Type 2 DM and CKD

T2DM and CKD
Role of the Glyptins in management
Dr Sanjay Maitra
MD,DM(PGI,Chd),Clin.Fellowship Toronto Univ.
Sr.Consultant Nephrologist,Apollo Health City, Hyderabad

Outline of Talk
 Current scenario of Diabetes
 What is Diabetic Nephropathy?
 What is the significance of Diabetic Nephropathy?
 Importance of Strict glycaemic control in the treatment of
Diabetic Nephropathy
 Role of Glyptins in the management of Diabetic
Nephropathy.
 Are Glyptins Nephroprotective?
 Sitaglyptin and other glyptins in patients of Diabetic CKD

India has around 61 Million diabetics

Approximately 35-40% of these patients will develop Diabetic kidney disease ultimately

What is Diabetic Nephropathy?
It is one of the long term microvascular complications of Diabetes
 It is a clinical syndrome characterized by
 Persistent albuminuria (>300 mg/d or >200 μg/min) that is confirmed on at least 2
occasions 3-6 months apart
 Progressive decline in the glomerular filtration rate (GFR)
 Elevated arterial blood pressure
 Present in patients with
 Worse glycaemic control
 Hypertension
 Glomerular Hyperfiltration
 Genetic Predisposition

Typical progression of diabetic kidney disease
 Exposure to diabetes is required
for diabetic nephropathy to
develop in susceptible patients.
 The time at which the
complication becomes clinically
apparent and the rate at which it
progresses is variable and can be
modified by careful management
of glycemia, hypertension, and
glomerular hypertension.
 ESRD, End-stage kidney disease.
6
Seaquist ER, Ibrahim HN. J Clin Endocrinol Metab. 2010 Jul;95(7):3103-10
Risk of developing Diabetic Nephropathy
equal in Type 1 & Type 2 Diabetes

Current Scenario of CKD
 Chronic kidney disease (CKD) is a
worldwide public health problem that
affects millions of people from all
racial and ethnic groups.
 Diabetes mellitus is the leading cause
of CKD.
 The latest United States Renal Data
System (USRDS) report indicates a
30% increase in incidence of ESRD in
persons with diabetes in the USA
between 1992 and 2008.
 Diabetic individuals with CKD needs
special attention and individualized
management of hyperglycemia.

Diabetes: The Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Diabetes
50.1%
Hypertension
27%
Glomerulonephritis
13%
Other
10%
No. of patients
Projection
95% CI
1984 1988 1992 1996 2000 2004 2008
0
100
200
300
400
500
600
700
r2=99.8%
243,524
281,355
520,240
No.ofdialysis
patients(thousands)

Diabetes-Related Complications in the United States
1990–2010
All five complications declined between 1990 and 2010
The largest relative declines in acute myocardial infarction (−67.8%; 95%
confidence interval [CI], −76.2 to −59.3) and death from hyperglycemic crisis
(−64.4%; 95% CI, −68.0 to −60.9),
followed by stroke and amputations, which each declined by approximately
half (−52.7% and −51.4%, respectively);
the smallest decline was in end stage renal disease (−28.3%; 95% CI,
−34.6 to −21.6).
N Engl J Med 2014;370:1514-2

Incidence of CKD in India – 800 per million population
Incidence of ESRD in India- 150-200 per million population

Cross sectional study involving 52,273 patients
Mean age 50.1±14.6 yrs
M:F ratio 70:30
Diabetic nephropathy –commonest cause of CKD (31%)
CKD of unknown aetiology (16%)
CGN (14%)
Hypertensive nephrosclerosis (13%)

Diabetics likely to be detected early
Patients of unknown etiology are likely to be younger ,females and to have CKD-5
INDIAN CKD REGISTRY DATA-2012

Monthly Cost Of haemodialysis at 3
HD/wk
Rs 12,000- Rs 30,000
Monthly cost Of Erythropoeitin per month Rs 7,000-Rs 10,000
Monthly cost of CAPD 3 exchanges per
day
Rs. 20,000-Rs 25,000
Cost of transplant procedure Rs 3,00,000- Rs, 7,00,000
Cost of immunosuppressive medicines
(Using Tacrolimus,MMF and steroids)
Rs 10,000-Rs 15,000 per
month
Approx.cost of renal replacement therapy in India

