3. Diabetes:
The Most Common Cause of ESRD
Primary Diagnosis for Patients Who Start Dialysis
Other Glomerulonephritis
10% 13% No. of patients
700 Projection
Diabetes Hypertension 95% CI
No. of dialysis patients
600 50.1% 27%
(thousands)
500
400
300 520,240
281,355
200
243,524
100 r2=99.8%
0
1984 1988 1992 1996 2000 2004 2008 2010
4. Quality of Diabetes Management
Glycemic Control, A1c
Declining renal function
Blood pressure control Lipid control, LDL-C
5. Definition of Diabetic Nephropathy
Diabetic nephropathy has been classically
defined by the presence of proteinuria >0.5
g/24 h. This stage has been referred to as overt
nephropathy, clinical nephropathy, proteinuria,
or macroalbuminuria
Diabetes Care 28:176–188, 2005
7. We conclude that microalbuminuria in patients with Type II
diabetes is predictive of clinical proteinuria and increased
mortality. (N Engl J Med 1984; 310:356–60.)
76 ( 30 to 140 μ/ml )vs
75 ( <15 μ/ml ) + 53 ( 16-29 μ/ml )vs
28 ( > 140 μ/ml )
Follow 9 years
9. Epidemiology
1. Approximately 7% of Diabetes naive pts already have microalbuminuria
(Adler et al., 2003). However, the prevalence of microalbuminuria before
5 years can reach 18% esp. in pts with poor glycemic and lipid control
and high normal BP.
2. Albuminuria: roughly 10% of the general population including patients
with diabetes.
3. USRDS report: diabetes accounted for 54% of new CKD patients in 2007;
and affects 40% of type 1 and type 2 diabetic patients (USRDS, 2003).
4. Admission for renal replacement therapy: 49% diabetes ( Heidelberg )
Table derived from: Maduka Ignatius C, European Journal of Scientific Research, ISSN 1450-216X Vol.26 No.2 (2009), pp.255-259
11. Change of Glomerular Basement Membrane at
Pre-diabetes stage
Blood tests for diabetes were positive in 20% of
patients at biopsy. In 44% of 6 months and 70%
at 24 months follow-up.
12. Diabetic Nephropathy
Not all DM patients in ESRD suffer from classic
Kimmelstiel-Wilson syndrome ( enlarged kidney and
heavy proteinuria, 70% ).
Terminal renal failure without major proteinuria and with
small kidney: 11%
DM in the presence of primary kidney disease: 19%
Classic glomerulosclerosis is characterized by increased glomerular basement membrane width,
diffuse mesangial sclerosis, hyalinosis, microaneurysm, and hyaline arteriosclerosis.
NDT ( 2010 ) 25:2044-2047
13. Prevalence of the different stages of nephropathy with
increasing duration of diabetes
UKPDS 64
15. UKPDS 74 Progression
38 % of 4031 developed MAU at 15 yrs
• 64 % had eCrCl > 60 ml/min/1.73m2
• 24 % had eCrCl < 60 ml/min/1.73m2 after MAU
• 12 % had eCrCl < 60 ml/min/1.73m2 pre MAU
29 % of 5032 developed reduced eCrCl
< 60 ml/min/1.73m2 at 15 yrs
• 51 % had UAC < 50 mg/L
• 16 % had UAC > 50 mg/L after reduced eCrCl
• 33 % had UAC > 50 mg/L pre reduced eCrCl
Thus MAU does not always precede declining renal
function
DIABETES, VOL. 55, JUNE 2006
16. UKPDS 74 Conclusions
Strong evidence of effectiveness of glycaemic and BP
control in prevention of increases in albuminuria
Significant reduction in those doubling plasma creatinine
(albeit small numbers)
Demonstration of poor prognosis for those with worsening
renal function
Relatively slow progression of albuminuria toward renal
impairment in T2DM
Discordance between eCrCl and UAC
20. Hypoglycaemia
―The major limiting factor to achieving
intensive glycaemic control for people
with type 2 diabetes‖
Briscoe VJ, et al. Clin Diab 2006;24:115-121.
