Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Oral Therapy for Type 2 Diabetes
Document related concepts
Transcript
Some Things You May Be Interested In With Regard To Therapy for Type 2 Diabetes Oliver Z. Graham, MD Mail-Order Endocrinologist Department of Internal Medicine The Agenda Dealing with severe hyperglycemia in clinic Sulfonyureas, Metformin The GLP -1 based therapies should we use them? What about TZDs? What should target HA1c be? A case study A 48 YO newly emigrated Mexican man comes to your clinic with polyuria, polydipsia and nocturia for the past month as well as 8 pounds of unintentional weight loss. Case study, continued Na 140 K 4.4 AG 10 BUN 12 Cr 0.9 U/A No ketones, ++ Glucose Blood sugar 498 What do you do now? Dealing with severe hyperglycemia in clinic Per ADA, insulin indicated as initial treatment in patients with: FBG > 250 Random BG > 300 HA1C > 10 Ketonuria Suspicion of DM type 1 Is this realistic for our patients? Guidelines for management of hyperglycemia in health centers If abnormal vital signs, ketones in urine, altered mental status, elevated anion gap --> send to ER Ketonuria in type 2 DM can be managed in clinic with hydration if clinically suspect starvation ketoacidosis (I/O DKA) and electrolytes normal Clinical guidelines for management of hyperglycemia, CCRMC 2005 6 An interesting study…. 55 patients with polyuria, polydipsia, weight loss, BS > 300 treated with high dose SU alone Those with suspected type 1 DM excluded and started on insulin immediately (age < 30, lean, no FH type 2 DM) If BS not improved at 1 week --> insulin started BS decreased 456 (baseline) --> 202 (1 week) --> 120 (5 months) Most had symptomatic improvement in 3 days HA1c decreased 18.1 (baseline) --> 8.1 (4 months) Peters et al, “Maximal Dose Glyburide Therapy…” JCEM, 1996 7 Recommended Initial Doses of Sulfonylurea Agents Agent BS<180 BS>180 Markedly Symptomatic Glyburide 1.25 < 65 Years Glyburide 1.25 >65 Years 2.5 20 1.25 10 Glipizide 2.5 <65 Years 5 40 Glipizide >65 years 2.5 15 2.5 Interesting SU facts! SU usually reduce FPG by 50-70 The higher the HA1c, the more dramatic the effect Should be started at lowest dose and can be titrated upward at weekly intervals to FPG < 120 Glyburide…. If patient does not respond to 10 mg/day, unlikely to respond significantly to a higher dose Maintenance doses 20 mg/day not recommended Usually dosed once daily Not recommended for GFR < 50 – “Y use Glyburide?” Glipizide… acting than glyburide – if > 15 mg/day given, divide BID prior to meals Maximum daily dose is 40 mg/day, but doses > 10-15 mg/day probably of little additional benefit for long term tx Given its lower potency and shorter half life, glipizide preferable agent in elderly patients Shorter Another patient walks in... 53 YO woman with a history of hypertension comes into your office. Her random blood sugar came back at 223. You subsequently confirmed the diagnosis by a fasting BS of 145. You counsel the patient regarding diet and exercise refer the patient for DM classes. What is your next step? 12 2009 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion. Diabetes Care. Published online Oct 22, 2008 Metformin!! Drug of choice in type 2 DM Reduction HA1c about 1.5% 85% of benefit seen from dose 1500 mg/day, little benefit from doses greater than 2000 mg/day May induce modest weight loss Risk of hypoglycemia low when used as monotherapy How To Titrate Metformin Tell patient about the possibility of GI side effects Begin with low dose metformin (500 mg) taken once or twice per day with meals (before break and dinner) or 850 once daily After 5-7 days, if GI side effects have not occurred, advance dose to 850, or two 500 mg tablets twice per day If GI effects appear as dose advanced, decrease to previous lower dose and advance at later time Per ADA consensus statement, 2009 Metformin and lactic acidosis Unclear exactly why metformin induces lactic acidosis (ummm… something to do with Krebs cycle) Occurs almost exclusively in patients with Renal, hepatic or cardiac failure Dehydration Hypoxia Recommended to stop in hospitalized patients with “the potential to get sick” or ARF from contrast In otherwise healthy patients, risk of LA very very low (“almost zero”) Contraindications to Metformin Renal failure Traditional cutoff Creat > 1.4 women, >1.5 