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After Metformin WhatIndian Scenario
DR A P NAVEEN KUMAR
Chief Specialist (G.M.)Visakha Steel General Hospital
CASE 1
• 32 year diabetic for 1 year• On metformin 500 mgs. BID• FBS 158 PPBS 196• Gly. Hb. - 7.8
Case 2
• 54 Yrs. DM-10 yrs• On glimulin 2 mf bid• FBS 142 PPBS 212 • HTN• DLD
CASE 3
• Newly detected DM 33 Yrs• FBS 158 PPBS 296• Gly. Hb. 8.8• Obese non smoker
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.
AAge
BBody Weight
CComplications
DDuration of Diabetes
EExpectancy
(Life)
EExpenses
Guideline Approach: ADA-EASD Consensus statement: 2008
Summary of glucose-lowering interventions
Tier 1 Well Validated, Core Therapy Step 1
Initial Therapy
Step 2Additional Therapy
LSM Metformin
SUsInsulin
Broad Benefits insufficient within
a year1-2%
1-2%
1-2%
1.5-3.5%No Dose limit, rapid, lipid benefits, hypo,
weight gain, injection, expensive analogues
Rapidly effectiveweight gain and hypo mainly with older SUs
Weight neutralGI 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 lossinjections, 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
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]
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 GainMinimize Cost of
Therapy
Metformin
DPP4i
TZDs Insulin
DPP4i SUs
MetforminMetformin
GLP1RA
GLP1RA
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?
Glycemic Targets in DiabetesThe 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
Issues to consider when choosing therapies
DeFronzo RA. Diabetes. 2009 58:773–95.
Issues to consider when choosing therapies
Nathan DM. Diabetes Care 2009
Issues to consider when choosing therapies
Nathan DM. Diabetes Care 2009
Issues to be considered while choosing a therapies
Minimize risk of
hypoglycemia
Minimize risk of
weight gain
Required reduction in
HbA1C
FPG and PPG as end points
CostAdverse events
Co-morbidity
Endocr Pract. 2009;15:540-559.
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
<7.3 7.3–8.4 8.5–9.2 9.3–10.2 >10.20
20
40
60
80
100
Fasting glucose Postprandial glucose
HbA1c
Con
trib
uti
on
, %
24
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
0.0H
bA
1c
Redu
ctio
n,
%
Change in HbA1c from baseline
26
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%
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): A100-117NEJM 1995; 333; 541-9
Issues to consider when choosing therapies
Most drugs achieve greater HbA1C reductions at higher HbA1Cs
Esposito K. Diabetes Obesity Metabolism 2011Nathan DM. Diabetes Care 2009.
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
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
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?
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 andexercise
OAD combinationOAD
up-titration
OAD + multiple daily
insulininjectionsOAD +
basal insulin
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
First-line treatment with SU/Met tablets provided superior glycemic control over component
monotherapy, but at a price…
SU Met SU-Met-2.5
-2
-1.5
-1
-0.5
0
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.
Met SU SU-Met0
10
20
30
40
50
60
% Hypoglycemia
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
• 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.
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.
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
LSM
A1
C C
hange F
rom
Base
line,
%
–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
–2.9bAll patients Treated Populationa 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%
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 /dayMetformin1g /dayMetformin2g /daySita100Met1g /daySita100Met2g /day
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
India: Growing Population of Elderly Diabetics
Snapshot of CV Outcome Trials with Gliptins
Size of study
Completion Comparator Background Primary Outcome measure
Observation
SAVORSaxagliptin
n=164922.1 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)
EXAMINEAlogliptin
n=53801.5 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
TECOSSitagliptin
n=~14000
~4.5 yrs.>63000pt.yrs.
2014 Placebo(on
Standard Care)
T2DM with h/o CVD>18 yrs
Time to CV event
CAROLINALinagliptin
n=6000 2018-2019 Glimepiride(on usual
care)
T2DM w/wo h/o CVD40-80yrs
Time to composite end point
CARMELINALinagliptin
n=8300 2018 Placebo (on usual
care)
T2DM w/wo CVD, renal impairment
Time to composite end point
VIVIDDVildagliptin
n=253 Completed 2013
Placebo (on usual
care)
T2DM + CHF
(NYHA 1-3)
Effect on LV function
LV ejection fraction improved similar to placeboSmall non-significant increase in all-cause mortality (8.6% vs. 3.2%) and CV mortality (5.5% vs. 3.2%) in Vildagliptin
arm
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
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
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
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
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
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
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
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.
• 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
THANK U