21. Elderly subjects with CKD stage 3-5 prone to
severe hypoglycemia, esp. SU related
57/6276 ER p’t ( 0.9% )
48/57, drug induced
60.4% > 70y/o
In above, >60% CKD 3-5
Masakazu Haneda et. NDT ( 2009 ) 24
22. Declining renal function increases risk of
severe hypoglycaemia
9
Risk for severe hypoglycaemia
8
(incidence rate ratio)
7
6
5
4
3
2
1
0
+ CKD
+CKD / + –– CKD +
CKD / + CKD / –
+ CKD – CKD
– CKD / –
+ Diabetes
Diabetes +Diabetes
Diabetes Diabetes
– Diabetes – Diabetes
Around 74% of sulphonylurea-induced severe hypoglycaemic events
(loss of consciousness) occur in patients with reduced renal function
Moen MF, et al. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121–1127
23. Reason for developing hypoglycemia in CKD
1. Altered insulin metabolism
2. Decreased appetite
3. Decreased renal gluconeogenesis
4. Impaired release of counter-regulatory hormones like
epinephrine due to autonomic neuropathy
5. Concurrent hepatic disease
6. Decreased metabolism of drugs that might promote
a reduction in plasma glucose concentrations such as
alcohol, nonselective β blockers, and disopyramide++
++ sustained insulin secretion related to K channel closing and impaired counter-regulatory
hormone response.
25. Counter regulatory hormone response
82 mg/dl Inhibition of endogenous insulin secretion
Counterregulatory hormone release
70 mg/dl GLUCAGON, CATECHOLAMINES: failed in
type 1 DM or advanced type 2 DM
50-60 mg/dl Onset of autonomic and
neuroglycopenic symptoms
< 50 mg/dl Cognitive dysfunction
Coma,
convulsion
McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor–2
agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats.
Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential
mechanism of HAAF ( hypoglycemia-associated autonomic failure ).
27. Effect of experimental hypoglycaemia on
QT interval
A B
QTc= 456 ms QTc= 610 ms
HR= 66 bpm HR= 61 bpm
5.0mM 2.5mM
International Diabetes Monitor 2009; 21(6): 234-241.
28. Intervention Works...but at a
Price: DCCT and UKPD
Severe Hypoglycemia
100 DCCT (Type 1) UKPDS (Type 2)
Major Episodes
5
80
Major Episodes Incidence (%)
Rate/100 Patient Years
4
60
Intensive 3
Intensive
40
2
20
1
Conventional Conventional
0 0
56 78 9 10 11 12 13 14 0 3 6 9 12 15
HbA1c (%) During Study
Years from Randomization
DCCT Research Group, Diabetes. 1997;46:271-286 UKPDS Group (33), Lancet. 352: 837-853, 1998
Stratton IM et al. BMJ. 2000;321:405-412.
29.
30.
31. Survival as a function of HbA1c in people with type 2
diabetes: a retrospective cohort study
Methods: Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from the
UK General Practice Research Database from November 1986 to November 2008. We identified 27 965
patients whose treatment had been intensified from oral monotherapy to combination therapy with oral
blood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin....
Lancet 2010; 375: 481–89
32. Relative Risk of Hypoglycemia between Sulphonylureas
UKPDS 33, in which the mean percentage of patients per year
with one of more episodes of hypoglycemia was 17.7% for
glyburide and 11.0% for chlorpropamide (RR 1.61), and the
mean percentage of patients per year with one or more major
hypoglycemic episodes was 0.6% for glyburide and 0.4% for
chlorpropamide.
DIABETES CARE, VOLUME30, NUMBER2, FEBRUARY2007
33. Hypoglycemia with sulphonylureas versus
insulin(UKPDS)
Any Severe
40 3.0
36.5
2.5 2.3
30
Mean (%)
Mean (%)
2.0
20 17.7 1.5
11 1.0
10 0.6
0.5 0.4
1.2 0.1
0 0.0
Diet Chlorpropamide Glibenclamide Insulin
UKPDS 33. Lancet 1998;352:837-853.
