Comprehensive

Management of Diabetes
and it’s Complications
X 3

IDF Atlas 2019; 9th edition

IDF Atlas 2019; 9th edition
IDF Atlas 2019; 9th
IDF 2019
Number of people (20-79 years) with diabetes globally and by
IDF Region
IDF Atlas 2019; 9th edition
IDF 2019
Top 10 countries with diabetes (20-79 years) and their health
expenditure, 2019
IDF Atlas 2019; 9th edition
Pathophysiology of
Type 2 DM
T2D - Pathophysiology

CLASSIC VIEW
T2D Pathophysiology – Ominous octet
Type 2 diabetes is a complex multifactorial disease
Diabetes Etiology
Fat Topography In Type 2 Diabetic
Subjects

Intramuscular
Subcutaneous

FFA*
TNF-alpha*
Intrahepatic
Leptin*
IL-6 (CRP)*
Intra- Tissue Factor*
abdominal PAI-1*
Angiotensinogen*
Obesity and Type 2 Diabetes
 Relative Contributions of Diabetic
Pathophysiologies Over Time
Both beta-cell Those who Beta-cell dysfunction
develop DM have determines the onset of
dysfunction + insulin hyperglycemia, glucose levels
resistance start years lost ~50% of beta- and disease progression, not
before diagnosis cell function insulin resistance

Hepatic glucose over-production

100%

Beta-cell dysfunction
100%
Insulin resistance

NGT IGT T2D Diagnosis Late Stage T2DM

NGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetes
Bell D. Treat Endocrinol 2006; 5:131-137; Butler AE et al. Diabetes 2003;52:102-110; Del Prato S and Marchetti P. Diabetes Tech Therp 2004;6:719-731
Gastaldelli A, et al Diabetologia 2004:47:31-39; Mitrakou A, et al. N Engl J Med 1992; 326:22-29; Halter JB, et al. Am J Med 1985;79S2B:6-12
 Decline of -cell function determines
the progressive nature of T2DM (UKPDS)
100
Time of diagnosis
?
% of Normal by HOMA

80
-cell function

60 - 5% per yr

40
Pancreatic function
= 50% of normal
20

0
―10 ―8 ―6 ―4 ―2 0 2 4 6

Time (years)
HOMA= Homeostasis model assessment.
UKPDS Group. Diabetes 1995;44:1249―58.
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S21―5.
Diabetes – Prognosis
 Insulin resistance is closely linked to
cardiovascular disease
Present in > 80% of people
with type 2 diabetes1

Insulin
IR Approximately doubles
Resistance the risk of a cardiac event2

Implicated in almost half

of
CHD events in individuals with type
2 diabetes2

Haffner SM, et al. Circulation 2000; 101:975–980.

1

2
The insulin resistance syndrome, or
cardiovascular dysmetabolic syndrome.

Vanita R. Aroda, and Robert R. Henry Diabetes Spectr

2003;16:120-125
 Obesity, Metabolic Syndrome, Type 2
Diabetes and Cardiovascular Disease

Insulin resistance

Obesity Metabolic syndrome Diabetes

2 Risk 4 Risk

Cardiovascular disease
Luscher et al. Circulation. 2003;108:1655.
Reilly and Rader. Circulation. 2003;108:1546.
Impact of 12 months Clinical inertia

Addressing clinical inertia in Type 2 Diabetes Mellitus: A review adv 25

Ther.
2018
Avoiding clinical inertia
The Importance of Tight Glycemic Control

Every 1% of HbA1c is important in the reduction of risk in

patients with type 2 diabetes (UKPDS)
Per 1% HbA1c Relative risk
(n=3642) p<0.001
reduction
Diabetes-related death 21%

Fatal and nonfatal myocardial

14%
infarction
1% Microvascular complications
37%

Amputations or death caused

by peripheral vascular 43%
disorders

Stratton IM, et al. BMJ 2000; 321: 405-412

7/5/21
 PROGRESSIVE
DECLINE IN
BETA CELL MASS
What is clinical /therapeutic inertia ?

 Clinical inertia may be defined as a failure to initiate

or intensify treatment in a timely manner in patient who is not at their
evidence-based HbA1c goal.

