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