38. The ACCORD Trial: Prescribed Glucose
Lowering Drugs—Single Class
Lower A1C in the intensive-therapy group was associated
with greater exposure to drugs from every class
Intensive Standard
Therapy Therapy
n=5128 n=5123
Metformin 4856 (94.7) 4452 (86.9)
Secretagogue 4443 (86.6) 3779 (73.8)
Glimepiride 4010 (78.2) 3465 (67.6)
Repaglinide 2574 (50.2) 908 (17.7)
Thiazolidinedione 4702 (91.7) 2986 (58.3)
Rosiglitazone 4677 (91.2) 2946 (57.5)
Data are n (%).
The ACCORD Study Group. N Engl J Med. 2008;358(24):2545-2559. 3
39. The ACCORD Trial:
Adverse Events and Clinical Measures
The intensive-therapy group had significantly higher rates
of hypoglycemia, weight gain, and fluid retention
Intensive Therapy Standard Therapy
Variable n=5128 n=5123 P Value
Hypoglycemia, n (%)
Requiring medical assistance 538 (10.5) 179 (3.5) <0.001
Requiring any assistance 830 (16.2) 261 (5.1) <0.001
Fluid retention, n/total no. (%) 3541/5053 (70.1) 3378/5054 (66.8) <0.001
Weight gain >10 kg since baseline,
1399/5036 (27.8) 713/5042 (14.1) <0.001
n/total no. (%)
Fatal or nonfatal heart failure, n (%) 152 (3.0) 124 (2.4) 0.10
Systolic blood pressure, mm Hg 126.4 ± 16.7 127.4 ± 17.2 0.002
Diastolic blood pressure, mm kg 66.9 ± 10.5 67.7 ± 10.6 <0.001
The ACCORD Study Group. N Engl J Med. 2008;358(24):2545-2559.
40. PROactive: Heart-failure events
End point Pioglitazone, n Placebo,
(%) n (%)
Reported HF 281 (10.8) 198 (7.5)
(nonadjudicated)
HF leading to 149 (5.7) 108 (4.1)
hospitalization
HF leading to death 25 (0.96) 22 (0.84)
Dormandy J et al. European Association for the Study of
Diabetes; September 10-15 2005; Athens, Greece.
41. Triad of fluid retention, edema and weight gain;
and Acute pulmonary edema
Kermani and Garg, in their recently published article, discussed 6
patients with CHF and acute pulmonary edema, which developed
because of the use of TZDs. In their risk evaluation, all of the
patients were older than 65 years, 4 patients had chronic renal
failure, 1 patient had ischemic cardiomyopathy, and 1 patient had no
predisposing factor.
Use of TZDs is associated with a triad of fluid retention, edema, and weight gain. Fluid
retention generally is considered mild and reversible and may result from a reduction in renal
excretion of sodium and an increase in sodium and free water retention. TZDs may interact
synergistically with insulin to cause arterial vasodilatation, leading to sodium reabsorption with
a subsequent increase in extracellular volume, thereby resulting in pedal edema. Increased
sympathetic nervous system activity, altered interstitial ion transport, alterations in endothelial
permeability, and PPAR-mediated expression of vascular permeability growth factor represent
other possible mechanisms for edema with these agents
Kermani A, Garg A Mayo Clin Proc. 2003;78:1088-1091
42. Renal Dysfunction – Frequent Comorbidity in CHF
% of patients with renal dysfunction
Clinical trials ‘Real life’
60% (patients with severe RD excluded)
62% GFR
40% 30−59
GFR 34%
<60
36% GFR GFR
60−75 60−90
20% GFR GFR
<60 45−60 GFR
<30
21% GFR
<45 GFR
>90
SOLVD-P SOLVD-T VALIANT ADHERE
NYHA I–II NYHA II–III (post AMI, CHF / LVD) (acute, decompensated HF)
(n=3673)1 (n=2161)1 (n=14,527)2 (n=118,465)3
1. Dries DL et al. J Am Coll Cardiol 2000;35:681−689
2. Anavekar NS et al. N Engl J Med 2004;351:1285−1295
GFR, glomerular filtration rate 3. Heywood JT et al. J Card Fail 2007;13:422−430
43. Renal Dysfunction – A Strong Predictor of Poor
Outcome in HF
1.0
• 1708 CHF patients
Proportion Survival
0.9
(NYHA III–IV) from PRIME II Trial
0.8 >76 mL/min
0.7 59−76 mL/min • GFR was the most predictive of
0.6 survival at multivariate analysis
44−58 mL/min
0.5
<44 mL/min • GFR <60 mL/min, 2.1 risk
0.4
of mortality
0.3
0 250 500 750 1000 1250 • Surpassed LVEF, NYHA class,
Days hypotension concomitant meds,
RR (for mortality)
3.0 2.85 diabetes mellitus, tachycardia
1.91
2.0 1.32
1.0
>76 59–76 44–58 <44
GFR Hillege HL et al. Circulation 2000;102:203−210
44. AHA/ADA consensus in December 2003:
In patients with NYHA class III or IV HF, TZDs
should not be used.
