Individualization of Diabetes treatment Indian Scenario
Dr. Pruthvi PuwarPhysician
05/01/2023 Dr Pruthvi Puwar
CASE can be• 32 year diabetic for 1 year• On Metformin 500 mgs. BID• FBS 158 PPBS 196• Gly. Hb. - 7.8
05/01/2023 Dr Pruthvi Puwar
OR• 54 Yrs. DM-10 yrs• On Glimulin 2 mg bid• FBS 142 PPBS 212 • HTN
05/01/2023 Dr Pruthvi Puwar
OR• Newly detected DM 33 Yrs• FBS 158 PPBS 296• Gly. Hb. 9.1• Obese, non smoker
05/01/2023 Dr Pruthvi Puwar
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)E
Expenses
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Guideline Approach: ADA-EASD Consensus statement: 2008
Summary of glucose-lowering interventionsTier 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 TherapiesAGIs 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
05/01/2023 Dr Pruthvi Puwar
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]
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
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?
05/01/2023 Dr Pruthvi Puwar
Issues to consider when choosing therapies
DeFronzo RA. Diabetes. 2009 58:773–95. [ADOPT TRIAL]
05/01/2023 Dr Pruthvi Puwar
Issues to consider when choosing therapies
Nathan DM. Diabetes Care 2009
05/01/2023 Dr Pruthvi Puwar
Issues to consider when choosing therapies
Nathan DM. Diabetes Care 2009
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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 >10.2
0
20
40
60
80
100Fasting glucose Postprandial glucose
HbA1c
Cont
ribut
ion,
%
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 10.0–11.8Number 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
0.0Hb
A 1c R
educ
tion,
%
Change in HbA1c from baseline
26
05/01/2023 Dr Pruthvi Puwar
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.
05/01/2023 Dr Pruthvi Puwar
GLITAZONESAdvantages
• 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
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
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?
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
SU –Lessons learnt so farADVANTAGES
• 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
05/01/2023 Dr Pruthvi Puwar
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.
05/01/2023 Dr Pruthvi Puwar
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
A1C
Cha
nge
From
Bas
elin
e, %
–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%
05/01/2023 Dr Pruthvi Puwar
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 patientsKalra 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
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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
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
SGLT: sodium glucose co-transporter
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
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
05/01/2023 Dr Pruthvi Puwar
05/01/2023 Dr Pruthvi Puwar
05/01/2023 Dr Pruthvi Puwar
05/01/2023 Dr Pruthvi Puwar
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.
05/01/2023 Dr Pruthvi Puwar
• 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
05/01/2023 Dr Pruthvi Puwar
THANK UThank You..