Addressing clinical inertia in Type 2 Diabetes Mellitus: A review

adv Ther. 2018
Addressing Clinical inertia in type 2 DM

Clinical inertia prolongs the duration of

patients hyperglycemia which
subsequently puts them at increased
risk of diabetes-associated
complications and reduced life
expectancy.

38
 The impact of a 12-month inertia on
outcomes
A T2DM cohort of 110543 UK patients, treated between January 1990 and
December 2012

Patients with HbA1c ≥ 7.0% At 5.3 years, significantly increased risk

not receiving therapy
intensification within 1 year
of:
 MI 67% (CI 39–101%)
 Stroke 51% (CI 25–83%)
 HF 64% (CI 40–91%)
 Composite CVE 62% (CI 46–80%)

26% of all patients

Delay in Treatment Intensification Increases the Risks of
Cardiovascular Events in Patients with Type 2 Diabetes
Retrospective cohort study (n = 105,477) from the United Kingdom Clinical
Practice Research Datalink
Compared to patients with HbA1c <7%, patients with HbA1c ≥7%,
with a ≥ 12 month delay in receiving treatment intensification had an
increased risk:

MI STROKE HF CVE
67% 51% 64% 62%
HR 1.67 HR 1.51 HR 1.64 HR 1.62
(CI: 1.39, (CI: 1.25, (CI: 1.40, (CI: 1.46,
2.01)* 1.83)* 1.91)* 1.80)*

MI= myocardial infarction, HF=Heart Failure, CVE= composite MI, Stroke & HF
Retrospective cohort study (n = 105,477) from the United Kingdom Clinical Practice
Research Datalink
Not Proof of Cause and Effect Relationship
* P <0.01
Adapted from Paul SK et al. Cardiovasc Diabetol. 2015 Aug 7;14:100.
7/5/21
7/5/21
 Multidimensional Approach for clinical Inertia

• No visit planning
• No disease registry
• No team approach to care
• Time constraints
• Lack of clear guidance or
individualizing treatment
• Reactive rather proactive
approach Physician
• Difficulty in navigating
guidelines and algorithm
• Lack of concern on patient
Patients
adherence

• Denial of disease
• Lack of awareness of progressive nature of disease
• Lack of awareness of implications of poor glycemic control
• Poor communication with physician
• Fear of side effects (hypoglycemia and weigh gain )
 44

Earlier and Appropriate Intervention May

Improve Patients’ Chances of Reaching Goal1
Published Conceptual Approach
OAD +
multiple daily
Diet and OAD OAD OAD OAD + insulin
exercise monotherapy up-titration combination basal insulin injections

10
9
HbA1c,%

8
HbA1c goal of 7%
7
6
Mean HbA1c Duration of Diabetes
of patients
Conventional stepwise Earlier and proactive
treatment approach intervention approach
OAD=oral antidiabetic agent.
1. Adapted from Del Prato S et al. Int J Clin Pract. 2005;59(11):1345–1355. Copyright © 2005. Adapted with permission of Blackwell Publishing Ltd.
 Glycemic targets

Glycemic Targets:
Standards of Medical Care in Diabetes - 2020. Diabetes Care 2020;43(Suppl. 1): S66-S76
Oral Therapies for Type 2 Diabetes:
Sites of Action

Edelman SV, Henry RR. Diagnosis and management of type 2 diabetes. Eleventh Edition.
.Professional Communications, Inc., Greenwich, CT. 288 pages, 2011
Position of Sulfonylurea in modern guidelines
IDF Treatment Algorithm 2017

IDF guidelines 2017 for management of type 2

If the person is symptomatically hyperglycaemic, consider insulin or an SU. Review
treatment when blood glucose control has been achieved.

