Update in Treatments for Diabetes

1. Update in Treatments for Diabetes General Medicine Noon Conference Stanford Massie M.D. January 30, 2007

2. Objectives To review several recent studies relevant to the treatment of Type 2 Diabetes To combine insights from these studies to create a framework for approaching the treatment of patients with T2DM To emphasize practical considerations for treatment of patients with T2DM using real cases To provide a glimpse of the future treatment of diabetes

3. Scope of this talk Type 2 Diabetes Outpatients Focus on established, proven therapies (not on complications or associated illnesses) Practical application of clinical trial data (emerging therapies will be introduced but not discussed in detail)

4. Some things I won�t cover Treatment of diabetes in hospitalized patients1 Treatment of diabetes related illnesses ACEI/ARB�s2 Rimonobant (weight loss agent)3 Inhaled Insulin (Exubera)4

5. Road Map Background: The Diabetes Epidemic Real life cases Therapy of Type 2 Diabetes Consensus guideline Recent Trials: PROactive, DREAM, ADOPT What about Insulin? Future directions A final algorithm

6. Case 1 81 y.o. AAM with T2DM for 22 years, retinopathy and peripheral neuropathy. He has had A1C 8-8.5 over the last year despite titrating his glimepiride and metformin to maximum doses. He has mild obesity with a central distribution of fat He is careful about diet, monitors BS�s regularly but does not exercise What should you do next to improve his control?

7. Case 2 58 y.o. WM with HTN, Hyperlipidemia and FH of CAD recently found to have elevated Fasting BS�s FBS 110-120 on 3 separate occasions, HgbA1C 6.1 No family history of diabetes He is not overweight, and exercises at a high level What can you do to prevent the onset of diabetes?

8. Case 3 57 y.o. WM with HTN, Hyperlipidemia, CAD and long standing Diabetes with poor control. Has refused insulin therapy in the past because �when you go on insulin the diabetes just gets worse.� He is currently on: Metformin 1000 BID, Glipizide ER 20 daily, Pioglitazone 45 daily HgbA1C at the most recent visit is 9.2 What should be your next step in therapy? If you choose to start Insulin, what type and regimen would you use?

9. Case 4 54 y.o. WF with HTN, Depression and Fibromyalgia presents with elevated Blood sugars. Two confirmed FBS�s are 135, 143 HgbA1C is 7.4 What should be your first step in therapy? If you choose to start a medication, which one would you use?

10. Case 5 33 y.o. AAF with Morbid Obesity (BMI 42) and Type 2 Diabetes diagnosed in 2003. Takes glipizide and rosiglitazone (max doses) She does not tolerate metformin due to diarrhea She does not exercise/ is poorly compliant with diet HgbA1C at the most recent visit is 7.9 What should be your next step in therapy?

11. Diabetes Type 2: The epidemic United States 20 million Americans have type 2 diabetes 1.5 million new cases per year # of cases projected to nearly double by 2050, resulting in 1/3 of Americans with DM Worldwide 150 million persons worldwide have type 2 diabetes # of cases projected to rise from 151 million in 2000 to 300 million by 2025

12. Diabetes: How are we doing? 5 new classes of anti-diabetes drugs in the past decade�three in the past year Among adult Americans with diabetes: 2 in 5 (40%) have suboptimal lipid control 1 in 3 (33%) has poor BP control 1 in 5 (20%) has poor glycemic control The concurrent epidemic of obesity promises to only further exacerbate the problem

13. What are the effects of treatment? Lowering blood glucose levels prevents long term complications Type 1: microvascular AND cardiovascular (DCCT) Type 2: microvascular ?and? cardiovascular (UKPDS) Both studies show strong correlations with HgbA1C level and complications Recent epidemiologic data from UKPDS suggests lowering glycemia may reduce CV disease in T2DM. Recent epidemiologic data from UKPDS suggests lowering glycemia may reduce CV disease in T2DM.