men Recent (not totally accepted) recommendation: GFR 36-49: Probably safe GFR < 30-36): Not safe Other Contraindications (basically more RF for Lactic Acidosis) Alcoholism Heart Failure (prob safe in stable, well compensated disease) Liver disease Decreased tissue perfusion or hemodynamic instability Weight Changes Associated with AntiHyperglycemic Therapies for Type 2 Diabetes Insulin tx 4 lb increase for every 1% A1c reduction!! ADA Scientific Meeting 2005 ABS 13-or GLP –1 based therapies: Exenatide and Sitagliptin (Byetta and Januvia) GLP - 1: a gut hormone that is secreted in gut in response to eating food Slow gastric emptying Inhibits postprandial glucagon secretion Reduction food intake Enhance insulin secretion Very rapidly degraded in body (2 min) Exanatide: GLP -1 mimic, but degrades slower in body (derived from Glia Monster saliva) Sitagliptin: Inhibits GLP -1 degradation No weight gain! Why use Exenatide (Byetta)? Most patients gain weight with DM tx With Byetta WEIGHT LOSS 12 A1c pound loss at 2 years tx reduction about 1.1% ? Animal studies suggest beta cell regeneration 21 Why not use (Exenatide) Byetta? Expensive (1 year -- $2700) Long term data not available (lessons from Avandia & Rezulin…) Possible association with necrotizing pancreatitis Nausea very common (50-60%) Because slows gastric emptying CONTRAINDICATED in GASTROPARESIS 2 injections/day Who might get Byetta? Obese patients not at A1C target who are already on metformin, sulfonyurea or both or glitazone +/- metformin Should be patients who HA1c < 8.5 (if greater than this should be started on insulin) Sitagliptin (Januvia) Reduction HA1c 0.5-0.8 Weight neutral, well tolerated Long term safety not established Relatively expensive No hypoglycemia when used as monotherapy Think about using it in: Patients with contraind to SU/Metformin (eg Januvia safe in renal failure) Patients who in whom hypoglycemia bad (elderly) Add on therapy in which you need marginal HA1c reduction What about Thiazolidinediones? (TZD) 0.5 – 1.4 reduction in HA1c Weight gain 5-12 lbs at 1 year Edema 4-30% 2 fold increase in CHF Small increase fracture rate, decrease BMD in women Rosigliazone (Avandia) – not recommended by ADA given possible 30-40% increased risk MI per metaanalysis (off CCRMC formulary) Pioglitasone (Actos) – 16% reduction death, MI, CVA (“questionable statistical significance” per ADA), modest improvement in lipid profile Per ADA TZD now second tier drug Drug Cost Comparison (per month) Drug and Dose Glucose Strips (2 per day) Sulfonylurea Rapaglinide 2 mg tid Acarbose 100 mg tid Metformin 1000 bid Rosiglitazone 8 mg qd Pioglitazone 45 mg/d Sitagliptin Exenatide Glargine, 45 U/d 24 hour fitness center YMCA Cost/mo $60 Generic $4-14 Brand $50 $175 $88 Generic $ 4-32 Brand $132 $223 $222 $181 5mcg $230 10mcg $255 $150 $44 $60 When to continue oral therapy when on insulin basal insulin stop TZD, but continue the SU, Metformin Start Better glycemic control with less insulin requirements, weight gain, hypoglycemia premeal insulin stop SU, Januvia Continue Metformin with basal/premeal insulin therapy Start Generic Oral Hypoglycemic Slide Change from Drug A to B, C, or D Add Drug A to B, or B to A HgA1c Add Drug C Add Drug D Time 2009 ADA Type 2 Consensus Statement Diabetes Treatment Algorithm An American Diabetes Association consensus statement represents the authors’ collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion. Diabetes Care. Published online Oct 22, 2008 TYPE 2 DIABETES SYMPTOMATIC NO And very high YES Start on sulfonylurea or insulin Start Metformin Referral for: •Diet •HGM •Sick Day Rules •Exercise (+/- EST) •Foot Care Goal Met NO YES Continue Current Treatment Add Medication Referral for: •Diet •HGM •Exercise •Foot Care Consider transition to metformin TYPE 2 DIABETES Metformin Thin or no injection OBESE Exenatide THIN Sulfonylurea Goal Not Met Add Sulfonylurea (consider TZD) Goal Not Met Sitagliptin (consider TZD) Goal Not Met •Start insulin – use pens •Add detemir, glargine or PM NPH (isolated fasting hyperglycemia or insurance) •? of which existing meds to continue, generally all •Change to bid premixed insulin •? of which existing meds to continue, generally just metformin •Change to basal and with premeal insulin •? of which existing meds to continue, generally just metformin