After Metformin What in management of Diabetes

1. After Metformin What
Indian Scenario
DR A P NAVEEN KUMAR
Chief Specialist (G.M.)
Visakha Steel General Hospital

3. CASE 1
• 32 year diabetic for 1 year
• On metformin 500 mgs. BID
• FBS 158 PPBS 196
• Gly. Hb. - 7.8

4. Case 2
• 54 Yrs. DM-10 yrs
• On glimulin 2 mf bid
• FBS 142 PPBS 212
• HTN
• DLD

5. CASE 3
• Newly detected DM 33 Yrs
• FBS 158 PPBS 296
• Gly. Hb. 8.8
• Obese non smoker

6. Two general approaches
to the treatment of T2DM
1) A “guideline” approach that advocates sequential addition of antidiabetes
agents with “more established use” this approach more appropriately should be
called the “treat to failure” approach,
2) A “pathophysiologic” approach using initial combination therapy with agents
known to correct established pathophysiologic defects in T2DM, taking into
account the patient’s general health status and associated medical disorders.
This “individualized approach” has been incorporated into the updated
American Diabetes Association (ADA) guidelines (2012)
Diabetes Care. 2013 Aug;36 Suppl 2:S127-38. doi: 10.2337/dcS13-2011.
Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes.
DeFronzo RA, Eldor R, Abdul-Ghani M.
A
Age
B
Body Weight
C
Complications
D
Duration of
Diabetes
E
Expectancy
(Life)
E
Expenses

7. Guideline Approach: ADA-EASD Consensus statement: 2008
Summary of glucose-lowering interventions
Tier 1
Well Validated,
Core Therapy Step 1
Initial Therapy
Step 2
Additional Therapy
LSM Metformin
SUsInsulin
Broad Benefits
insufficient within
a year
1-2%
1-2%
1-2%
1.5-3.5%
No Dose limit, rapid, lipid
benefits, hypo, weight
gain, injection, expensive
analogues
Rapidly effective
weight gain and hypo
mainly with older SUs
Weight neutral
GI side effects,
contraindicated in renal
insufficiency
Tier 2
Less Well Validated TZDs 0.5-1.4% GLP1ra0.5-1%
Other Therapies
AGIs 0.5-1.4% Glinides 0.5-1.4% Pramlintide 0.5-1% DPP-4i 0.5-0.8%
Potential CV (MI) benefit
(Pio), lipid benefits
Fluid retention, CHF,
fractures, potential CV
(MI) hazard (Rosi),
expensive
Weight loss
injections, GI tolerability,
?long term safety,
expensive
Weight neutral,
GI side effects, TDS dosing,
expensive
Rapidly effective,
weight gain, TDS dosing,
hypo, expensive
Weight loss,
TDS injections, GI side effects,
?long term safety, expensive
Weight neutral,
?long term safety, expensive
Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy A consensus statement of the American Diabetes
Association and the European Association for the Study of Diabetes DAVID M. NATHAN et al, Diabetes Care 31:1–11, 2008
numbers in pink represent %HbA1c reduction

8. Pathophysiologic Approach: ADA-EASD Consensus
Statement; 2012 Antihyperglycemic Therapy for “most
patients”
LSM LSM + MetforminDiagnosis
SU TZD DPP4i GLP1RA Insulin+
TZD
or
DPP4i
or
GLP1RA
SU
or
TZD
or
Insulin
SU
or
TZD
or
Insulin
TZD
or
DPP4i
or
GLP1RA
++ SU
or
DPP4i
or
GLP1RA
or
Insulin
Insulin
+++
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

9. Example of Individualized approach:
We Have Options if We Want To…
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Avoid Hypoglycemia Avoid Weight Gain
Minimize Cost of
Therapy
Metformin
DPP4i
TZDs Insulin
DPP4i SUs
MetforminMetformin
GLP1RA
GLP1RA

10. Challenges in implementing the
International Guidance in India
• Challenges of using HbA1c for screening and monitoring. Are the
new therapies effective in lowering FPG as well?
• Most of our patients want to see a rapid reduction of blood glucose.
Are the Gliptins as quick as SUs?
• Late Diagnosis, High Baseline HBA1c at diagnosis; How effective are
the new therapies?
• Is the issue of hypoglycemia properly addressed?
• Earlier onset of Diabetes in India; Do we have therapies which are
reasonably durable?