Current treatment regimens for treating
Diabetic kidney disease
 Strict Glycaemic Control
 PPAR Agonists
 ACE Inhibitors/ARB for
 BP control
 Primary prevention
 Proteinuria reduction
 Preservation of renal functions
 Role of Diltiazem and verapamil
 Cholesterol control
 Lifestyle modification-Weight reduction/Smoking
 Diet –Sodium and protein restriction

Efficacy depends on stage at which it is begun
and the degree of normalisation –best seen in
Type 1 DM

KDOQI Diabetes Guideline:
Nov. 2012 Update
Summary of Recommendations
 A target HbA1c of ~7.0% to prevent or delay progression
of the microvascular complications of diabetes,
including DKD.
 Not treating to an HbA1c target of <7.0% in patients at
risk of hypoglycemia.
 Target HbA1c be extended above 7.0% in individuals
with co-morbidities or limited life expectancy and risk
of hypoglycemia.
Am J Kidney Dis. 2012 Nov;60(5):850-86. doi: 10.1053/j.ajkd.2012.07.005.
KDOQI Clinical Practice Guideline for Diabetes and CKD: 2012 Update.
National Kidney Foundation.

T2DM and CKD:
Management of hyperglycemia
 Management of hyperglycemia involves a multifactorial
approach that includes medicines, proper nutrition and
meal planning, and physical activity.
 Each of these approaches may need to be modified in the
setting of CKD.
Am J Kidney Dis. 2012 Nov;60(5):850-86. doi: 10.1053/j.ajkd.2012.07.005.

Risk of hypoglycemia in patients of
Diabetes and CKD

Symptom Recognition of Hypoglycemia is Lower
Among Older Individuals
Adapted with permission from Matyka K et al. Diabetes Care. 1997;20(2):135–141.
Change in Plasma Glucose
200
Time, min
–40
36
54
72
90
108
0 40 80 120 160
Young Without Diabetes
Elderly Without Diabetes
ChangeinTotalSymptomScore
0
14
12
10
8
6
4
2
PlasmaGlucose,mg/dL

Estimated Rates of Emergency
Hospitalizations for Adverse Drug
Events in Older U.S. Adults 2007-2009
Budnitz et al. NEJM, 365:21, 2011
Hypoglycemia is a Major Cause of Adverse
Drug Reactions Resulting in Hospitalization

ADVANCE: Severe Hypoglycemia Was Associated With
Adverse Clinical End Points and Death
15.9
11.5
19.5
9.5 10.010.2 10.1
9.0
4.8 4.3
0
5
10
15
20
25
Major
Macrovascular
Event
Major
Microvascular
Event
Death From Any
Cause
CV Disease Non-CV Disease
PatientsWithEvents,%
Severe Hypoglycemia (n=231) No Severe Hypoglycemia (n=10,909)
ADVANCE=Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation; CI=confidence interval; CV=cardiovascular; HR=hazard ratio.
aHypoglycemia was defined as a blood glucose level <2.8 mmol/L (50 mg/dL) or the presence of typical signs and symptoms of hypoglycemia without other apparent cause. bAdjusted for the
baseline covariates of age, sex, treatment assignment, duration of diabetes, presence or absence of a history of macrovascular disease, presence or absence of a history of microvascular disease,
and smoking status and for the time-dependent covariates of the use of sulfonylurea, metformin, thiazolidinedione, insulin, and any diabetes drug and the use of antihypertensive therapy; glycated
hemoglobin; body-mass index; creatinine level; ratio of urinary albumin to creatinine; and systolic blood pressure..cPrimary end points. Major macrovascular event=CV death, nonfatal myocardial
infarction, or nonfatal stroke; major microvascular event=new or worsening nephropathy or retinopathy.
1. Zoungas S et al. N Engl J Med. 2010;363:1410–1418.
HR (95% CI):
3.53 (2.41–5.17)b
HR (95% CI):
2.19 (1.40–3.45)b
HR (95% CI):
3.27 (2.29–4.65)b
HR (95% CI):
3.79 (2.36–6.08)b
HR (95% CI):
2.80 (1.64–4.79)b
c c