If HbA1c rises to 48 mmol/mol (6.5%) on lifestyle interventions:

 Offer standard–release metformin
 Support the person to aim for an HbA1c level of 48 mmol/mol (6.5%)

FIRST INTENSIFICATION:
If HbA1c rises to 58 mmol/mol (7.5%):
• Consider dual therapy with:
-metformin and an SU
-metformin and a DPP-4i
- metformin and pioglitazone
- metformin and an SGLT-2i
• Support the person to aim for an HbA1c level of 53 mmol/mol (7.0%)
 SU
Insulin

K channel closer
+

Insulin
vesicles
Ca++ Ca++ Ca++ K+

X
Mem. Dep.
SUR
Ca channel
++ − 40 mV K+ channel 140 KD
(Voltage (ATP sensitive)
dependent)
SUs are backed by a large body of
evidence
Effectiveness of Antidiabetic Agent
Biguanides DPP-4
SUs (metformin) Glinides inhibitors TZDs Insulin Antidiabetic
agents

0.0

0.5
1.5 1.5 1.0-1.5 0.5-0.9 0.8-1.0
1.0
HbA1c Reduction (%)

≥2.5
1.5

2.0

2.5

3.0

Efficacy as
monotherapy Nathan DM. N Engl J Med. 2007;356(5):437-440.
 Hypoglycemia

Concerns
Weight gain
about SUs
Beta cell apoptosis

Ischemic preonditioning &

cardiovascular safety
Are all sulfonylureas
the same?
GLIMEPIRIDE
Glimepiride
Hypothetical Model of Sulfonylurea Receptor
Glimepiride binds to the 65 kDa subunit of the sulfonylurea receptor;
glibenclamide -cells
inbinds to the 140 kDa subunit

Glibenclamide Glimepiride  cell membrane

K +

140 kDa
65 kDa

Sulfonylurea
receptor K+
Solubilisation Potassium channels

Glibenclamide Glimepiride

140 kDa
65 kDa

Kramer W et al., Biochim Biophys Acta 1994;1191: 278-290

Acting on Both Phases of Insulin Secretion
Glimepiride: The only sulfonylurea to treat
fasting and postprandial hyperglycemia
First and second phase insulin secretion
before and after treatment with Glimepiride
p=0.02

s Euglycemic and
100 in
s ul hyperglycemic clamp
Incremental plasma insulin

In studies in 11 obese
patients with T2DM
with good glycemic
(pmol/L)

p=0.04 +Glimepiride
control before and after
50
4 months treatment
%
55 with Glimepiride to
+Glimepiride assess effect of
Glimepiride on insulin
secretion
0
First Phase Second Phase
Insulin secretion

Before treatment After Glimepiride treatment

Korytkowski M et al. Diabetes Care 2002; 25(9):1607-11.

 2nd Action
Extra-Pancreatic: Insulin
The extrapancreatic effect Resistance
of Glimepiride

Rate limiting step for glucose utilization

is glucose uptake via GLUT4
transporter
Glimepiride ↑ translocation of GLUT4
transporters from low-density
microsomes to plasma membrane
of insulin-resistant fat and muscle cells1
Glimepiride ↑ GLUT4 protein and
glucose utilization in oxidative muscles
in vivo2
Glimepiride appears to ↑ peripheral
glucose uptake1,2 and to mimic
the action of insulin1

1
Müller & Wied. Diabetes. 1993;42: 1852-1867; 2Mori et al. Diabetes Obes Metab 200; epub ahead of print
EFFICACY
 Effectiveness of Antidiabetic Agent
Biguanides DPP-4
(metformin) inhibitors Antidiabetic
SUs Glinides TZDs Insulin agents

0.0

0.5
1.5 1.5 1.0-1.5 0.5-0.9 0.8-1.0
HbA1c Reduction (%)

1.0
≥2.5
1.5

2.0

2.5

3.0

Efficacy as
monotherapy

Nathan DM. N Engl J Med. 2007;356(5):437-440.

SAFETY
Hypoglycemic Events
Impact on Weight
Cardiovascular Effects
• Hypoglycaemia

• Weight

• CV outcome
 Hypoglycemia vs Glibenclamide
Significantly lower incidence of severe hypoglycemic events with Glimepiride vs
glibenclamide (0.86 vs 5.6/1000 person-years)
Incidence of severe* hypoglycemic events
according to treatment

6
# Episodes/1000 person-years

Prospective, population-
based, 4-year study to
compare frequency of severe
hypoglycemia in patients with
6.5x 4 T2DM treated with
less risk Glimepiride (estimated
of hypo 5.6 n=1768)
versus glibenclamide
(estimated n=1721)