11. Glycemic Targets in Diabetes
The ADA/AHA position statement
• Short duration of diabetes
• Long life expectancy
• No significant cardiovascular
disease
• History of severe hypoglycemia
• Limited life expectancy
• Long-standing diabetes
• Advanced micro-macrovascular
complications
A1c <7.0%
Skyler J et al. Diabetes Care 2009; 32:187
A1c >7.0%
Patient’s phenotype B=body weight
C=complications
D=duration
A=age

12. Issues to consider when choosing
therapies
DeFronzo RA. Diabetes. 2009 58:773–95.

13. Issues to consider when choosing therapies
Nathan DM. Diabetes Care 2009

14. Issues to consider when choosing therapies
Nathan DM. Diabetes Care 2009

15. Issues to be considered while choosing a therapies
Minimize
risk of
hypoglycem
ia
Minimize
risk of
weight
gain
Required
reduction
in HbA1C
FPG and
PPG as end
points
Cost
Adverse
events
Co-
morbidity
Endocr Pract. 2009;15:540-559.

16. Relative Contribution of FPG and PPG to Overall
Hyperglycemia Depending on HbA1c Quintiles
Adapted from Monnier L et al. Diabetes Care. 2003;26:881–885.
n=58 n=58 n=58 n=58n=58
0
20
40
60
80
100
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.2
Fasting glucose Postprandial glucose
HbA1c
Contribution,%
24

17. Higher HbA1c Baseline Level Correlates With Larger HbA1c
Reduction With Pharmacologic Intervention
Baseline HbA1c, % 6.0–6.9 7.0–7.9 8.0–8.9 9.0–9.9 10.0–11.8
Number of patients
enrolled in clinical trials
n=410 n=1620 n=5269 n=1228 n=266
Adapted from Bloomgarden ZT et al. Diabetes Care. 2006;29:2137-2139.
-0.2
-0.1
-0.6
-1.0
-1.2
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
HbA1cReduction,%
Change in HbA1c from baseline
26

18. Efficacy of various interventions as Monotherapy
Intervention Efficacy to decrease A1c
• Life style modification 1-2%
• Metformin 1.5%
• Sulfonylurea 1.5%
• Glitazones 0.5-1.4%
•  glucosidase inhibitors 0.5-0.8%
• Glinides 0.5-1.5%
• GLP-1 analogues 0.5-1%
• Insulin 1.5-2.5%
• DPP4 0.5-1.4%

19. Efficacy as a combination therapy
Regimen HbA1c FPG
Metformin+SU ~1.7% ~65mg/dl
Metformin+Rosi ~1.2% ~50mg/dl
Metformin+Pio ~0.7% ~40mg/dl
SU + Rosi ~1.4% ~60mg/dl
SU + Pio ~1.2% ~50mg/dl
Diabetes 1999:48(Supple 1): A100-117
NEJM 1995; 333; 541-9

20. Issues to consider when choosing therapies
Most drugs achieve greater HbA1C reductions at higher HbA1Cs
Esposito K. Diabetes Obesity Metabolism 2011
Nathan DM. Diabetes Care 2009.

21. GLITAZONES
Advantages
• PPAR gamma agonists
• Potent muscle sensitizer
• Favourable lipid action
• No e/o hypoglycemia
Disadvantages
• Weight gain
• Contraindicated in
failures
• Prone for fracture
• Monitor liver enzymes

22. Alpha Glucosidase Inhibitors
Advantages
• Reduces PPBS
• No hypoglycemia
• Good add on drug
• Ideal for obese and
overeating patients
Disadvantages
• GI side effects
• Hepatotoxicity
• Contraindicated in
renal failure

23. Addressing Patients with high baseline
HbA1c at diagnosis: ONE is NOT Enough
• No OAD as monotherapy is expected to reduce HbA1c by >1%
from a baseline of 8-8.5%
• No single antidiabetic agent can correct all of the
pathophysiologic disturbances present in T2DM, and multiple
agents, used in combination, will be required for optimal
glycemic control.
• Hence the International guidelines recommends dual therapy at
initiation if the HbA1c is >8%
• SU and Met combination therapy is most widely used initiation
therapy in India.
• Any advantage of a DPP4i-Met combination over SU-Met
combination?

