 diabetic patients.
• However, modest dietary protein restriction may be helpful in a
number of DKD patients and will likely do no harm.
• KDIGO 2020 suggest maintaining a protein intake of 0.8 g
protein/kg (weight)/d for those with diabetes and CKD not
treated with dialysis
 OTHER LIFESTYLE MODIFICATIONS

• Sodium restriction in hypertensive DKD patients

• Exercise should be part of lifestyle modification as tolerated.
• Supplementation with monounsaturated and polyunsaturated fats
have improved glycemic control, lowered blood pressure, reduced
albuminuria, and altered high-risk inflammatory biomarkers in the
general population and may be beneficial in patients with
diabetes and CKD.
• Smoking cessation parts of lifestyle modification.
• Weight loss has beneficial renal effects by reducing proteinuria
and decreasing blood pressure in patients with mild to moderate
CKD with or without diabetes.
 Multifactorial approach for modifying Renal & cardiovascular risk in type 2
diabetes
ASA Generally, A1C <7.0%
Indicated for secondary
prevention
A1C targets should be
Minimal net benefit in primary individualized
prevention
6.8

Lipid-lowering Multifactorial
Management
agents
• High-intensity statin for
people with diabetes and
ASCVD
• Consider moderate-
intensity statin for
people <40 years old
with diabetes and ASCVD
risk factors
• Moderate-intensity statin
for people 40–75 years
with diabetes and >75 a,
years without ASCVD with drugs to protect the heart.
Rydén L et al. Eur Heart J. 2013;34(39):3035-87; Fox CS et al. Diabetes Care. 2015;38(9):1777-803; Piepoli MF et al. Eur Heart J.
2016;37(29):2315-2381; Davies MJ et al. Diabetes Care. 2018;41(12):2669-2701.
Change in management of T2D from a glucocentric
focus to a cardio-renal-metabolic focus
2018 Canadian Algorithm6:
Stratification by HbA1c and 2019 PERKENI Guideline4
clinical CVD Risk factors screenings are done
for T2D and prediabetes patients.

2016 2018 2019 2020 2021

2020-2021 ADA Algorithm3:
The treatment approach for T2D is to consider
the indicators of high-risk or established ASCVD,
HF, or CKD predominates independent of A1c

2018 ADA/EASD consensus7:

Patient stratification by CV
and renal risk

Number of available therapies18

AACE, American Association of Clinical Endocrinologists; ADA, American Diabetes Association; CV, cardiovascular; CVD, cardiovascular disease; EASD, European Association for
the Study of Diabetes; HbA1c, glycated haemoglobin; T2D, Type 2 diabetes
1. Houlden RL, et al. Can J Diabetes 2018;42:S1–S5; 2. Davies MJ, et al. Diabetes Care 2018;41:2669–2701; 3. American Diabetes Association Dia Care 2020;43:S98-S110 4. 27
PERKENI Guideline on management and prevention of T2D
 The Evolving Armamentarium for Type 2 Diabetes

Paradigm shift in T2DM treatment approach

Goals in T2DM Management : Should be a combination of Intermediate and Ultimate Goals

T2DM is a progressive disease requiring a multifaceted approach to reduce risk factors

Incorporating
New Classes
in the Treatment of
Our Patients
10/14/2021
29
TREATMENT ALGORITHM FOR SELECTING ANTIHYPERGLYCEMIC
DRUGS FOR PATIENTS WITH T2D AND CKD

KDIGO,2020
• As recommended by the ADA, metformin is the
firstline pharmacologic agent for treatment of
hyperglycemia in patients with type 2 diabetes,
including those with DKD.
• Metformin is effective, safe, and inexpensive, and
may reduce the risk of cardiovascular events and
death.
• Compared to sulfonylureas, metformin has
beneficial effects on A1C, weight, and
cardiovascular mortality.
• In the past, metformin was felt to be
contraindicated in CKD patients with S[Cr] >1.5
mg/dL, because of its structural similarity to
phenformin, which caused lactic acidosis in
diabetic patients.
• KDIGO 2020 recommend treating patients with
T2D, CKD, and an eGFR ≥ 30 ml/min per 1.73 m2
with metformin
• SGLT2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, should be
considered for glycemic control in patients with type-2 diabetes and established
atherosclerotic cardiovascular disease.
• SGLT2 inhibitors (empagliflozin, canagliflozin, and dapagliflozin) lower glucose levels by
blocking glucose reabsorption by the proximal renal tubules.
• There is also a strong indication from trials that SGLT2 inhibitors prevent eGFR decline
and development of albuminuria.
• Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical
Evaluation (CREDENCE) trial which studied the effects of canagliflozin treatment in
macroalbuminuric patients with DKD and eGFR between 30 and 90 mL/min/1.73m2
already receiving maximum tolerated standard treatment (including ACEIs or ARBs),
canagliflozin reduced the development of ESRD, doubling of S[Cr] and cardiovascular or
renal death by 30%.
• SGLT2 inhibitors are approved only for patients with eGFRs >30 mL/min/1.73 m2.
• It should be noted that SGLT2 inhibitors are contraindicated all type 1 diabetic
patients, due in part to the higher incidence of diabetic ketoacidosis in patients using
these drugs
• GLP-1 receptor agonists, such as lixisenatide, liraglutide, semaglutide, exenatide,
lower glucose by stimulating glucose-dependent insulin secretion, suppressing
glucagon secretion, slowing gastric emptying, and reducing appetite.
• It is yet unclear whether GLP-1 receptor agonists prevent progression of CKD to
ESRD.
• Like the SGLT2 inhibitors, GLP-1 agonists are contraindicated in patients with eGFR <
30 mL/min/1.73 m2.
 SUMMARY
✓ DKD remains the leading cause of ESRD.
✓ Diabetic patients should be monitored for the development of DKD.
✓ Measurement of S[Cr], calculation of eGFR, and monitoring for albuminuria (UACR >30) should
be performed at least annually starting 5 years after diagnosis of type 1 diabetes, and at the
time of diagnosis of type 2 diabetes.
✓ Excellent glycemic control with an HbA1c of 7% can prevent or delay the development of DKD.
✓ Treatment of elevated blood pressure to <140/90 mm Hg can also reduce the development and
progression of nephropathy.
✓ Targeting a BP of <130/80 mm Hg should be considered when it is safe and tolerable.
✓ Use of an ACEI or ARB as the first-line antihypertensive therapy is recommended for
hypertensive patients with DKD to reduce the incidence of major cardiovascular events and
progression of DKD.
✓ Reduction of daily protein intake to 0.8 g/kg body weight is recommended in DKD patients who
are not treated with dialysis.
✓ Lifestyle modification, including exercise, weight loss, smoking cessation, and dietary
consultation should be incorporated into a multidisciplinary approach to treatment for DKD
patients.
Thank
You