0.86
0
Glimepiride Glibenclamide

*Defined as requiring IV glucose or glucagon

Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73

 Weight
Reduction in glycemia with Glimepiride is accompanied by significant and
stable weight loss

Mean intra-individual changes from baseline in body weight and

HbA1c

Months of treatment
4 12 18
0 Open, uncontrolled,
observational study.
Change from baseline

1770 T2DM patients were

-1 -1.4* enrolled and 284 were
-1.5* followed-up for 1.5 years.
-1.7* Patients received 0.5 to >
-1.9* 4 mg Glimepiride once
-2 daily. Baseline HbA1c:
-2.9† 8.4%; body weight:
-3.0‡ 79.8kg
-3

Body weight (kg) HbA1c (%)

*p<0.0001; †p<0.05; ‡p<0.005 vs baseline

Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19

 1st June 2016

Diabetes Obes Metab 2016; 18(10):973–979

Study Conclusion: In Real Life, when weight gain does occur,
factors other than medication effects (for example, life style
associated factors) are likely to be more important.

Diabetes Obes Metab 2016; 18(10):973–979

NEUTRAL CARDIOVASCULAR PROFILE FOR
MODERN SULFONYLUREAS
 Cardiovascular safety

Newer SUs (Gliclazide and Glimepiride) were associated with a lower

risk of all cause and cardiovascular related mortality compared with
glibenclamide
Cardiovascular safety

• Meta-analysis comparing a SU with a non-SU agent in T2DM

• Endpoints: Major cardiovascular events (MACE) and mortality

The use of sulfonylureas was not associated with any significant

difference in the incidence of MI with respect to comparators .
Breaking News Presented at the ADA 2019

Rosentock J et.al ,Journal of American Medical Association JAMA 2019

 CAROLINA: Trial design

Patients with T2D were randomised to daily oral treatment

with linagliptin or glimepiride1,2

SCREENING
N=6033 Linagliptin 5 mg qd† + standard of care‡

Placebo ≥631
run-in* 1:1 CV EVENTS

RANDOMISATION Glimepiride 1–4 mg qd§ + standard of care‡

Event-driven

• Investigators were encouraged to treat all other CV risk factors in accordance with local guidelines

*2- to 4-week, open-label placebo run-in period, during which background glucose-lowering therapy was continued unchanged; †Prior SU or glinide was discontinued in both
groups at randomisation; ‡To ensure an adequate level of glycaemic control for patients, investigators could institute glycaemic rescue medication provided specific protocol
criteria were met; §Starting dose of 1 mg/day up-titrated to a potential maximum of 4 mg/day every 4 weeks for the first 16 weeks. Doses could be up- or down-titrated at any
point of the study as required. Patients on previous glimepiride treatment were continued on their current dose if randomised to the glimepiride arm
CVOT, cardiovascular outcomes trial; T2D, type 2 diabetes
1. Marx N et al. Diab Vasc Dis Res 2015;12:164; 2. Rosenstock J et al. JAMA 2019;322:1155
 CAROLINA: Endpoints

Key secondary outcomes

Primary outcome
• Time to first occurrence of 4P-MACE*
• Time to first occurrence of 3P-MACE
− CV death Composite outcomes
(including fatal MI and fatal stroke) • Proportion of patients on treatment and
− Non-fatal MI maintaining HbA1c ≤7.0% at final visit
− Non-fatal stroke • Without the need for rescue
medication, without
moderate/severe hypoglycaemic
episodes and without >2% weight
gain†
• Without the need for rescue
medication and without >2% weight
gain†

*Composite of 3P-MACE and hospitalisation for unstable angina; †Between end of titration and final visit
3P-MACE, 3-point major adverse cardiovascular events; 4P-MACE, 4-point major adverse cardiovascular events; HbA1c, glycated haemoglobin;
MI, myocardial infarction
Rosenstock J et al. JAMA 2019;322:1155
Baseline demographics and clinical characteristics