24. Concept: Early-Aggressive Intervention May Improve
Treating to Target Compared With Conventional
Therapy
7
6
9
8
10
Mean A1C
of patients
A1C,
%
Duration of Diabetes
OAD
monotherapy
Diet and
exercise
OAD
combinationOAD
up-titration
OAD +
multiple daily
insulin
injectionsOAD +
basal insulin
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.

25. First-line treatment with SU/Met tablets provided
superior glycemic control over component
monotherapy, but at a price…
-2.5
-2
-1.5
-1
-0.5
0
SU Met SU-
Met
HbA1c Reduction
Patients (n = 486) were
randomized to receive
glyburide/metformin tablets
(1.25/250 mg), metformin (500
mg), or glyburide (2.5 mg).
HbA1c Baselines:
SU/Met 8.78%
Met 8.42%
SU 8.67%
J Clin Endocrinol Metab. 2003 Aug;88(8):3598-604.
Efficacy of glyburide/metformin tablets compared with initial monotherapy in type 2 diabetes.
Garber AJ, Donovan DS Jr, Dandona P, Bruce S, Park JS.
0
10
20
30
40
50
60
Met SU SU-Met
% Hypoglycemia

26. SU –Lessons learnt so far
ADVANTAGES
• Time tested
• Robust glucose reduction in
early stage
• Cheap
• Randomised trials did not
give bad CV signal
DISADVANTAGES
• Glucocentric
• Durability less
• Hypoglycemia big issue
• Weight gain
• Possible B cell apoptosis
• Overall meta analysis shows
increased CV mortality

27. • Until recently SUs have been considered the
drug of choice for add-on therapy to
metformin, primarily attributed to their low
cost and rapid onset of hypoglycemic effect.
• However, they lack “glycemic durability” and
within 1–2 years lose their efficacy, resulting in
steady HbA1crise to or above pretreatment
levels
• Both sulfonylureas and glinides fail to prevent
the progressive decline in β-cell function
characteristic of T2DM
• Sulfonylurea treatment does not correct any
pathophysiologic component of the
“ominous octet” and is associated with
significant weight gain and hypoglycemia
• However, in many countries newer
antidiabetic agents are not available or are
expensive (ABCDE). In such circumstances,
sulfonylureas may be the only option.
Sulfonylureas: the “treat to fail approach”.
Diabetes Care. 2013 Aug;36 Suppl 2:S127-38. doi: 10.2337/dcS13-2011.
Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes.
DeFronzo RA, Eldor R, Abdul-Ghani M.

28. How DPP-4 Inhibitors address FPG
• DPP-4 inhibitors are “Incretin Enhancers”
• Continuous DPP-4 inhibition over 24hrs ensures
physiological elevation of active Incretin hormones,
which in presence of hyperglycemia enhances
insulin synthesis and suppresses glucagon.
• It is thus important that DPP-4 enzyme is
meaningfully inhibited over 24 hours for optimal
enhancement of Incretin hormones.

29. Sitagliptin With Metformin Co-administration
Initial Therapy Study
Mean A1C = 8.8%
Sitagliptin 50 mg +
metformin 1,000 mg bid
Metformin 1,000 mg bid
Sitagliptin 100 mg qd
Sitagliptin 50 mg +
metformin 500 mg bid
Metformin 500 mg bid
LSMA1CChangeFromBaseline,%
–3.5
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0.0
0.5
n=178 n=177 n=183 n=178n=175
–0.8a
–1.0a
–1.3a
–1.6a
–2.1a
Open label
n=117
–2.9b
All patients Treated Population
a LSM placebo adjusted change
b LSM change from baseline without adjustment for placebo.
bid=twice a day; qd=once a day.
24-Week Placebo-Adjusted Results
Mean A1C = 11.2%