 Decreased renal glucose production
 Reduced gluconeogenesis in liver from alanine, pyruvate, glycerol with
decreased mitochondrial ATP/ADP ratio
 Decreased glycogen reserve
 Reduced systemic response to adrenalin and glucagon
 Decreased insulin degradation (normal kidney extracts 40% insulin),
which intensifies and prolongs insulin actions
 Reduced renal clearance of hypoglycemic oral agents and their active
metabolites
Reasons Why Chronic Kidney Disease
Increases Risk of Hypoglycemia
Arem R, Endocrinol Metab Clin N Am 18:103, 1989; Rigalleau V and Gin H, Curr Opin Clin Nutr Metab Care 8:463, 2005; Frohlich J et al,
Am J Clin Nutr 31:1541, 1978; Cano N, Curr Opin Clin Nutr Metab Care 4:279, 2001

Special Considerations in Advanced CKD
Risk of hypoglycemia is increased in patients with advanced CKD
( stages 4 and 5) for two reasons:
 Decreased clearance of insulin and of some of the oral agents used
to treat diabetes,
 Impaired renal gluconeogenesis with reduced kidney mass.

KDOQI 2012 update: Dose adjustment for Antidiabetic
medications
Drug Class Drug CKD stages 3, 4, 5
Insulin Glargine, Detemir, NPH,
Regular, Aspart, Lispro,
Glulisine
Adjust dose based on patient response
1st Gen SUs Acetohexamide,
Chlorpropamide, Tolazamide,
Tolbutamide
Avoid Use*
*except Chlorpropamide (50% dose in GFR 50-80 ml/min, avoid use in GFR <50 ml/min)
2nd Gen SUs Glipizide, Gliclazide
Glimepiride
Glyburide
No dose adjustment
Start conservatively at 1mg/day
Avoid use
Meglitinides Repaglinide, Nateglinide Start conservatively with lower dose
Biguanides Metformin Avoid* if SCr >1.5mg/dL (men) and >1.4mg/dL (women) *USFDA
TZDs Pioglitazone, Rosiglitazone No Dose Adjustment
AGIs Acarbose
Miglitol
Avoid if GFR <30ml/min
Avoid if GFR <25ml/min
DPP4i Sitagliptin
Saxagliptin
Linagliptin
Vildagliptin
GFR >50ml/min 100mg, 30-50ml/min 50mg, <30ml/min 25mg
GFR >50ml/min 5mg, <50ml/min 2.5mg
No Dose adjustment
GFR >50ml/min 50mg bid, <50ml/min 50mg qd
Incretin Mimetics Exenatide
Liraglutide
Avoid in GFR <30ml/min
Avoid in GFR <60ml/min
Amylin Analog Pramlintide No dose adjustment, not recommended in CKD stage 4 or greater
Dopamine receptor
agonist
Bromocriptine mesylate Not studied in patients with reduced GFRAm J Kidney Dis. 2012 Nov;60(5):850-86. doi: 10.1053/j.ajkd.2012.07.005.

Role of Incretin based therapies

The “Incredible” Incretins
Intestine+Secretion +Insulin = Incretin
 Basically a factor that reduces blood glucose levels
without affecting exocrine pancreatic secretion
 It was observed that oral glucose administration caused a
greater increase in insulin secretion than same amount of
Intravenous, despite higher blood glucose levels in the
latter
 Impact of Incretin secretion on glucose control is
significant.
 Levels depended on oral glucose intake
 For e.g. 75% of insulin response after 50 gm glucose intake

The “Incredible” Incretins
Intestine+Secretion +Insulin = Incretin
 Two of the most important incretins are
 Gastric Inhibitory Peptide (GIP) secreted by the K cells in the stomach,
duodenal mucosa ,proximal jejunum
 Glucagon Like Peptide –I (GLP-I) secreted by L cells in the ileum and
colon
 After secretion GLP-I and GIP are both degraded by DPP-4 enzyme
 Exists in a soluble and membrane bound form
 Highest levels of membrane bound form is in the kidneys
 In diabetes the insulinotropic effects of GLP-I are preserved
despite lower levels as compared to non-diabetics
 Available options is GLP-I agonists or DPP-4 inhibitors
 In Diabetes the insulinotrpic actions of GIP are severely impaired

GLP-1 Modes of Action in Humans
GLP-1 is secreted
from the L-cells
in the intestine
This in turn…
• Stimulates glucose-dependent
insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
Long term effects
demonstrated in animals…
• Increases beta-cell mass and
maintains beta-cell efficiency
• Reduces food intake
Upon ingestion of food…