Circulation December 9, 2003
46. Effect of Pioglitazone on Cardiovascular Outcome in
Diabetes and CKD
Post hoc analysis from PROactive study
Secondary: Individual components of primary outcome, CV mortality
J Am Soc Nephrol 19: 182-187, 2008
48. Approximately 40% of type 2 diabetes
patients have renal complications†
CKD prevalence was greater among people with diabetes than
among those without diabetes (40.2% versus 15.4%)
2.3
Data missing
9.5 no CKD
CKD stage 1
17.7
CKD stage 2
50.8
CKD stage 3
CKD stage 4/5
11.1
CKD Stage eGFR (mL/min)
8.6
No CKD ≥90*
1 ≥90**
2 60–89
3 30–59
4 15–29
* Normal kidney function, no sign of kidney damage 5 <15 or dialysis
** Albuminuria – kidney damage
†Based on data from 1462 patients aged ≥20 years with T2DM who participated in the Fourth National
Health and Nutrition Examination Survey (NHANES IV) from 1999 to 2004.
1. Koro CE, et al. Clin Ther. 2009;31:2608–17; 2. Coresh J, et al. JAMA. 2007;298(17) 2038-2047
49. Cardiovascular risk is greatest when
both diabetes and nephropathy are present1
x 2.1
Incidence per 100 patient-years
x 1.7
x 2.5
x 2.2
CKD chronic kidney disease
AMI acute myocardial infarction
CVA/TIA cerebrovascular accident/transient ischemic attack
PVD peripheral vascular disease
Death all-causes
Foley RN, et al. J Am Soc Nephrol. 2005;16:489–95.
50. Patients at risk of declining renal function (e.g. microalbuminuria)
have an increased cardiovascular risk
The risk of CV outcomes according to degree of albuminuria in patients with T2DM:
The HOPE Study ACR clinical threshold for
30 microalbuminuria
(2.0 mg/mmol)*
20
Cardiovascular
events (%) 10
0
20
All-cause
mortality (%)
10
0
1+2 3 4 5 6 7 8 9 10
Categorical increase in albuminuria (deciles)
*The 8th decile includes ACR of 2 mg/mmol, which is the current threshold for a diagnosis of microalbuminuria
Deciles 1 and 2 are combined due to very low incidence rates in these two deciles mcg/mg ÷ 8.84 = mcg/mmol
4.5 year median follow-up (1994 – 1999) The ACR values 17 to 250 μg/mg in men and 25 to 355 μg/mg in women corresponded to 30 to
300 μg/min of urine albumin excretion measured in a timed urine specimen
n = 3498 patients with T2D
Cardiovascular events = composite (myocardial infarction, stroke, or CV death)
HOPE Study Investigators. JAMA. 2001;286:421-426. ACR = urine albumin/creatinine ratio
51. At least 67% of all patients with type 2 diabetes have
cardiovascular risk factors that also affect the kidneys
Prevalence of risk factors for declining renal function:
Prevalence in T2DM
Risk factor
patients
1 Arterial 67%1
Hypertension
2 Poor glycemic 63%2
control*
3 Microalbuminuria** 30%3
4 Dyslipidemia† 24%** 4,5
Risk range is likely to be significantly higher than 67% due to overlap of risk factors in individuals
*Defined as not reaching the target HbA1c of 7.0%2. **Defined as defined as a urinary albumin-to-creatinine ratio ≥ 30 ug/mg
