After Metformin What- Indian Scenario


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After Metformin What in management of Diabetes

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After Metformin What- Indian Scenario

  1. 1. After Metformin What Indian Scenario DR A P NAVEEN KUMAR Chief Specialist (G.M.) Visakha Steel General Hospital
  2. 2. CASE 1 • 32 year diabetic for 1 year • On metformin 500 mgs. BID • FBS 158 PPBS 196 • Gly. Hb. - 7.8
  3. 3. Case 2 • 54 Yrs. DM-10 yrs • On glimulin 2 mf bid • FBS 142 PPBS 212 • HTN • DLD
  4. 4. CASE 3 • Newly detected DM 33 Yrs • FBS 158 PPBS 296 • Gly. Hb. 8.8 • Obese non smoker
  5. 5. 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
  6. 6. 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
  7. 7. 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]
  8. 8. 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
  9. 9. 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?
  10. 10. 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
  11. 11. Issues to consider when choosing therapies DeFronzo RA. Diabetes. 2009 58:773–95.
  12. 12. Issues to consider when choosing therapies Nathan DM. Diabetes Care 2009
  13. 13. Issues to consider when choosing therapies Nathan DM. Diabetes Care 2009
  14. 14. 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.
  15. 15. 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
  16. 16. 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
  17. 17. 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%
  18. 18. 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
  19. 19. 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.
  20. 20. 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
  21. 21. 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
  22. 22. 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?
  23. 23. 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.
  24. 24. 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
  25. 25. 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
  26. 26. • 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.
  27. 27. 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.
  28. 28. 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%
  29. 29. 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
  30. 30. 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
  31. 31. India: Growing Population of Elderly Diabetics
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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
  37. 37. 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
  38. 38. 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
  39. 39. 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
  40. 40. 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.
  41. 41. • 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
  42. 42. THANK U