Possible Cytoprotective effects Of DPP-4 Inhibitors on target organ damage

The DPP-4 Inhibitors
Name of Drug Remarks
Sitagliptin FDA approved 2006, marketed by Merck & Co. as Januvia
Vildagliptin EU approved 2007, marketed in the EU by Novartis as Galvus
Saxagliptin FDA approved in 2009, marketed as Onglyza
Linagliptin FDA approved in 2011, marketed as Tradjenta by Eli Lilly Co and Boehringer
Ingelheim
Anagliptin Approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and
Kowa Company, Ltd
Teneligliptin Approved in Japan in 2012
Alogliptin FDA approved 2013, marketed by Takeda Pharmaceutical Company
Trelagliptin Approved for use in Japan in 2015
Gemigliptin Being developed by LG Life Sciences
Dutogliptin Being developed by Phenomix Corporation in Phase III trials
Omarigliptin MK-3102,approved in Japan in 2015, developed by Merck & Co.
Omarigliptin can be used as once-weekly treatment and generally well-tolerated
throughout the base and extension studies[

Gliptins: Route of Elimination
Use of Gliptins in Special Population
Sitagliptin1 Vildagliptin2 Saxagliptin3 Linagliptin4
Elimination Renal
(80% unchanged)
Renal 85%
(33% unchanged)
Renal
(12%–29% as parent; 21%–
52% as metabolite)
Feces
(>70% unchanged)
In renal
impairment a
lower dose
achieves similar
plasma
concentration
as usual dose in
patients without
renal
impairment
In renal
impairment a
lower dose
achieves similar
plasma
concentration
as usual dose in
patients without
renal
impairment
In renal
impairment a
lower dose
achieves similar
plasma
concentration
as usual dose in
patients without
renal
impairment
No lowering of
dosage in renal
impairment
1. Deacon CF. Expert Opin Investig Drugs. 2007;16(4):533–545. 2. European Public Assessment Report for Galvus. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000771/WC500020327.pdf. Accessed August 5, 2012. 3. European Public Assessment Report for Onglyza. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/001039/WC500044316.pdf. Accessed August 5, 2012.
Lower Dose
Similar DPP-
4 inhibition
Lower Dose
Similar DPP-
4 inhibition
Lower Dose
Similar DPP-
4 inhibition
Same dose
in Renal
impairment

CKD and medication safety
Fink et al. KI 2009;76:1123–1125
Chronic kidney disease represents an assembly of several high-risk factors,
which, under circumstances of poor disease recognition, can lead to adverse
patient
safety events .

Metabolism / Clearance and Dosing Adjustments of Drugs for
T2DM
DRUG Metabolism / Clearance Dose Adjustment in CKD
Metformin Renal
D/C if creatinine  1.4 Female;  1.5 Male
Glyburide
Hepatic/renal
High risk hypoglycemia; decrease dose in CKD
Glimepiride Hepatic/renal Decrease dose in CKD
Glipizide Hepatic Decrease dose in CKD
Repaglinide Hepatic Decrease dose in CKD
Nateglinide Hepatic/renal Decrease dose in CKD
TZD (pioglitazone) Hepatic No dose adjustment required
DPP-4 inhibitors Renal, hepatic Decrease dose in CKD
GLP-1 RA Renal, proteolysis Exenatide not recommended if GFR<30
Insulin Tissue/renal Decrease dose in CKD
Adapted from Fonseca , Am J Med 124LS54-S61, 2011

DPP4i in Renal impairment
 All DPP4i are considered generally safe in various degrees of renal
impairment.
Sitagliptin, Vildagliptin, Saxagliptin
• Much of the drug excreted via kidneys
• In Renal impairment a lower dose can
achieve plasma concentrations similar
to usual dose
• Effective dose in renal impairment is
lower than the usual dose
Linagliptin
• Excretion is primarily via the hepato-
biliary route
• Renal impairment: Plasma drug
concentration not significantly
changed
• Effective dose in renal impairment
is same as the usual dose

Efficacy of lower doses (50mg/25mg) of
Sitagliptin in patients with renal impairment