14. How low should we go? Ideally, HgbA1c should be as close to normal as possible without imposing a high risk of severe hypoglycemia Upper limit of normal A1C~6.1% (DCCT)

16. What is the Natural History? Type 2 DM is a progressive disease characterized by relentless deterioration of pancreatic � cell function Insulin resistance + declining insulin secretion Increasing requirements for powerful medications to combat hyperglycemia Most patients will eventually require Insulin

17. Fig 1 Traditional treatment strategy for type 2 diabetes and its consequences. In type 2 diabetes Beta cell function declines over the years, irrespective of treatment with metformin, sulfonylurea (as monotherapy or dual therapy), or insulin. Treatment therefore has to be adjusted at regular intervals according to the level of glycaemia. Because doctor and patient need to agree about adding another drug at each step, glycated haemoglobin values will recurrently fail to reach target Fig 1 Traditional treatment strategy for type 2 diabetes and its consequences. In type 2 diabetes Beta cell function declines over the years, irrespective of treatment with metformin, sulfonylurea (as monotherapy or dual therapy), or insulin. Treatment therefore has to be adjusted at regular intervals according to the level of glycaemia. Because doctor and patient need to agree about adding another drug at each step, glycated haemoglobin values will recurrently fail to reach target

18. Lifestyle and Behavioral Changes Diet/exercise can be very effective, but� Diet dropped A1C by 2.25% in one study of newly diagnosed T2DM Exercise also demonstrated benefits Most benefits disappear within one year The most impressive and sustained effects are seen in those who have bariatric surgery

21. Fig 2 Established and *putative mechanisms of action of blood glucose lowering drugs in humans Fig 2 Established and *putative mechanisms of action of blood glucose lowering drugs in humans

22. Road Map Background: The Diabetes Epidemic Real life cases Therapy of Type 2 Diabetes Consensus guideline Recent Trials: PROactive, DREAM, ADOPT What about Insulin? Future directions A final algorithm

23. Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy(ADA/EASD Consensus Statement) Diabetes Care. 2006 Aug;29(8):1963-1972.

24. Background and Rationale �Although numerous reviews on the management of type 2 diabetes have been published in recent years, practitioners are often left without a clear pathway of therapy to follow.� Guideline based on clinical trials and �authors� clinical experience and judgment� Paucity of high quality evidence comparisons

25. Key assumptions Inadequate evidence for one class over any other in reducing complications of DM Therefore, effectiveness in lowering glycemia is primary factor in choosing (use A1C) Secondary factors should be considered if efficacy equivalent Pramlintide, exenatide, a-glucosidase inhibitors and the glinides are not included in algorithm: Generally lower glucose lowering effectiveness Limited clinical data And/or relative expense

26. Key recommendations-1 Metformin is first line Metformin should be initiated concurrently with lifestyle intervention (at diagnosis) If don�t achieve goal in 2-3 months, add another medication No strong consensus on second medication, unless A1C >8.5 In that case, Insulin should be started

27. Key recommendations-2 If metformin, lifestyle change and second medication fail, starting insulin is preferred over adding a third agent (unless A1C <=8.0) When adding second/third agents, consider mechanisms/potential for synergy Insulin + metformin or TZDs particularly effective When short acting Insulin is started, secretagogues should be stopped/tapered off

28. Goal of treatment should be a glycated haemoglobin value as close to the non-diabetic range (<6.1%) as possible; treatment should be started or changed if the value is =7%. Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is >8.5%. Insulin can be started at any point in the course of diabetes, including at the time of diagnosis. Insulin treatment (plus metformin) is generally preferred to three oral agents as it is at least as effective in lowering glycaemia and is much cheaper. Goal of treatment should be a glycated haemoglobin value as close to the non-diabetic range (<6.1%) as possible; treatment should be started or changed if the value is =7%. Choose the most effective regimen (metformin plus insulin) if glycated haemoglobin is >8.5%. Insulin can be started at any point in the course of diabetes, including at the time of diagnosis. Insulin treatment (plus metformin) is generally preferred to three oral agents as it is at least as effective in lowering glycaemia and is much cheaper.