Sitagliptin Goal Not Met Add Sulfonylurea (consider TZD) Another case study A 64 YO man with Type 2 DM comes in to see you for his first visit. Meds: Nifedipine, ASA, lovastatin, metoprolol, 70/30 insulin BID PMH: DM 2 dx 15 years ago + Diabetic Retinopathy Creatinine 2.3, 1.4 g/dl protein/day PE BP 167/94, BMI 36 HA1C 8.3 LDL 145 What is your target HA1c? Some big DM studies you may be familiar with Recent trials that evaluated HA1c with focus on cardiovascular mortality ACCORD, ADVANCE, VA Diabetes Prior trials that evaluated HA1c with less stringent HA1c goals mostly that demonstrated improvement in microvascular complications DCCT (Type 1 DM), UKPDS (Type 2) The ACCORD Trial (2008) 10,251 patients x 3.5 years (terminated early) Inclusion criteria: H/O CVD event or significant CVD risk Average 62 years old Baseline HA1c 8.1 Achieved Median HA1c 6.4 (intensive) vs 7.5 (control) ACCORD TRIAL Outcomes Primary outcome (MI, stroke, CV Death) reduced in intensive Glycemic group (not statistically Significant) BUT: Significant increase in all cause death and CVD disease! (1.41 vs 1.14% per year 257 vs. 203 deaths over 3.5 yrs HR 1.22) Why did more people die in with intensive glucose control in ACCORD? No ? one really knows Severe hypoglycemia increased risk of CV death ? Weight gain ? Med interactions ? Rapid reduction of HA1c by 2% ADVANCE Trial (2008) 11,140 Patients x 5 years History of major or microvascular disease or at least one other RF for vascular disease Average age 66, baseline HA1c 7.2 Median HA1c 6.3 (intensive) vs 7.0 (control) No difference in overall mortality or macrovascular events Most significant finding: reduced development of macroalbuminuria VADT - Veterans Administration Diabetes Trial •1742 Enrollees •97% male •Mean age 60.4 •BMI 31.3 •Majority had multiple CV risk factors •72% HTN •40% macrovascular dx •62% retinopathy •43% neuropathy VADT - Veterans Administration Diabetes Trial Primary Endpoint: NO DIFFERENCE IN CARDIOVASCULAR DISEASE OUTCOMES, but overall LESS PATIENTS DIED THAN PREDICTED Standard: 29.3% Intensive: 27.4% Why (predicted – 40%) (predicted – 31.6%) was mortality better than expected? Probable answer: Statin, ASA, really good BP control So what does this all mean? Based on ACCORD, ADVANCE, VA trial no clear evidence aggressive reduction HA1c results in improvement mortality or macrovascular complications at 3-5 years BUT --- Recent data from UKPDS (10 years followup) suggest long term reduction in MI with improved glycemic control Very clear correlation between reducing microvascular events and improved glycemic control DCCT trial: Getting HA1c from 9% to 7% resulted in 60% reduction in retinopathy, nephropathy and neuropathy at 6.5 years Feel proud of any HgA1c reduction From “horrible control” to “poor control” – pat yourself on the back!! 43 So just tell me what to do! Target HA1c < 7% for the majority Consider a lower HA1c in younger, healthier, newly diagnosed patients Higher target HA1c if life expectancy < 5 years, severe hypoglycemia, advanced microvascular or macrovascular complications, other significant co-morbid conditions Aggressive tx with ASA, statin, and BP control ADA consensus statement, 2009 To really make a difference, go beyond the HA1c Blood pressure: <130/80 in most, consider <125/75 in those with > 1 g/day protienuria Statin use: LDL < 100 in most LDL < 70 in established vascular disease or mult risk factors Consider ASA for primary prevention: > 40 years old, FH, tob use, obesity, albuminuria, hyperlipidemia (per ADA, not great evidence) Not recommended in < 30 yo 45 The main points Sulfonyureas Can probably be given safely in severe hyperglycemia with type 2 DM Avoid glyburide in elderly, renal failure Glyburide > 10 mg/day, glipizide > 15 mg/day prob not too effective Metformin Use in initial therapy in all DM 2 Can possibly be used up to GFR > 35 New recommendations: consider rapid titration 46 More main points ALL non-generic DM meds are expensive GLP -1 drugs: sexy, no weight gain, but long term data lacking Consider exenatide in your obese patients Sitagliptin not particularly potent, but well tolerated TZDs -- associated with weight gain, fracture risk, now “second line” drug 47 Even more points!! Target HA1c < 7% in most, higher in those with multiple comorbidities, less in younger patients 48