Sitagliptin 25mg and 50mg
Efficacy and Safety Data in T2DM with CKD
 The optimum dose of Sitagliptin in most patients is 100mg/day
 In Phase I multiple-dose studies, there were no dose-related clinical adverse
reactions observed with Sitagliptin with doses of up to 600 mg per day for periods of
up to 10 days and 400 mg per day for up to 28 days.
 The DPP4 inhibition achieved with a DPP-4 inhibitor is dependent on the active
concentration of the molecule in plasma.
 The active plasma concentration achieved with Sitagliptin 100mg, Sitagliptin 50mg
and Sitagliptin 25mg is similar in patients with no/mild renal impairment, moderate
renal impairment and severe renal impairment/ESRD respectively.
 This suggests that a lower dose of Sitagliptin may be as effective in patients with
moderate or severe renal impairment as usual dose of Sitagliptin in patients without
renal impairment.

Safety and efficacy of sitagliptin in
patients with type 2 diabetes and
chronic renal insufficiency. • After 12 weeks, the mean change
[95% CI] from baseline in HbA1c was
-0.6% (-0.8, -0.4) in
the sitagliptin group compared with
-0.2% (-0.4, 0.1) in the placebo
group [between-group difference
(95% CI) = -0.4% (-0.7, -0.1)].
• At 54 weeks, patients continuously
treated with sitagliptin had a mean
change (95% CI) from baseline in
HbA1c of -0.7% (-0.9, -0.4).
• The overall incidence of adverse
experiences was generally similar
between groups.
Method: In a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated
haemoglobin A(1c) (HbA(1c)) values of 6.5-10% were allocated (2:1) to sitagliptin (for 54 weeks) or the
sequence of placebo (for 12 weeks) followed by active treatment with glipizide (for 42 weeks). To achieve
plasma concentrations similar to those observed in patients with normal renal function treated with 100
mg sitagliptin once daily, patients with moderate renal insufficiency were allocated to receive sitagliptin 50
mg once daily and patients with severe renal insufficiency to receive 25 mg once daily. Glipizide treatment
was initiated at 2.5 or 5 mg/day and uptitrated to a maximum of 20 mg/day.
Diabetes Obes Metab. 2008 Jul;10(7):545-55. doi: 10.1111/j.1463-1326.2008.00914.x. Epub
2008 Jun 1.
Safety and efficacy of sitagliptin in patients with type 2 diabetes and
chronic renal insufficiency.
Chan JC, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, Stein PP, Kaufman
KD, Amatruda JM, Williams-Herman D.

Efficacy and Safety of Sitagliptin 50mg/25mg
monotherapy versus Glipizide
in Patients with T2DM and Moderate to Severe CRF
Baseline (%)
Mean (SD)
Change from Baseline at Week 54
LS Mean (95% CI)
Sitagliptin 7.76 (0.65) -0.8 (-0.9, -0.6)
Glipizide 7.79 (0.70) -0.6 (-0.8, -0.5)
Arjona Ferreira JC et al. Diabetes Care. 2013 May;36(5):1067-73. doi: 10.2337/dc12-1365. Epub 2012 Dec 17
Glipizide starting dose 2.5mg/day
electively uptitrated to 20mg/day
The proportion of patients reporting AEs of symptomatic
hypoglycemia was
significantly lower (P = 0.001) in the sitagliptin group (6.2%)
compared with the glipizide group (17.0%). Overall, 1.4% of patients
in the sitagliptin group were reported with a severe episode of
hypoglycemia compared with 2.8% in the glipizide group (between-
group difference 21.4 [95% CI 24.8 to 1.5]).

Efficacy and Safety of
Sitagliptin 25mg q.d. vs. Glipizide
in Patients With T2DM and ESRD on Dialysis
 Monotherapy with sitagliptin, 25 mg
daily or glipizide (initiated with 2.5
mg daily and titrated up to a
potential maximum dose of 10 mg
twice daily or down to avoid
hypoglycemia
 The incidences of symptomatic
hypoglycemia and severe
hypoglycemia were 6.3% versus 10.8%
(between-group difference, -4.8%
[95% CI, -15.7% to 5.6%]) and 0%
versus 7.7% (between-group
difference, -7.8% [95% CI, -17.1% to -
1.9%]) in the sitagliptin and glipizide
groups, respectively.N
Baseline (%)
Mean (SD)
Change from Baseline at Week 54
LS Mean (95% CI) p-Value
Sitagliptin 62 7.89 (0.74) -0.72 (-0.96, -0.49) <0.001
Glipizide 58 7.78 (0.68) -0.88 (-1.12, -0.64) <0.001
Am J Kidney Dis. 2013 Apr;61(4):579-87. doi: 10.1053/j.ajkd.2012.11.043. Epub 2013 Jan 24.
Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week
randomized trial. Arjona Ferreira JC, Corry D, Mogensen CE, Sloan L