† defined as hypertriglyceridemia in male subjects
1. CDC National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm (Accessed Sept 2011)
2. Saydah SH, et al. JAMA. 2004;291:335–342; 3. Cheung BMY, et al. Am J Med. 2009;122:443–53.
4. Mooradian A, Nat Clin Pract Endocrinol Metab. 2009:5;150–15; 5. Kannel WB. Am Heart J. 1985;110;1100–7.
52. There is a close relationship between cardiac and renal
pathophysiology in type 2 diabetes
Concomitant cardiorenal dysfunction in type 2 diabetes1
Acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the
other
Cardiorenal Risk factors Heart Disease
CKD Stage 1-2
Glomerular/Interstitial Type 2 diabetes Increased ischaemic risk
damage Smoking Left ventricular hypertrophy
Obesity
Hypertension
Dyslipidemia
Genetic risk factors
Acquired
risk factors
1. Ronco C, et al. J Am Col Cardiol. 2008;52(19):1527–1539; 2. AACE. Endocr Pract. 2007;13 Suppl 1:1-683;
3. Afghahi H et al. Nephrol Dial Transplant. 2011;26(4):1236-43;
4. Radbill B et al. Mayo Clin Proc. 2008;83(12):1373-1381; 5. UKPDS Group. BMJ. 2000;321:405-412.
55. Metformin (Activates the AMP-Activated Protein Kinase)
Mode of Action
Decreases hepatic gluconeogenesis, decreases glucose
absorption in the intestines, and increases sensitivity to insulin by
increasing peripheral glucose uptake and utilization.
Contraindications
Hypersensitivity
Renal disease (males with serum creatinine >1.5 mg/dL, females
with serum creatinine >1.4 mg/dL)
AMI, CHF exacerbation, surgery, or shock
Acute or chronic metabolic acidosis
Hebel SK, Katstrup EK (eds): Drug Facts and Comparisons. St. Louis, Mo. 2001
For conversion of creatinine expressed in conventional units to SI units, multiply by 88.4
56.
57. MALA
Incidence: 0.03 cases/1000 patient-years
Mortality: about 50% of cases
Sign and symptoms: non-specific (nausea, vomiting,
altered consciousness, fatigue, abdominal pain, and
thirst).
61. Acarbose and Possible Toxicity
1. Elderly use: 1.5x AUC than normal health
2. Severe renal impairment: 5x peak plasma
concentration and 6X AUC
3. In 1117 subjects ( phase III trial ): 14%, 6%, 3% liver
transaminase elevation ( woman, black, obese, DM of
>5 years )
4. Dosage > 300 mg/d: 15% abnormal liver function
5. Animal study: increased risk of renal tumor; but nil in
human beings.
內科學誌 2009;20: 434-439
67. Glucose-dependent Effects of GLP-1 Infusion on
Insulin and Glucagon Levels in T2DM Patients
15.0
mmol/L
250
12.5 Placebo
mg/dL
200
Glucose 10.0
7.5 *
*
* 150
GLP-1
* *
5.0 * * 100 *P<0.05
2.5 50 Patients with T2DM
0 (N=10)
0
250 40
pmol/L
200
mU/L
30
Insulin 150
20
When glucose levels
approach normal values,
100 * *
* * 10 insulin levels decrease.
50 * * * *
0 0
20 20
pmol/L
pmol/L
15 15 When glucose levels
Glucagon 10 * 10 approach normal
* * * values, glucagon levels
5 5 rebound.
0 Infusion 0
–30 0 60 120 180 240
Minutes
Adapted from Nauck MA et al. Diabetologia. 1993;36:741-744.