30. Case 1--Revisited 81 y.o. AAM with T2DM for 22 years, retinopathy and peripheral neuropathy. He has had A1C 8-8.5 over the last year despite titrating his glimepiride and metformin to maximum doses. He has mild obesity with a central distribution of fat He is careful about diet, monitors BS�s regularly but does not exercise What should you do next to improve his control? Add Insulin or third oral agent (glitazone)

31. Can any of the available treatments change the course of the disease?(i.e. preserve � cell function)

32. Disease changing agents? Are there benefits independent of glucose lowering effect (delay in disease progression, diminished CV outcomes etc.)? Metformin, Acarbose Glitazones (TZDs) Newer agents?? A UKPDS retrospective analysis of overweight pts who got metformin suggested a significant reduction in CV disease and total mortality. Glitazones have a number of beneficial effects which might lead to benefits in CV disease. Some small trials suggest that they may preserve beta cell function too. A UKPDS retrospective analysis of overweight pts who got metformin suggested a significant reduction in CV disease and total mortality. Glitazones have a number of beneficial effects which might lead to benefits in CV disease. Some small trials suggest that they may preserve beta cell function too.

33. Trials to assess whether glitazones can change the course of the disease DREAM1: prevention trial in patients with prediabetes PROactive2: prevention of CV outcomes in high risk diabetics ADOPT3: Comparison of durability of effect in new onset DM for three commonly used oral agents

34. DREAM Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Rosiglitazone 8mg daily vs. placebo Ramipril 15mg daily vs. placebo Combination of rosiglitazone and ramipril Ramipril results were reported elsewhere, and the combination did not reveal significant effects. Ramipril did not significantly reduce the incidence of diabetes, although there was a trend toward improvement in glucose levels. Ramipril results were reported elsewhere, and the combination did not reveal significant effects. Ramipril did not significantly reduce the incidence of diabetes, although there was a trend toward improvement in glucose levels.

35. DREAM Design: randomized placebo controlled trial Partipants: 5269 patients with prediabetes�(excluded those with CV disease) Primary outcome: composite (death, diabetes) Results: Compared with placebo, rosiglitazone group had (over median f/u of 3 years): a 62% decreased chance of developing diabetes 7 times the chance of developing heart failure Reduction is similar to that seen with lifestyle approaches, and greater than that with metformin or acarbose. Reduction is similar to that seen with lifestyle approaches, and greater than that with metformin or acarbose.

36. DREAM outcomes Excluded patients with known CV diseaseExcluded patients with known CV disease

37. DREAM Conclusions: While rosiglitazone 8mg/day reduced the incidence of diabetes, it did not come without a cost Increased incidence of heart failure (in low risk group) Weight gain (2.2 kg) Cost Follow up after washout is key in determining whether there is a long term benefit Excluded patients with known CV diseaseExcluded patients with known CV disease

38. Case 2--Revisited 58 y.o. WM with HTN, Hyperlipidemia and FH of CAD recently found to have elevated Fasting BS�s FBS 110-120 on 3 separate occasions, HgbA1C 6.1 No family history of diabetes He is not overweight, and exercises at a high level What can you do to prevent the onset of diabetes?