Efficacy and tolerability of sitagliptin monotherapy
in elderly patients with type 2 diabetes
 Among randomized patients (N = 206), mean
age was 72 years and mean baseline HbA(1c)
was 7.8%. At week 24, HbA(1c) decreased by
0.7%, 2-h PMG by 61 mg/dL, and FPG by 27
mg/dL in sitagliptin-treated patients
compared with placebo (all p < 0.001).
 Treatment with sitagliptin was generally
well-tolerated in this study. Clinical AEs
overall were reported in 46.1% of patients in
the sitagliptin group and 52.9% in the
placebo group
This was a randomized, double-blind, placebo-controlled, parallel-group study
conducted at 52 sites in the United States. Patients were treated with once-
daily sitagliptin (100 or 50 mg, depending on renal function) or placebo for 24
weeks. Key endpoints included change from baseline in glycated hemoglobin
(HbA(1c)), 2-hour post-meal glucose (2-h PMG) and fasting plasma glucose (FPG) at
week 24, and average blood glucose on treatment days 3 and 7.
Curr Med Res Opin. 2011 May;27(5):1049-58. doi: 10.1185/03007995.2011.568059. Epub 2011 Mar 23.
Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized,
double-blind, placebo-controlled trial.
Barzilai N, Guo H, Mahoney EM, Caporossi S

Sitagliptin 3 doses: Efficacy and Tolerability
 Durability of sitagliptin in elderly
patients with type 2 diabetes
 All the patients enrolled in the study
followed up for at least 4 years
 0.8% reduction from a mean baseline
of 7.11% within first 6 months
 Different doses of sitagliptin had the
same HbA1c-lowering effect
No apparent changes in baseline renal function after 48
months of treatment
(Cr, 1.36±0.73 mg/dL and 1.32±0.67 mg/dL, respectively [P=0.20]; eGFR,
53.4±24.3 mL/minute/1.73 m2 and 57.6±23.0 mL/minute/1.73 m2,
respectively; P=0.36).
Hsieh et al, The durability of sitagliptin in elderly patients with type 2
diabetes, Clinical Interventions in Aging 2014:9 1905–1911

Sitagliptin therapy in kidney transplant recipients with
new-onset diabetes after transplantation (NODAT).
NODAT is a frequent and serious complication after kidney transplant, occurs within the first 3
months post-transplant. An ideal antidiabetic agent should stimulate b-cell function, improve IR, be
easily administered, and well tolerated without hypoglycemia.
Transplantation. 2011 Nov 27;92(10):e56-7. doi: 10.1097/TP.0b013e3182347ea4.
Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation.
• 3-month pilot study: Sitagliptin 100mg in a
population diagnosed with NODAT. (n=15, eGFR
>30ml/min)
• Over the course of the study, there was no
significant change in tacrolimus or sirolimus levels;
there was no change in eGFR over the course of
the study. eGFR was 58.9 + 4.4 mL/min at entry
and 60.5 + 5.6 mL/min at week 12.
• HbA1c improved from a baseline of 7.2%+ 0.1% to
6.7%+0.2% (P=0.002).
• No patient discontinued the use of sitagliptin
because of side effects. No patients had
symptomatic hypoglycemia, although some were
on more than one agent for NODAT. Side effects
included mild abdominal discomfort, loose stools,
nausea, and headaches.
Mean drug levels for sirolimus, tacrolimus, and eGFR over time.