Linagliptin Glimepride
(n=3023) (n=3010)
Men, n (%) 1838 (60.8) 1781 (59.2)
Age, years, mean ± SD 63.9±9.5 64.2±9.5
Weight, Kg, mean ±SD 84.3±18.0 83.6±17.9
BMI, Kg/m2, mean ±SD 30.2±5.2 30.0±5.1
A1C, %, mean ±SD 7.2±0.6 7.2±0.6
T2D duration, median (IQR) 6.3 (3.0, 11.1) 6.2 (2.9, 10.9)
T2D duration ≤ 5yrs, n(%) 1224 (40.5) 1212 (40.3)
Glucose lowering drugs , n(%)
None 274(9.1) 272 (9.0)
1 1984 (65.6) 1982 (65.8)
2 736 (24.3) 725 (24.1)
3 20 (0.7) 21 (0.7)

Rosenstock J et.al ,Journal of American Medical Association JAMA 2019

 CAROLINA - results
CAROLINA: Time to first occurrence of 3P-MACE
(primary outcome)
Linagliptin was non-inferior to glimepiride for 3P-
MACE*
30 Linagliptin Glimepiride
Rate:
25 2.1/100 PY
Patients (%)

20 HR 0.98
362 patients
(95.47% CI 0.84, 1.14)†
15 p<0.001 for non-inferiority 356 patients
p=0.76 for superiority
10 Rate:
2.1/100 PY
5

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
No. at risk Years
Linagliptin 3023 2957 2901 2846 2803 2762 2725 2679 2627 2582 2534 2451 1830 1040
Glimepiride 3010 2940 2890 2833 2797 2757 2710 2662 2618 2569 2509 2414 1865 1020
*Composite of CV death, non-fatal MI, non‑fatal stroke; †The 95.47% bound for the CI reflects an O’Brien–Fleming alpha-spending adjustment for the two interim analyses of the primary outcome, in addition to
Bonferroni adjustment for change from 4P-MACE to 3P-MACE. Treated set; Kaplan–Meier estimate; hazard ratio and CI derived from Cox regression with treatment assignment as factor; 1-sided p-value for non-
inferiority and 2-sided p-value for superiority
3P-MACE, 3-point major adverse cardiovascular events; 4P-MACE, 4-point major adverse cardiovascular events; MI, myocardial infarction; PY, patient-years
Rosenstock J et al. JAMA 2019;322:1155
CAROLINA: Individual components of MACE

The individual components of MACE were not significantly

different between linagliptin and glimepiride
Linagliptin Glimepiride
p-value
n with event/N analysed HR (95% CI) HR (95% CI)
(2-sided)
(%)
356/3023 0.98 (0.84,
3P-MACE 362/3010 (12.0) 0.76
(11.8) 1.14)*
CV death 169/3023 (5.6) 168/3010 (5.6) 1.00 (0.81, 1.24) 0.99
Non-fatal MI 145/3023 (4.8) 142/3010 (4.7) 1.01 (0.80, 1.28) 0.91
Non-fatal
91/3023 (3.0) 104/3010 (3.5) 0.87 (0.66, 1.15) 0.34
stroke
4P-MACE 398/3023 (13.2) 401/3010 (13.3) 0.99 (0.86, 1.14) 0.87
HUA 60/3023 (2.0) 56/3010 (1.9) 1.07 (0.74, 1.54) 0.72

Favours linagliptin Favours glimepiride

*95.47 CI. Treated set; hazard ratio and CI based on Cox regression model
3P-MACE, 3-point MACE; 4P-MACE, 4-point MACE; HUA, hospitalisation for unstable angina; MACE, major adverse cardiovascular events;
MI, myocardial infarction; PY, patient-years
Rosenstock J et al. JAMA 2019;322:1155 8
 CAROLINA: CV mortality
CV mortality was not significantly different between
linagliptin and glimepiride

Rate:
8 Linagliptin Glimepiride 0.9/100 PY

169 patients
6 168 patients
Patients (%)

HR 1.00
(95% CI 0.81, 1.24) Rate:
4
p=0.99 0.9/100 PY

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
No. at risk Years
Linagliptin 3023 3009 2991 2976 2951 2934 2908 2873 2838 2808 2780 2706 2045 1164
Glimepiride 3010 2999 2982 2955 2937 2916 2885 2857 2823 2797 2751 2656 2068 1144