30. Sitagliptin and Metformin Initial Combination:
Sustained A1C Reductions Over 2 Years
• The proportions of patients with an HbA1c <7% at week 104 were 60% (higher dose
combination), 45% (lower dose combination), 45% (higher dose), 28% (lower dose)
and 32% (sitagliptin)
• Of the patients with an HbA1c <7% in the week 24 analysis, the proportions with an
HbA1c <7% in the week 104 analysis were 71% for the higher dose co-administration
Diabetes Obes Metab. 2010 May;12(5):442-51. doi: 10.1111/j.1463-1326.2010.01204.x.
Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in
patients with type 2 diabetes.
Williams-Herman D, Johnson J, Teng R, Golm G, Kaufman KD, Goldstein BJ, Amatruda JM.
71% of the patients who were at target after
6 months were still at target after 2 years
Sitagliptin 100mg /day
Metformin1g /day
Metformin2g /day
Sita100Met1g /day
Sita100Met2g /day

31. Concerns about hypoglycemia in India:
The Diabetes Attitudes Wishes and Needs (DAWN2)
• More than 60% of all Indian diabetics worry about the risk of hypoglycemia events.
• Family members worry about this risk to an even greater excellent (79.0%)
Clinical Implications
• Diabetic patients should be offered treatments, which pose less risk of
hypoglycemia; these include injectable drugs such as detemir, glargine and
degludec, and oral antidiabetic drugs like metformin, gliptins, pioglitazone
and AGIs.
• Use of drugs that need less frequent SMBG should be encouraged. These are
the same molecules that are less prone to causing hypoglycemia.
• Active SMBG and adherence to HCP- suggested advice, must be promoted.
• Patient and FM empowerment: Large scale Educational programmes and
activities designed to improve awareness of hypoglycemia and its
management.
• The high risk of hypoglycemia in periods of fasting should be emphasized.
• Hypoglycemia awareness training (HAT)for patients
Kalra S, Sahay R, Unnikrishnan AG. Concerns about hypoglycemia in India: The Diabetes
Attitudes Wishes and Needs (DAWN2) study. J Soc Health Diabetes 2014;2:48-9

32. India: Growing Population of Elderly Diabetics

33. Snapshot of CV Outcome Trials with Gliptins
Size of
study
Completion Comparator Background Primary
Outcome
measure
Observation
SAVOR
Saxagliptin
n=16492
2.1 yrs.
>34600 pt. yrs.
Completed
2013
Placebo
(on
Standard
Care)
T2DM w/wo
h/o CVD
>40yrs
Time to
composite
end point
Primary hazard ratio (HR) 1.0, HbA1c reduction 0.2%
Suggesting Safety of Saxagliptin similar to placebo, but failed to show any
benefit over standard care + placebo, Reduced progression of micro-
albuminuria
No increase in pancreatitis,
Small increase in risk of hospitalization related to heart failure
(HR 1.27)
EXAMINE
Alogliptin
n=5380
1.5 yrs.
>8000 pt. yrs.
Completed
2013
Placebo
(on
Standard
Care)
T2DM with
recent h/o
ACS
Time to
primary
MACE
Primary HR 0.96 (non-inferior to placebo), HbA1c
reduction 0.36%
No increase in risk of Pancreatitis
TECOS
Sitagliptin
n=~14000
~4.5 yrs.
>63000pt.yrs.
2014 Placebo
(on
Standard
Care)
T2DM with
h/o CVD
>18 yrs
Time to CV
event
CAROLINA
Linagliptin
n=6000 2018-2019 Glimepiride
(on usual
care)
T2DM w/wo
h/o CVD
40-80yrs
Time to
composite
end point
CARMELINA
Linagliptin
n=8300 2018 Placebo
(on usual
care)
T2DM w/wo
CVD, renal
impairment
Time to
composite
end point
VIVIDD
Vildagliptin
n=253 Completed
2013
Placebo
(on usual
care)
T2DM + CHF
(NYHA 1-3)
Effect on LV
function
LV ejection fraction improved similar to placebo
Small non-significant increase in all-cause mortality (8.6% vs.
3.2%) and CV mortality (5.5% vs. 3.2%) in Vildagliptin arm