68. GLP-1—Effects in Humans
Central nervous system
Promotes satiety and
The most smart way to regulate plasma reduction of appetite
sugar, increased insulin secretion and
inhibited glucagon release when the blood
Liver
Glucagon reduces
sugar rises;output vice versa. The risk of of
and
hepatic glucose β cell
Enhances secretion
hypoglycemia is low. glucose-dependent
insulin
Potential increase in
β-cell mass
α cell
Glucagon Stomach
secretion post-meal Regulates gastric
emptying
Flint A et al. J Clin Invest. 1998;101:515-520. Larsson H et al. Acta Physiol Scand.
1997;160:413-422. Nauck MA et al. Diabetologia. 1996;39:1546-1553. Drucker DJ. Diabetes.
1998;47:159-169.
69. Because of its short half-life, native GLP-1 has
limited clinical value
DPP-IV i.v. bolus GLP-1 (15 nmol/l)
1000
Healthy individuals
Intact GLP-1 (pmol/l)
His Ala Glu Gly Thr Phe Thr Ser Asp
Val Type 2 diabetes
7 9
Ser
500
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Phe 37
0
Ile Ala Trp Leu Val Lys Gly Arg Gly
–5 5 15 25 35 45
Time (min)
Enzymatic t½ = 1.5–2.1 minutes
cleavage (i.v. bolus 2.5–25.0
High clearance nmol/l)
(4–9 l/min)
Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.
70. GLP-1 enhancement
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues Block DPP-4, the enzyme
with longer half-life: that degrades GLP-1:
• Sitagliptin
• Exenatide ( Byetta )
• Saxagliptin
• Liraglutide ( Victoza )
• Vildagliptin
• Linagliptin
Injectables • Alogptin
Oral agents
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
71. DPP-IV inhibitor: Mechanism of Action
Glucose-
dependent
Insulin Glucose
Ingestion (GLP-1and uptake by
of food Pancreas GIP) peripheral
tissue
Release of Beta cells
active incretins
GI tract Alpha cells Blood glucose
GLP-1 and GIP
in fasting and
postprandial
Sitagliptin DPP-4 Glucose- states
(DPP-4
inhibitor)
X enzyme dependent
Glucagon
Hepatic
glucose
(GLP-1) production
Inactive Inactive
GLP-1 GIP
Incretin hormones GLP-1 and GIP are released by the intestine
throughout the day, and their levels in response to a meal
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
72. Linagliptin – a DPP-4 inhibitor with a unique
xanthine-based structure
DPP-4 inhibitors mimicking dipeptides DPP-4 inhibitors directly binding to
the active site of the enzyme
O
N
N
N
N
N
Sitagliptin N
O N
NH2
Linagliptin
Xanthine-based structure
Saxagliptin
Alogliptin
Vildagliptin
Peptidomimetic DPP-4 inhibitors Non-peptidomimetic DPP-4 inhibitors
Adapted from Deacon CF. Diabetes Obes Metab. 2011; 13: 7–18.
73. Pharmacokinetic Properties of DPP-4 Inhibitors
Sitagliptin Vildagliptin Saxagliptin Alogliptin Linagliptin
(Merck)1 (Novartis)2 (BMS/AZ)3 (Takeda)5 (BI)6–9
Absorption tmax 2 h (4 h for active
1–4 h 1.7 h 1–2 h 1.34–1.53 h
(median) metabolite)
Bioavailability ~87% 85% >75 %4 N/A 29.5%
Half-life (t1/2) at 2.5 h (parent) 12.4–21.4 h 113–131 h
clinically relevant 12.4 h ~2–3 h
3.1 h (metabolite) (25–800 mg) (1–10 mg)
dose
Prominent
concentration-
dependent protein
Distribution 38% protein bound 9.3% protein bound Low protein binding N/A
binding:
<1 nM: ~99%
>100 nM: 70%–80%
69% metabolized Hepatic
Metabolism ~16% metabolized mainly renal (active metabolite) <8% metabolized ~10% metabolized
(inactive metabolite) CYP3A4/5
Feces 81.5%
Renal 75% Renal (74.1% unchanged);
Renal 87% Renal 85%
Elimination (24% as parent; 36% as (60%–71%
(79% unchanged) (23% unchanged) Renal 5.4%
active metabolite) unchanged)
(3.9% unchanged)
DPP-4=dipeptidyl peptidase-4.