39. PROactive PROspective pioglitAzone Clinical Trial in macroVascular Events Secondary prevention of macrovascular events in patients with T2DM in the PROactive Study Pioglitazone daily vs. placebo Titrated to 45mg/d and added to current therapy In patients with existing CV disease

40. PROactive Design: randomized placebo controlled trial Partipants: 5238 patients with T2DM and known vascular disease Primary outcome: composite--death, CV event or procedure over a mean follow up 35 months Results: Compared with placebo, pioglitazone had No clear benefit for the primary endpoint Did reduce a �main secondary� endpoint of all cause mortality, nonfatal MI and stroke 40% higher chance of developing heart failure

41. PROactive outcomes

42. PROactive conclusions Pioglitazone added to current therapy for T2DM patients with vascular disease reduced CV events (secondary endpoint) at a cost: For every CV event prevented, pioglitazone was associated with ~2 cases of heart failure 4 cases of edema Weight gain of 4kg CONTROVERSIAL STUDY:Some argue that the secondary endpoint they use in the analysis was not clearly defined upfront. On the other hand, some believe that the reason for failure to reach primary endpoint was poor design (including need for procedure adds uncontrolled variables since physicians vary on when procedures used etc.)CONTROVERSIAL STUDY:Some argue that the secondary endpoint they use in the analysis was not clearly defined upfront. On the other hand, some believe that the reason for failure to reach primary endpoint was poor design (including need for procedure adds uncontrolled variables since physicians vary on when procedures used etc.)

43. Case 3--Revisited 57 y.o. WM with HTN, Hyperlipidemia, CAD and long standing Diabetes with poor control. Has refused insulin therapy in the past because �when you go on insulin the diabetes just gets worse.� He is currently on: Metformin 1000 BID, Glipizide ER 20 daily, Pioglitazone 45 daily HgbA1C at the most recent visit is 9.2 What should be your next step in therapy? If you choose to start Insulin, what type and regimen would you use? Pioglitazone could have been added thinking it might reduce risk for CV events. Nevertheless, reducing A1C is most important factor in reducing long term complications, and given his CAD, he should be monitored closely for CHF symptoms while on the Pioglitazone. Pioglitazone could have been added thinking it might reduce risk for CV events. Nevertheless, reducing A1C is most important factor in reducing long term complications, and given his CAD, he should be monitored closely for CHF symptoms while on the Pioglitazone.

44. ADOPT Title: Glycemic durability of rosiglitazone, metformin or glyburide monotherapy Comparison of durability over time of three different agents as initial therapy for newly diagnosed T2DM

45. ADOPT Design: randomized placebo controlled trial Partipants: 4360 patients with new dx of T2DM Primary outcome: time to treatment failure FBS>180 on consecutive testing >6wks therapy at max tolerated dose Results: At 4 yrs., proportion with A1C <7 Rosiglitazone 40% Metformin 36% Glyburide 26% Overall study dropout rate was ~40%! Median follow up 3.3 years (metformin) 4 years (rosiglitazone) Treatment failure defined as FBS>180 on consecutive testing after at least 6 weeks of treatment at the maximum dictated or tolerated dose of the study drug. Use of FBS instead of A1C is not the standard, has drawn some criticism. Treatment failure defined as FBS>180 on consecutive testing after at least 6 weeks of treatment at the maximum dictated or tolerated dose of the study drug. Use of FBS instead of A1C is not the standard, has drawn some criticism.

46. ADOPT outcomes Figure 2. Kaplan�Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years. Treatment was considered to have failed if a patient had a confirmed or adjudicated level of fasting plasma glucose of more than 180 mg per deciliter. Risk reduction is listed for comparisons of pairwise groups from a baseline covariate-adjusted Cox proportional-hazards model. Gray�s estimates of cumulative incidence adjusted for all deaths were smaller than Kaplan�Meier estimates of treatment failure: 10% in the rosiglitazone group, 15% in the metformin group, and 25% in the glyburide group. I bars indicate 95% CIs. Figure 2. Kaplan�Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years. Treatment was considered to have failed if a patient had a confirmed or adjudicated level of fasting plasma glucose of more than 180 mg per deciliter. Risk reduction is listed for comparisons of pairwise groups from a baseline covariate-adjusted Cox proportional-hazards model. Gray�s estimates of cumulative incidence adjusted for all deaths were smaller than Kaplan�Meier estimates of treatment failure: 10% in the rosiglitazone group, 15% in the metformin group, and 25% in the glyburide group. I bars indicate 95% CIs.