Saxagliptin 2.5mg q.d. in renal impairment
 Reductions in adjusted mean HbA(1c)
were numerically greater
with saxagliptin than placebo in patients
with renal impairment rated as moderate
(-0.94% vs. 0.19% respectively) or severe
(-0.81% vs. -0.49%), but similar to
placebo for those with ESRD (-1.13% vs. -
0.99%).
 Saxagliptin was generally well tolerated;
similar proportions of patients in
the saxagliptin and placebo groups
reported hypoglycemic events (28% and
29% respectively).Double-blind study in patients stratified by baseline renal impairment
(moderate, severe or end-stage renal disease [ESRD] on haemodialysis)
randomised to saxagliptin 2.5 mg once daily or placebo added to other
antidiabetic drugs in use at baseline, including insulin.
A total of 170 adults with glycated haemoglobin (HbA(1c) ) 7-11% and
creatinine clearance < 50 ml/min or ESRD were randomised and treated.
Int J Clin Pract. 2011 Dec;65(12):1230-9. doi: 10.1111/j.1742-1241.2011.02812.x. Epub 2011 Oct 7.
Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes
mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study.
Nowicki M, Rychlik I, Haller H, Warren M, Suchower L, Gause-Nilsson I, Schützer KM.

Vildagliptin 50mg q.d. in renal impairment
Double-blind, randomized, parallel-group, 52-week clinical trial
comparing safety and efficacy of vildagliptin (50 mg qd, n = 216) and
placebo (n = 153) added to ongoing stable antihyperglycaemic
treatment, in patients with T2DM and moderate or severe (glomerular
filtration rate [GFR] ≥ 30 to <50 ml/min/1.73 m(2) and < 30 ml/min/1.73
m(2) ) RI.
Diabetes Obes Metab. 2012 Nov;14(11):1032-9. doi: 10.1111/j.1463-1326.2012.01634.x. Epub
2012 Jul 8.
One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and
moderate or severe renal impairment.
Kothny W, Shao Q, Groop PH, Lukashevich V.
HbA1c reduction
-0.4 ± 0.2% (p = 0.005)
HbA1c reduction
-0.7 ± 0.2% (p < 0.0001)

Linagliptin in patients with type 2
diabetes and severe renal impairment
 In this 1-year, double-blind study,
133 patients with type 2 diabetes
and severe RI (eGFR <30
mL/min/1.73 m2) at screening
were randomized to linagliptin 5
mg (n = 68) or placebo (n = 65)
once daily, added to existing
background therapy.
 HbA1c improvements were
sustained with linagliptin (-0.71%)
over placebo (0.01%) at 1 year
(treatment difference -0.72%, -
1.03 to -0.41; P < 0.0001).
Diabetes Care. 2013 Feb;36(2):237-44. doi: 10.2337/dc12-0706. Epub 2012 Oct 1.
Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: a 1-year,
randomized, double-blind, placebo-controlled study.
McGill JB, Sloan L, Newman J, Patel S, Sauce C, von Eynatten M, Woerle HJ.

DPP-4 inhibitors in Renal Impairment
 No head on trial to compare any two gliptins in this population
 Less than usual dose of Sitagliptin (50mg/25mg) as monotherapy
is documented in all degrees of renal impairment including ESRD
and dialysis and demonstrated to be as effective as glipizide,
the SU of choice in renal impairment, in multiple standalone
studies.
 Less than usual dosage of Saxagliptin (2.5mg q.d.) and
Vildagliptin (50mg q.d.) is studied as add on therapy in various
stages of renal impairment.
 Linagliptin 5mg is not studied as monotherapy in patients with
renal impairment in any standalone trial. However, pooled
analysis and add-on studies suggest that an usual dose (5mg) of
Linagliptin is safe and effective in this population.

These drugs have a wide therapeutic margin and should protect against
toxicity if patients of renal failure inadvertantly are prescribed higher doses

HbA1c Reduction Associated With DPP-4 Inhibitor Use in
Patients With Renal Impairment
G Ramirez et al; DPP-4 inhibitors in kidney disease ; Endocrine Practice ;2013

Efficacy of dipeptidyl peptidase-4 (DPP-4) inhibitor therapy in people with
diabetes and renal impairment in studies in which there was a prospective
study design and a duration of at least 3 months
T. M. E. Davis; Dipeptidyl peptidase-4 inhibitors: pharmacokinetics,efficacy, tolerability and safety in renal impairment; Diabetes, Obesity and Metabolism 2014.

Can DPP-4 inhibitors be beneficial
for the kidneys?