1. EU-SPC for JANUVIA, 2010. 2. EU-SPC for Galvus, 2010. 3. EU-SPC for Onglyza, 2010. 4. EPAR for Onglyza.
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed May 4, 2011. 5.
73
Christopher R et al. Clin Ther. 2008;30:513–527. 6. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 7. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840.
8. Fuchs H et al. J Pharm Pharmacol. 2009;61:55–62. 9. Blech S et al. Drug Metab Dispos.2010;38:667–678.
74. Prescribing characteristics of DPP-4 inhibitors
Renal Impairment* Hepatic Impairment
Inhibitor
Linagliptin
Not recommended (EU) Not recommended (EU)
Sitagliptin ½ dose (US)1 ¼ dose (US)1 Not recommended1
Vildagliptin2 Not recommended1 Not recommended1 Not recommended Not recommended
½ dose (EU) ½ dose (use with caution)
Saxagliptin3 ½ dose (US)1
not recommended in ESRD (EU)
(Moderate: use with Not recommended1
½ dose (US)1 caution)
Alogliptin ½ dose ¼ dose Not recommended1
CrCl = Creatinine clearance; ESRD = end-stage renal disease
* Assessment of renal function recommended prior to initiation of treatment and periodically thereafter
1. Not studied/no clinical experience
2. Assessment of hepatic function recommended prior to initiation of vildagliptin and periodically thereafter
3. Dose reduction (2.5 mg) when saxagliptin co-administered with strong CYP450 3A4/5 inhibitors (e.g. ketoconazole)
Adapted from Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.
75. Linagliptin provides long-lasting DPP-4 inhibition in patients
with type 2 diabetes
Steady-state plasma levels are already reached after the third dosing interval providing >91%
of DPP-4 inhibition at peak levels
100
80
DPP-4 Inhibition [%]
60
40
20
0
0 4 8 12 16 20 24
Time after administration (h)
Steady State linagliptin 5mg once daily – oral
Tablet taken application
Tablet taken
linagliptin 5 mg linagliptin 5 mg
Adapted from Heise T et al. Diabetes Obes Metab. 2009;11(8):786–94
76. Current treatments for type 2 diabetes have limitations
when renal function declines
Injectables
Dose Reduction
Insulin
Liraglutide
Dose Reduction
Exenatide
Linagliptin
Sitagliptin
Vildagliptin
Dose Reduction
Saxagliptin
Oral drugs
Metformin
Acarbose
Dose Reduction
Repaglinide
Glimepiride
Dose Reduction Dose Reduction
Gliclazide
Pioglitazone
>60 30 – 60 <30 Hemodialysis
Declining GFR
Adapted from: Schernthaner G, et al. Nephrol Dial Transplant. 2010;25(7):2044–2047 and respective EMEA SmPCs
77. Linagliptin CV meta-analysis
Cardiovascular risk with linagliptin in
patients with type 2 diabetes: A pre-
specified, prospective, and adjudicated
meta-analysis from a large phase 3
program
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
79. In a prospective, pre-specified meta-analysis, Linagliptin
was not associated with an increased CV risk
Individual components of composite primary endpoint*
Linagliptin n = 3,319
12 Total comparators n = 1,920
11
10
Number of events
8 7
6
6
4 3
2 2 2
2 1
0
Non-fatal Non-fatal MI Hospitalization CV death
stroke due to
unstable
angina
Hazard ratio 0.11 0.52 0.24 0.74
95% CI 0.02/0.51 0.17/1.54 0.02/2.34 0.10/5.33
*Individual components are tertiary endpoints
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
80. Linagliptin CV meta-analysis: Time to onset of first
primary endpoint
Kaplan Meier plot for time to primary endpoint (Linagliptin vs Combined comparator)
3.0 Linagliptin
2.7 Combined comparator
2.4
2.1
1.8
1.5
1.2
0.9
0.6
0.3
0.0
0 10 20 30 40 50 60 70 80 90 100
Patients at risk: Time (weeks)
Linagliptin 3319 3218 2988 798 715 670 440 223 49 0 0
Combined 1920 1820 1601 729 690 650 421 213 48 0 0
comparator
Note: Patient numbers decline as only patients are depicted that participated in any of the studies included in the meta-analysis at the specific time points.