47. ADOPT conclusions When choosing initial monotherapy for newly diagnosed T2DM: A1C was maintained below 7% for: 60 months with rosiglitazone 45 months with metformin 33 months with glyburide Weight gain was a complicating factor Rosiglitazone group gained 6.9kg compared with metformin Most experts recommend metformin as initial therapy in light of its effectiveness, tolerability and cost

48. Case 4 54 y.o. WF with HTN, Depression and Fibromyalgia presents with elevated Blood sugars. Two confirmed FBS�s are 135, 143 HgbA1C is 7.4 What should be your first step in therapy? If you choose to start a medication, which one would you use? Metformin + Lifestyle change

49. Hirsch I et al. A Real World Approach to Insulin Therapy in Primary Care Practice. Clinical Diabetes. 23(2):78-86, 2005.

50. What about Insulin? Relentless progressive nature of disease Insulin is the most effective agent�glucose lowering only limited by hypoglycemia Delaying insulin may have detrimental effects Glucotoxicity to � cells Post prandial glucose reduction may be associated with reduced CV risk1,2 Most patients will eventually need it 1. Control of postprandial glycemia and regression of carotid atherosclerosis 2. Insulin aspart effects on postprandial state and endothelial dysfunction1. Control of postprandial glycemia and regression of carotid atherosclerosis 2. Insulin aspart effects on postprandial state and endothelial dysfunction

51. New Insulin Analogs More closely match normal physiology Rapid acting agents: Lower post prandial glucose excursions Shorter durations of postprandial hyperglycemia Significantly reduced incidence of severe hypoglycemia in patients with T2DM Combination agents (rapid plus intermediate acting insulins): improved postprandial control with reduced hypoglycemia

53. Key considerations for Insulin therapy Basal-bolus regimens most closely simulate normal physiology but have drawbacks: Requires motivated patient and physician Requires comprehensive training in carb counting and insulin adjustment Must tailor treatment plan to each patient Start low (0.15 U/kg body wt/day), titrate steadily Monitor and adjust therapy until goals achieved Some who are uncomf with MDI (multiple daily injection) regimens may first use less intensive regimens (mix combos) to gain confidence. Some who are uncomf with MDI (multiple daily injection) regimens may first use less intensive regimens (mix combos) to gain confidence.

56. Which Insulin regimen should I use? Treat to Target Trial1 Glargine vs. NPH added to oral therapy in obese T2DM 60% of patients achieved A1C<7 (mean entry A1C 8.6%) Significantly less nocturnal hypoglycemia with glargine Triple Therapy in T2DM2 Glargine vs. rosiglitazone added to oral therapy in T2DM Glargine superior if A1C>8.5, similar if <8.5 Treat to Target Notes: Starting dose: 10 units at bedtime, titration schedule Triple Therapy Notes: Glargine caused more hypoglycemia, less weight gain and less cost. Glargine also had more beneficial effect on lipids. Treat to Target Notes: Starting dose: 10 units at bedtime, titration schedule Triple Therapy Notes: Glargine caused more hypoglycemia, less weight gain and less cost. Glargine also had more beneficial effect on lipids.

57. Take home points on Insulin Rx Start Insulin earlier Best option if A1C >8.5 despite oral therapy Basal insulin added to oral medications a safe and effective way to initiate Titrate to effect, if still not controlled, go to multiple daily injections Newer Insulin analogs are safer�less hypoglycemia

58. Case 3 57 y.o. WM with HTN, Hyperlipidemia, CAD and long standing Diabetes with poor control. Has refused insulin therapy in the past because �when you go on insulin the diabetes just gets worse.� He is currently on: Metformin 1000 BID, Glipizide ER 20 daily, Actos 45 daily HgbA1C at the most recent visit is 9.2 What should be your next step in therapy? Educate about natural history, benefits of glucose lowering with insulin If you choose to start Insulin, what type and regimen would you use? Start bedtime basal Insulin, then convert to BID insulin once he is comfortable

