Medical Management of Hyperglycemia in Type 2 Diabetes

Transcription

1 Medical Management of Hyperglycemia in Type 2 Diabetes Rana Malek M.D. Assistant Professor of Medicine Division of Endocrinology, Diabetes, and Nutrition University of Maryland School of Medicine

2 Objectives Review classes of non-insulin based therapies for type 2 diabetes Apply current treatment guidelines to the medical management of patients with Type 2 Diabetes Discuss the potential roles of emerging therapies for diabetes

3 Case 45 year old male diagnosed with type 2 diabetes HTN Obesity (BMI 37 kg/m 2 ) Hyperlipidemia Physical exam: acanthosis nigricans and central obesity Hgb A1c: 8.6% TG: 186 mg/dl, LDL: 138 mg/dl, HDL: 45 mg/dl He tells you he does not want to take insulin

4 American Diabetes Association Treatment Guidelines

5 Biguanides Metformin Mechanism of action: Decreases hepatic gluconeogenesis Lowers fasting glucose Increases insulin mediated glucose utilization in muscle/liver A1c reduction: 1-2% Side effects: GI: Diarrhea, nausea, anorexia Lactic acidosis Weight: Modest weight loss or weight neutral Hypoglycemia: No

6 Metformin and Lactic Acidosis Pre-disposing factors: Renal dysfunction Cr 1.4 mg/dl women, 1.5 mg/dl men Concurrent liver disease or alcohol abuse Heart failure Past history of lactic acidosis Decreased tissue perfusion or hemodynamic instability Hold prior to IV contrast and for 48 hours after

7 UKPDS: Any Diabetes Related overweight patients Proportion of patients with events Endpoint Conventional (411) Intensive (951) Metformin (342) M v C p= M v I p= Years from randomisation

8 UKPDS: Metformin in Overweight Patients Compared with conventional policy 32% risk reduction in any diabetes-related endpoints p= % risk reduction in diabetes-related deaths p= % risk reduction in all cause mortality p= % risk reduction in myocardial infarction p=0.01

9 Back to the Case Started on Metformin 500 mg Titrated to 1 gm BID A1c reduced to 6.9% After a year, A1c slowly trends upwards Today 8.0% Remains obese and hypertensive What are your options?

10 American Diabetes Association Treatment Guidelines

11 Sulfonylureas Glyburide, glimepiride, glipizide Mechanism of action: Depolarizes beta cell Increased insulin secretion A1c reduction: 1-2% Side effects: Nausea, skin reactions (photosensitivity), abnormal liver function tests Weight Weight gain 2 kg Special Considerations: Full glycemic benefits seen at half-maximal doses Hypoglycemia: Yes

12 American Diabetes Association Treatment Guidelines

13 Incretins

14

15 Glucagon-Like Peptide GLP-1 GLP and GLP Dipeptidyl petpidase-4 Insulin secretion Glucagon secretion Food intake GI motility Insulin biosynthesis B-cell proliferation Stimulates Inhibits Reduces Participates in ileal break Stimulates Promotes

16 Action of GLP-1 1 on Peripheral Tissue

17 Target Tissue for Incretins

18 Glucagon-Like Peptide Exenatide Liraglutide GLP-1 GLP and GLP1 X 9-36 Dipeptidyl petpidase-4 Sitagliptin Saxagliptin Vildagliptin

19 Glucagon-like like peptide-1 1 agonists Exenatide, liraglutide Mechanism of action: Potentiates glucose stimulated insulin secretion Suppresses glucagon secretion and slows gastric motility A1c reduction: 0.5-1% Side effects: Nausea, vomiting, diarrhea? Risk of pancreatitis? C-cell C thyroid tumors (liraglutide) Weight: Loss of kg Special Consideration: FDA approved for combination use with sulfonylurea, metformin, or TZD

20 DPP-4 4 inhibitors Sitagliptin, saxagliptin, linagliptin Mechanism of action: Inhibit dipeptidyl peptidase-4 Increases endogenous GLP-1 1 levels A1c reduction: % 0.9% Side effects: Increased risk for URI, UTI?pancreatitis (FDA advisory) C-cell hyperplasia Weight: Weight neutral