Most studies ended after 24 weeks and patients were therefore not examined further.
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
81. In a prospective, pre-specified meta-analysis, Linagliptin
was not associated with an increased CV risk
Incidence rate of CV events1
Number and percentage of patients
Risk ratio
0.34
95% CI
(0.15/0.74)
p<0.05
Out of Out of
3,319 patients 1,920 patients
= 0.3% = 1.2%
Linagliptin Comparator2
Years of exposure 2,060 1,372
1. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 voglibose
Johansen O-E., et al. ADA 2011 Late breaker 30-LB
82. Linagliptin restores ß-cell survival in isolated human islets
With linagliptin, less apoptosis is seen under stress conditions. The study provides evidence of
a direct protective effect of linagliptin on ß-cell survival and insulin secretion
5 Vehicle Linagliptin
*
Example of TUNEL Staining
* Insulin (ß-cell marker)
4 **
% TUNEL +β-cells
TUNEL (marker for apoptosis)
3 *
*
* Vehicle
2
** ** **
**
1 Linagliptin
(100 nM)
0
Oxidative
Physiological Glucotoxicity Glucotoxicity Lipotoxicity Inflammatory
stress
condition stress
Note: Human isolated islets were exposed for 48 h. ß-cell apoptosis was analyzed by double labeling for the TUNEL assay and insulin. Results
are means from 3 independent experiments from 3 donors *P<0.05 to 5.5 mM glucose alone, **P<0.05 to vehicle
Source: Shah P, et al. ADA 2010, Poster 1742-P
83. Why DPP-4 Inhibitors?
Excellent in patients with mild hyperglycemia
requiring insulin secretagogue
No contraindication in heart failure and no risk of
edema or lactic acidosis
Can be used in renal insufficiency without risk of
hypoglycemia or lactic acidosis
No weight gain
Immediate activity without causing hypoglycemia
84. Should DPP-4 Inhibitors Be First-line Agents?
If β-cell-sparing effect shown in rats proves to be true in
humans, DPP-4 inhibitors could become the preferred
first-line agents
Appropriate for patients with mild elevation of glucose
with contraindications to other agents that cause
hypoglycemia
Should be considered early in overweight patients
Should be considered in patients with heart failure
Strongly considered in patients with renal failure
85. Summary: Kidneys matter in type 2 diabetes
• Many patients with type 2 diabetes face an inevitable decline in renal
function
• CKD doubles the risk of cardiovascular events and death in patients
with type 2 diabetes
• Patients with poor glycaemic control, high blood pressure and/or
microalbuminuria are at high risk for declining renal function
• Renal function should be considered when choosing a glucose-
lowering therapy
• Declining renal function in type 2 diabetes: Effective glycemic control
slows progression of CKD
87. ADA/EASD Position Statement 2012
Safety first: primum non nocere (first, do no harm); SU, TZD, pre-mixed insulin and non-
analogue insulin were highlighted, especially as that concept has been shaped by results of the
ACCORD,4 ADVANCE,5 and VADT6 trials.
Proceed with caution: affordability; but the real cost of diabetes management is controlling the
cost of complications, not just the price of the pills
TZD: pioglitazone viable only. Many negative issues ( edema, weight gain, heart failure, fracture etc )
against modest CV benefits. Bladder cancer issue: not clarified yet.
Premixed insulin and NPH/RHI: It is difficult to titrate pre-mixed insulins to maximum
effectiveness without causing hypoglycemia or weight gain. The later: not physiologically met with
inadvertent hypoglycemia.
DPP4i: weight neutrality, freedom from hypoglycemia, and a very favorable adverse-effect profile
(primum non nocere )
GLP-1RA: robust reduction of A1C and weight—two prized properties of any antidiabetic agent.
Pancreatitis might be a part of disease itself.
Basal insulin: place value on it, adding on after MF with low risk of hypoglycemia and weight gain.