59. Relationship of PPG to A1C

60. Case 1--Revisited 81 y.o. AAM with T2DM for 22 years, retinopathy and peripheral neuropathy. He has had A1C 8-8.5 over the last year despite titrating his glimepiride and metformin to maximum doses. He has mild obesity with a central distribution of fat He is careful about diet, monitors BS�s regularly but does not exercise What should you do next to improve his control? Add Insulin or third oral agent (glitazone) OR�. Choose an agent that will target Post Prandial glycemia

61. Novel agents for diabetes Metaglinides (repaglinide, netaglinide): Non-sulfonylurea secretagogues More rapid onset and less hypoglycemia Timed with meals to target PPG Repaglinide (Prandin) Netaglinide (Starlix)Repaglinide (Prandin) Netaglinide (Starlix)

62. Novel agents for diabetes Amylin/GLP-1 based therapies: Actions: Improve glucose-dependent insulin secretion and suppress glucagon secretion (delaying gastric emptying and decreasing appetite) Glucagon like peptide-1 agonists (Exenatide) BID injections Add on to oral therapy, induce weight loss Dipeptidyl peptidase-IV inhibitors (Sitagliptin) Amylin analog (Pramlintide) For use with Insulin only, mealtime injections Exenatide (Byetta) Sitagliptin (Januvia) is oral, weight neutral recently FDA approved. Exenatide (Byetta) Sitagliptin (Januvia) is oral, weight neutral recently FDA approved.

64. Projecting the future: newer agents may be substituted in the second or third line�especially if they are weight neutral or negativeProjecting the future: newer agents may be substituted in the second or third line�especially if they are weight neutral or negative

65. Case 5--Revisited 33 y.o. AAF with Morbid Obesity (BMI 42) and Type 2 Diabetes diagnosed in 2003. Takes Glipizide and Avandia (max doses) She does not tolerate metformin due to diarrhea She does not exercise/ is poorly compliant with diet HgbA1C at the most recent visit is 7.9 What should be your next step in therapy? Consider referral for Bariatric Surgery Add one of the novel agents that promote weight loss (ex. exenatide)

66. Conclusions-1 Correcting hyperglycemia is the key to reducing complications from diabetes The target for treatment should be as close to normal as possible without causing serious hypoglycemia With so many treatment options, a rational approach is important. Adequate trials comparing treatment regimens are still needed. Metformin is first line oral therapy, should be started concurrently with lifestyle change Think twice about adding a third oral agent

67. Conclusions-2 Insulin should be strongly considered if A1C >8.5 Starting basal insulin at night is a simple initial approach to starting insulin (glargine>NPH) Newer insulins are more physiologic and less prone to hypoglycemia When choosing a drug for diabetes, attention to side effect profile is important�especially weight gain Newer agents target post prandial hyperglycemia�especially important as A1C declines. (They are also weight neutral or negative).

68. Selected References Dormandy J et al. Secondary prevention of macrovascular events in patients with T2DM in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events). Lancet. 2005:366:1279-1289. DREAM Trial: Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105. Heine RJ et al. Management of hyperglycemia in Type 2 Diabetes: The End of Recurrent Failure? BMJ. 2006;333: 1200-1204. Hirsch I et al. Real-World Approach to Insulin Therapy in Primary Care Practice. Clinical Diabetes. 23(2);2005: 78-86. Kahn S et al. ADOPT Trial: Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. NEJM 2006;355:2427-2443. Laine C, Wilson J. In the Clinic: Type 2 Diabetes. Annals of Int Med. 2007 Jan 2. Nathan DM et al. Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. ADA/EASD Consensus Statement. Diabetes Care. 29(8):2006 August.