21 American Diabetes Association Treatment Guidelines

22 Thiazolidinediones Rosiglitazone, pioglitazone Mechanism of action: PPAR γ modulators Increase sensitivity of muscle, fat, and liver to insulin by increasing glucose transporter expression Inhibition of hepatic gluconeogensis A1c reduction: 1-1.5% 1.5% Side effects: Weight gain, fluid retention, peripheral edema, CHF Weight: Gain up to 10 pounds Contraindications: Class III or IV heart failure

23 Rosiglitazone vs Pioglitazone Rosiglitazone: PPAR-gamma agonist Pioglitazone: PPAR-gamma and alpha LDL HDL TG Rosiglitazone Pioglitazone

24 The beginning of the end Nissen, NEJM 2007: Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Meta-analysis analysis of 42 trials showed increase risk of MI Odds ratio (1.43, 95% CI ) 1.98) 86 MI rosi group vs 72 in control Graham, JAMA 2010: Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone Compared to pioglitazone, rosiglitazone associated with significantly increased risk of stroke, HF, and all cause mortality (HR 1.27, 1.25, and 1.15) Risk of MI not sig increased

25 Cumulative Incidence of Time to Event for the Composite of Acute Myocardial Infarction, Stroke, Heart Failure, and All-Cause Mortality in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone Graham, D. J. et al. JAMA 2010;304:

26 RECORD To evaluate effect of rosiglitazone on CV events and mortality in 4447 patients Interim and final results inconclusive for CV events Increased risk of HF (HR % CI ) Lower event rate and high dropout rate decreased power of study to assess primary outcome

27 Concerns for Safety 2010: European Medicines Agency suspends sales of rosiglitazone 2010: FDA restricts use of rosiglitazone to type 2 diabetics who cannot achieve adequate glycemic control with other meds including pioglitazone Current users can continue to take it Must review and acknowledge associated CV risks Clinicians must document patient eligibility and enroll them in Risk Evaluation and Mitigation Strategy Program

28 PROactive trial Evaluate effect of pioglitazone on CV events and mortality in 5238 patients Stopped prematurely Decrease in secondary composite end point (all-cause mortality, MI, or stroke) in pioglitazone group HR 0.84, 95% CI Insignificant impact on predefined primary endpoint of study

29 PROactive not all good news Dormandy, J et al. Drug Safety. 32(3): , March 1, 2009.

30 More Bladder Cancer Kaiser diabetes registry (interim analysis) Ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI ]) Use >24 months of therapy had an increased risk (HR 1.4 [95% CI ]) Lewis, Diabetes Care 2011

31 Pioglitazone and Bladder Cancer June 2011: French and German Medicines Agencies suspend use of pioglitazone because of potential increased risk of bladder cancer European Medicines Agency, FDA, and Japanese regulators have an ongoing review 6/15/11: FDA adds bladder cancer to warning label Not to be used in patient with active bladder cancer Use with caution in patients with previous bladder cancer

32 Estimate of event rate for fracture in women enrolled in PROactive Dormandy, J et al. Drug Safety. 32(3): , 202, March 1, 2009.

33 Drugs not on the Algorithm

34 Glinides Repaglinide, nateglinide Mechanism of action: Stimulate insulin secretion Short acting Given tid with meals A1c reduction: 1-2% Side effects: Hypoglycemia Weight: Gain 2 kg

35 Amylin agonists Drugs: pramlinitide Mechanism of action: Synthetic analogue of the β-cell hormone amylin Slows gastric emptying Inhibits glucagon production in glucose dependent fashion Predominantly decreases post-prandial prandial glucose excursions A1c reduction: % 0.7% Side effects: nausea Weight: loss of kg over 6 months Special Consideration: approved for use only as adjunctive therapy with regular insulin or rapid-acting acting insulin analogues

36 Amylin

37 α-glucosidase inhibitors Drugs: acarbose Mechanism of action: reduce rate of polysaccharides absorption in proximal small intestine Lower post-prandial prandial glucose levels A1c reduction: % 0.8% Side effects: GI discomfort Weight: weight neutral

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39 Case (con t) He was on exenatide, metformin, SU Did well for about 2 years A1c started to climb Had dropped some weight on exenatide, but creeping up. BMI now 39 kg/m 2 Today A1c 9.5% He says doc, no insulin? Please? What are your latest options?