34. DPP4 Inhibitors –lessons learnt so far
ADVANTAGES
• A1c reduction at par with SU
• Minimal hypoglycemia with
weight neutrality or loss
• Possible pleiotropic effect
• Randomised trials showed CV
neutrality
• Pancreatitis,UTI and
nasopharyngitis no large issues
DISADVANTAGES
• Cost
• Issues of increased HF in
SAVOR
• Slightly higher mortality in
VIVIDD
• Possible off-target effects

35. GLP 1 Receptor agonists
• ↑ insulin secretion –glucose dependent
• ↑ insulin synthesis
• ↓ glucagon secretion
• ↑ beta cell mass
• ↓ brain energy intake
• ↓ hepatic glucose output
• ↓ GI motility
Exenatide ,Liraglutide ,Exenatide LAR ,Lixisenatide ,Albiglutide

36. DPP4 INHIBITORS
• Oral
• ↑ GLP 1 to physiologic range
• Limited by endogenous
incretin secretion
• Moderate efficacy
• Weight neutral
• Well tolerated
GLP-1
• Injectable
• Pharmacologic range
• Not limited by endogenous
incretin secretion
• Enhanced efficacy
• Weight loss
• GI side effects

37. GLP -1
• Insulin secretion –glucose
dependent
• Glucagon secretion –
glucose dependent
• Body weight
• PPG / FPG
Low risk of hypoglycemia
BASAL INSULIN
• ↑ Insulin levels –glucose
independent
• ↑ beta cell rest
• ↑ body weight
• ↓ FPG (PPG )
Moderate risk of hypoglycemia

38. GLP Agonist-lessons learnt so far
ADVANTAGES
• Robust A1c reduction
• Better PPBS control with short acting
• Better FBS control with long acting
• Consistent weight loss
• Added BP lowering
• Possible pleiotropic effects and pooled
CV data encouraging
DISADVANTAGES
• Injectable
• Costly
• Nausea in early stage
• Increased HR especially with long
acting
• No CV studies published as of now

40. SGLT-2 Inhibitors
• Inhibit glucose reabsorption in PCT of kidney through these
receptors
• Significant weight loss
• Increased glycosuria
• Sodium loss resulting in BP decrease
• Better durability
Canagliflozin ,Dapagliflozin ,Empagliflozin

41. SGLT-2 inhibitors –lessons learnt so far
ADVANTAGES
• A1 c reduction at par with
metformin,SU,Gliptin
• Durability seems superior to
SU
• Wt. loss superior to
metformin and gliptins
• BP reduction robust than
metformin and gliptins
DISADVANTAGES
• Genital and urinary infection
• Volume depletion with loop
diuretics
• Postural hypotension with
RAAB and diuretics
• Safety in elderly > 75
• Loosing effectiveness in
renal insufficiency
• CV safety ↑ LDL and↑ fatal
and nonfatal stroke
• Malignancy
• Bone health ↑ PTH

48. Take Home
• The International Guidelines are changing to a more “Individualized
Approach” which is more suitable for the needs of a diverse country
like India than the older International guidance which were more
rigid in terms of choice of therapy and were less considerate towards
the real life patient issues.
• Depending on the patient needs, options are now available which
needs to be selected based on their mode of action, efficacy, safety
and possible benefits in that population.
• Drugs are Different: All antidiabetics belonging to different classes or
within the same class differ from each other and the same should be
kept in mind while the choice is made.
• We need to continue to identify “uniquely Indian” unmet needs to
further customize the international guidance.

49. • If obese- think of GLP, DPP4, AGI , SGL2
• If thin - think of SU, TZD ,DPP4
• If between 7-8 - monotherapy
• If between 8-9 - combination
• If > 9 - insulin

50. THANK U