Provides data that DPP-4 inhibition in kidney prox.tubular cells
may contribute to renoprotection in diabetic milieu through GLP-1
independent pathways

A pooled analysis of pivotal Phase III, placebo-controlled, registration studies
of linagliptin further showed a significant reduction of urinary albumin excretion
after 24 weeks of treatment. The observation suggests direct renoprotective effects
of DPP-4 inhibition that may go beyond its glucose-lowering potential

Sitagliptin reduces albuminuria in patients
with T2DM  Diabetic patients (n=36) were enrolled into this study and
were successfully followed over 6 months
of sitagliptin treatment.
 Sitagliptin (50 mg/day) treatment significantly lowered both
systolic and diastolic blood pressures, fasting blood glucose
and postprandial blood glucose, HbA1c, and glycated
albumin at 3 months and 6 months.
 Significant reductions in highly sensitive C-reactive protein
and soluble vascular cell adhesion molecule 1 were also
observed at 6 months.
 Urinary albumin excretion (measured as urinary albumin-to-
creatinine ratio (ACR: mg/g Cr)) did not change in the 6
months before sitagliptin treatment (ΔACR: 2.3 ± 19.9) and
decreased in the 6 months after sitagliptin treatment (ΔACR:
-20.6 ± 24.6); these differences were statistically
significant.
 The present findings strongly suggest
that sitagliptin reduces albuminuria without lowering the
estimated glomerular filtration rate, most likely depending
on known factors such as blood sugar reduction, blood
pressure reduction, and inflammation reduction, as well as
yet undetermined factors caused by an increase in active
glucagon-like peptide-1.
Endocr J. 2011;58(1):69-73. Epub 2010 Dec 28.
ptin reduces albuminuria in patients with type 2 diabetes.
Hattori S.
Baseline Follow-up
(6months)
P value
Normoalbuminur
ic (ACR<30)
11.6 ± 8.4 4.5 ± 5.0 p=0.0012
Microalbuminuric
(30 <ACR <300)
98.4 ± 79 24.9 ± 20 p=0.0152
Macroalbuminuri
c (ACR>300)
1263 ± 492 561 ± 89 p=0.0211
hsCRP (ng/mL) 448 ± 314 203 ± 126 p<0.017
sVCAM (ng/mL) 723 ± 236 634 ± 173 p<0.017

Properties of frequently used
antihyperglycaemic drugs in patients
Muskiet et al ;Lancet Diabetes Endocrinol;2015; 3: 367–81

Anti diabetic treatment in chronic renal failure
according to the KDIGO staging of CKD
Adapted from Schernthaner GH. Strict glycaemic control in diabetic patients with CKD or ESRD: beneficial or deadly? Nephrol Dial Transplant.

AACE 2015
ENDOCRINE PRACTICE Vol 21 No. 4 April 2015

Avoiding drug toxicity in CKD patients

Dosing Adjustments
Don’t rely on SCr alone – calculate eGFR or Cr
clearance
SCr misleading in: extremes of body weight, poor nutrition
Cannot rely on eGFR in AKI
If SCr rapidly rising, assume eGFR <10 ml/min
When in doubt, look up dosing adjustment/
potential interactions or call pharmacy

Key Points
CKD patients at high risk for drug-related adverse
events
Several classes of drugs renally eliminated
Consider kidney function and current eGFR (not just
SCr) when prescribing meds
Minimize pill burden as much as possible
Remind CKD patients to avoid NSAIDs

Take Home Message
 Individualization is core to the management of T2DM associated with CKD.
 The usual HbA1c treatment target for DM+CKD is <7% for most patients
 DPP-4 inhibitors may be a preferred alternative to the conventional
therapies as they are as effective yet associated with less adverse effects.
 All DPP-4 inhibitors are indicated in renal impairment, however only
Sitagliptin, Saxagliptin and Vildagliptin are effective even at a lower dose
in renal impairment and only Sitagliptin is documented as monotherapy in
patients with renal impairment.
.

Take Home Message
 Linagliptin needs no dose modification and also reduces proteinuria
 Sitagliptin is also the only gliptin with standalone trial in patients on
ESRD/hemodialysis and with active comparator trial (compared with Glipizide).
 Smaller studies (preclinical and clinical) have also demonstrated specific
Renoprotective benefits with Sitagliptin in patients with renal impairment

Type 2 DM and CKD

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