40 Newly Approved (but not very useful)

41 Bile Acid Sequestrants Drugs: Colesevelam (welchol) Mechanism of action: unknown A1c reduction: % 0.4% (in combination with metformin, SU, or insulin) Side effects: Constipation, nausea, dyspepsia Hypoglycemia Maybe Weight: neutral Extra: Reduction in LDL, 20% increase in TG

42 Dopamine Agonist Drugs: Bromocriptine (Cycloset) Mechanism of action: unclear A1c reduction: % 0.5% Side effects: nausea, vomiting, dizziness, headache Hypoglycemia: Maybe (6.9% vs 5.3% placebo) Weight: Neutral Extra: Do not prescribe in patients with psychotic disorders, taking neuroleptic agents

43 No Insulin?

44 Couple slides on bariatric surgery

45 Indications for Surgery Body Mass Index >40 kg/m 2 BMI 35 kg/m 2 with a life threatening illness that can be improved by weight loss Sleep apnea Type 2 diabetes Heart disease

46 Bypass vs. Banding

47 Surgical results excess weight loss (95% CI) RYGB (bypass) 62% (66-57) LAGB/AGB (banding) 47% (54-41) Buchwald, H. et al. JAMA 2004;292:

48 Outcomes: Diabetes All patients Gastric banding Gastric bypass Resolved Mean (95% CI) 77% (71 to 83) 48% (29 to 67) 84% (77 to 90) Resolve/Improved Mean (95% CI) 86% (78 to 94) 81% (72.2 to 89.4) 93% (79 to 100) Buchwald, H. et al. JAMA 2004;292:

49 Treatment Guidelines

50 ADA A1c A1c goal <7%

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52 VA/DoD Clinical Practice Guidelines for the Management of Diabetes Mellitus

53 New drugs? SGLT-2 2 inhibitors Glucagon receptor antagonists Sirtuins Glucokinas activators

54 Sodium Glucose Co- Transporter (SGLT) Inhibitors SGLT mediates renal tubular glucose reabsorption SGLT2 exclusively expressed in renal proximal tubules Selective inhibition of SGLT2 increases urinary glucose excretion by inhibiting glucose reabsorption Sergliflozin (GlaxoSmithKline) Dapagliflozin (Bristol-Myers Squibb and AstraZeneca)

55 In the pipeline Glucagon receptor antagonists: To reduce hepatic glucose overproduction Glucokinase activators: to promote hepatic glucose uptake and pancreatic insulin secretion Sirtuins (Resveratrol): mimic effect of dietary restriction Enhanced glucose utilization Improved insulin sensitivity Increased exercise tolerance

56 Questions?

57 Thank You

58 Bibliography Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med 2007; 356: David J. Graham, MD, MPH et al. Risk of Acute Myocardial Infarction, Stroke, Heart Failure, and Death in Elderly Medicare Patients Treated With Rosiglitazone or Pioglitazone. JAMA 2010;304(4): Philip D. Home et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. The Lancet, Volume 373, Issue 9681, Pages , 20 June 2009 Dormandy, J et al. Safety and Tolerability of Pioglitazone in High-Risk Patients with Type 2 Diabetes: An Overview of Data from PROactive. Drug Safety. 32(3): , 202, March 1, 2009 Dormandy, J et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitazone Clinical Trial In macrovascular Events): a randomised controlled trial. The Lancet, Volume 366, Issue 9493,, Pages , 8 October 2005 Lewis, James D. et al. Risk of Bladder Cancer Among Diabetic Patients Treated With Pioglitazone Interim report of a longitudinal cohort study. Diabetes Care April 2011 vol. 34 no Buchwald, Henry et al. Bariatric Surgery: A Systematic Review and Meta-analysis. JAMA 2004;292(14): Nathan, David et al. Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 2009; 32 (1);

59 Glycemic Control in CKD Chronic renal failure results in increased insulin resistance in liver and skeletal muscle Increased insulin requirements At GFR < 20 ml/min, dramatic drop in insulin clearance and hepatic insulin metabolism Decreased insulin requirements

60 What to avoid? Metformin Excreted unchanged in urine Lactic acidosis Glyburide/Glimepiride Renal excretion of active metabolites

61 Glipizide What you can use Metabolized by liver Excreted in urine as inactive metabolites No dose adjustment needed Thiazolidinediones No dose adjustment needed Edema may preclude use Sitagliptin Dose reduction once GFR < 50 ml/min Repaglinide No dose adjustment needed