Treated set; Kaplan–Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value
PY, patient-years
Rosenstock J et al. JAMA 2019;322:1155 8
 CAROLINA: All-cause mortality

All-cause mortality was not significantly different

between linagliptin and glimepiride

Rate:
1.8/100 PY
14 Linagliptin Glimepiride
12 336 patients
308 patients
Patients (%)

10
HR 0.91
8 (95% CI 0.78, 1.06) Rate:
6 p=0.23 1.7/100 PY

4
2
0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
No. at risk Years
Linagliptin 3023 3009 2991 2976 2951 2934 2908 2873 2838 2808 2780 2706 2045 1164
Glimepiride 3010 2999 2982 2955 2937 2916 2885 2857 2823 2797 2751 2656 2068 1144

Treated set; Kaplan–Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value
PY, patient-years
Rosenstock J et al. JAMA 2019;322:1155 8
 CAROLINA: Non-CV mortality

Non-CV mortality was not significantly different between

linagliptin and glimepiride

Rate:
0.9/100 PY
8 Linagliptin Glimepiride
168 patients
6
Patients (%)

HR 0.82 139 patients

(95% CI 0.66, 1.03)
4 Rate:
p=0.08
0.8/100 PY
2

0
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5
No. at risk Years
Linagliptin 3023 3009 2991 2976 2951 2934 2908 2873 2838 2808 2780 2706 2045 1164
Glimepiride 3010 2999 2982 2955 2937 2916 2885 2857 2823 2797 2751 2656 2068 1144

Treated set; Kaplan–Meier estimate; hazard ratio and 95% CI derived from Cox regression with factor treatment; 2-sided p-value
PY, patient-years
Rosenstock J et al. JAMA 2019;322:1155
 Effect on HbA1c
Compared with Glimepiride, Linagliptin demonstrated similar overall effects on HbA1c

Rosenstock J et.al ,Journal of American Medical Association JAMA 2019

 CAROLINA: HF-related outcomes

There was no significant difference in the risk of HF-related

outcomes with linagliptin compared with glimepiride

Linagliptin Glimepiride
p-value
HR (95% CI) HR (95% CI)
(2-sided)
n with event/N analysed (%)

HHF* 112/3023 (3.7) 92/3010 (3.1) 1.21 (0.92, 1.59) 0.18

HHF or CV death* 236/3023 (7.8) 234/3010 (7.8) 1.00 (0.84, 1.20) 0.97

Investigator-reported
166/3014 (5.5) 155/3000 (5.2) 1.06 (0.85, 1.32) 0.58
HF events†

Favours linagliptin Favours glimepiride

Treated set; hazard ratio and 95% CI based on Cox regression model. *Adjudicated; †Analysis based on 6014 participants (3014 in the linagliptin group and
3000 in the glimepiride group)
HF, heart failure; HHF, hospitalisation for HF
Rosenstock J et al. JAMA 2019;322:1155
CLEAR UP THE CONTROVERSARY
CONCERNING THE LONG TERM
CARDIOVASCULAR SAFETY OF
SULFONYLUREAS
Pioglitazone in T2DM
management
Effectiveness of Antidiabetic Agent
Biguanides DPP-4
SUs (metformin) Glinides inhibitors TZDs Insulin Antidiabetic
0.0 agents
0.5
HbA1c Reduction (%)

1.5 1.5 1.0-1.5 0.5-0.9

1.0
0.8-1.0 ≥2.5
1.5

2.0

2.5

3.0
Efficacy as
monotherap
y

DPP-4 = dipeptidyl peptidase 4; TZD = thiazolidinedione.

Nathan DM. N Engl J Med. 2007;356(5):437-440.
Efficacy

Dormandy JA et al. Lancet. 2005;366:1279-89.

PROactive: Study design
Objective: Assess the effects of pioglitazone on reducing
macrovascular events in type 2 diabetes
Design: Randomized double-blind, controlled outcome
Population: N = 5238 with type 2 diabetes and history of
macrovascular disease
Treatment: Pioglitazone (up to 45 mg) or placebo
Primary
outcome: Composite of all-cause mortality, MI, ACS,
coronary or peripheral revascularization, amputation,
stroke
Secondary
outcomes: Individual components of primary outcome,
CV mortality
Follow-up: 4 years
Dormandy JA et al. Lancet. 2005;366:1279-89.
Treatment
N=2605
Pioglitazone as add-on
therapy to existing
N= 5238 medication
patients type 2 “forced titration from
Diabetes at increased 15 mg to 45 mg,
risk of macrovascular depending on
disease managed by tolerability”
glucose lowering
drugs and other N=2633
medications matching placebo as add-
on therapy to existing
medication

Average time of observation = 34.5 months

Dormandy JA et al. Lancet. 2005;366:1279-89.

 All-cause mortality, MI, ACS, coronary or peripheral revascularization,
amputation, stroke
25
10% Relative
risk reduction
20 HR* 0.90 (0.80–1.02)
Placebo
P = 0.095 (572 events)
15 Pioglitazone
Proportion (514 events)
of events 10
(%)
5

0
0 6 12 18 24 30 36
Time from randomization
Number at risk
Pioglitazone 2488 2373 2302 2218 2146 348
Placebo 2530 2413 2317 2215 2122 345
*Unadjusted
Dormandy JA et al. Lancet. 2005;366:1279-89.
 All-cause mortality, MI (excluding silent MI), stroke
25

20
Placebo
16% Relative
15 risk reduction
(358 events)
Proportion HR* 0.84 (0.72–0.98)
of events 10 P = 0.027
(%) Pioglitazone
(301 events)
5

0
0 6 12 18 24 30 36
Time from randomization
Number at risk
Pioglitazone 2536 2487 2435 2381 2336 396
Placebo 2566 2504 2442 2371 2315 390
*Unadjusted
Dormandy JA et al. Lancet. 2005;366:1279-89.
Diabetes, Obesity and Metabolism 18: 266–273, 2016
Additional benefits - Lipid profile

• At the final visit, the changes in TGs for the overall population
TGs were -11.4% with pioglitazone vs. -1.8% with placebo (p<
0.0001)

• Pioglitazone was associated with significant increases in HDL

cholesterol seen at 6 months and persistent throughout the
HDL study.
• At the final visit, the change in HDL cholesterol in the overall
population was nearly twice that observed with placebo.

• A greater decrease in the LDL cholesterol/HDL cholesterol

ratio was associated with pioglitazone treatment.
LDL/HD
• Durable improvement in TGs and HDL cholesterol levels, Was
L ratio
irrespective of baseline antihyperglycemia therapy or statin
use.
 Additional benefits

Liver function

• In PROactive, there was a trend towards normalization

of markers of liver function (ALT and AST) in pioglitazone
group compared with no change or an increase in theses
enzymes levels in placebo group.
• Changes in ALT with pioglitazone may reflect improved
hepatic insulin sensitivity and a reduction in liver fat
Effect of pioglitazone on patients with previous stroke

Pioglitazone reduced the risk of a recurrent

fatal/non fatal stroke significantly by 47%.
Effect of pioglitazone on patients with history of MI

1. Pioglitazone significantly reduced risk of fatal or non fatal

MI by 28%
2. Acute coronary syndrome (ACS) risk was reduced by 37%.
3. Risk of non fatal MI, coronary revascularization, ACS, or
cardiac death was significantly reduced by 19%.
 Safety results from PROactive study

General safety profile

• The proportion of patients who had any adverse event while
participating in PROactive was similar for pioglitazone &
placebo groups.
• The overall incidence of serious adverse events was also
similar in both groups, if somewhat lower in Pioglitazone
group.
• The proportion of patients who permanently ceased study
medication because of a serious adverse event was
approximately 4% in both groups.
 Safety

1-Oedema and weight gain

• From PROactive: Pioglitazone was associated with typical, but
manageable increase in oedema
• From SPCs of Pioglitazone: Oedema was reported in 6–9% of
patients treated with pioglitazone over one year in controlled
clinical trials. The reports of oedema were generally mild to
moderate and usually did not require discontinuation of
treatment.

• From PROactive: Average weight gain from baseline with

pioglitazone was +3.8 kg by the end of the study.
 Safety

2- Bone fractures
• From SPCs: A higher rate of fractures was observed in women
taking pioglitazone (2.6%) versus comparator (1.7%). No
increase in fracture rates was observed in men treated with
pioglitazone (1.3%) versus comparator (1.5%).
Safety

3- Heart Failure (from PROactive safety results)

• Although incidence of serious HF was increased with
pioglitazone vs. placebo, mortality due to HF was similar for
both groups.
• Heart failure developing while on pioglitazone therapy would
appear to be reversible and manageable and not suggestive
of progressive Cardiomyopathy.
Safety

4- Malignancies results from PROactive: There was no

evidence for any differences in the frequency of
malignancy
– The incidence of bladder cancer in the pioglitazone and
placebo groups was similar (throughout 13 years). The
bladder cancer imbalance (during the 3 years PROactive
study) didn’t persist in the 10 years follow up.
– The percentage of patients who reported any type of
malignancies was similar in the pioglitazone and placebo
groups (throughout 13 years).
Pioglitazone and bladder cancer
 Background

Objective: examine the effect of exposure to pioglitazone on

bladder cancer risk internationally across several cohorts.

Analyses were conducted in six populations (British Columbia,

Finland, Manchester, Rotterdam, Scotland and the UK Clinical
Practice Research Datalink [CPRD]), using identical methods for
formatting and analysing the data.

Data were collected over all centers for 1.01 million persons over
5.9 million person-years.

Follow up duration : 4 to 7.4 years

Conclusion
Pioglitazone and bladder cancer
Pioglitazone and bladder cancer
• Patients: 193,099 patients more than or equal 40 years
of age
• Results: The group treated with pioglitazone comprised
30,173 patients. There were 90 cases (0.3%) of bladder
cancer among pioglitazone users and 791 cases (0.5%)
of bladder cancer among nonpioglitazone users.
• Conclusion: Overall, ever use of pioglitazone was not
associated with risk of bladder cancer , with similar
results in men and women
 IRIS
Trial design: Patients without diabetes with a history of stroke or TIA within 6 months, with
objective evidence of insulin resistance (HOMA-IR value >3.0), were randomized to either
pioglitazone 45 mg or placebo. They were followed for 4.8 years.

Results
(p = 0.007) • The primary outcome, stroke or MI, for pioglitazone
vs. placebo: 9.0% vs. 11.8%, HR 0.76, 95% CI 0.62-
0.93, p = 0.007
• All strokes: 6.5% vs. 8.0%, p = 0.19; ACS: 5.0% vs.
6.6%, p = 0.11; new-onset DM2: 3.8% vs. 7.7%, p <
0.001
• Bone fracture: 5.1% vs. 3.2%, p = 0.003; weight gain
% >4.5 kg: 52.2% vs. 33.7%, p < 0.0001

• Conclusions
• Pioglitazone was superior to placebo in reducing
the composite of stroke/MI in patients with
recent stroke/TIA, no history of DM2, and
Primary endpoint objective evidence of insulin resistance
• There was an increase in previously described side
Pioglitazone Placebo
(n = 1,939) (n = 1,937) effects with TZDs, including bone fractures, edema,
and weight gain

Kernan WN, et al. N Engl J Med 2016;374:1321-31

Protection effects of pioglitazone relating to various organs

Diabetes Care. 2013 Aug; 36(Suppl 2): S155–S161.

 61 trials including 26367 patients

Oral agents A1C (%)*

Sulfonylureas ~ 1.25
Biguanides (metformin) ~ 1.0
Glinides ~ 0.75
Thiazolidinediones ~ 1.25
DPP-IV inhibitors ~ 0.75
α-Glucosidase inhibitors ~ 1.0
RESULTS
• Pioglitazone reduced HbA1c by 0.9%; decreased systolic and diastolic
blood pressure (P < 0.05); and increased whole-body insulin
stimulated glucose uptake by 71% in subjects with T2D.
• Pioglitazone enhanced myocardial perfusion by 16%; (P < 0.05),
diastolic function, E/A ratio and peak LV filling rate (P < 0.01), the
ejection fraction and stroke volume increased significantly, P < 0.05).
Wiad Lek. 2017;70(5):881-890
N Engl J Med. 2016 Apr 7;374(14):1321-31
Thank you