Medication Options for Diabetes Mellitus Type 2

Outpatient Management of Diabetes Mellitus Type 2:Oral Medications

John Atlee Jay Snyder, D.O.Assistant Professor of Internal MedicineEast Tennessee State UniversityJanuary 24th 2012 Todays Goals1. To recognize the importance of knowledge of treatment of diabetics by reviewing the increasing prevalence of type 2 Diabetes2. To review the numerous classes of medicines currently used for oral management of Diabetes3. To recognize strategies used for treatment of Diabetes 4. To discuss Diabetes & driving

www.cdc.gov/diabetesAge-adjusted percent

County-level Estimates of Diagnosed Diabetes among Adults aged 20 years: United States 2004

www.cdc.gov/diabetesAge-adjusted percent

County-level Estimates of Diagnosed Diabetes among Adults aged 20 years: United States 2005

www.cdc.gov/diabetesAge-adjusted percent

County-level Estimates of Diagnosed Diabetes among Adults aged 20 years: United States 2006

www.cdc.gov/diabetesCounty-level Estimates of Diagnosed Diabetes among Adults aged 20 years: United States 2007

Age-adjusted percent

www.cdc.gov/diabetesCounty-level Estimates of Diagnosed Diabetes among Adults aged 20 years: United States 2008

Age-adjusted percent

2004 Age-Adjusted Estimates of the Percentage of Adults with Diagnosed Diabetes in Tennessee

Centers for Disease Control and Prevention: National Diabetes Surveillance System. Available online at: http://apps.nccd.cdc.gov/DDTSTRS/default.aspx. Retrieved 1/20/201282005 Age-Adjusted Estimates of the Percentage of Adults with Diagnosed Diabetes in Tennessee

2006 Age-Adjusted Estimates of the Percentage of Adults with Diagnosed Diabetes in Tennessee

2007 Age-Adjusted Estimates of the Percentage of Adults with Diagnosed Diabetes in Tennessee

2008 Age-Adjusted Estimates of the Percentage of Adults with Diagnosed Diabetes in Tennessee

Who will help us stop this destructive pattern?The food industry???

http://www.foxnews.com/entertainment/2012/01/17/paula-deen-reveals-secret-struggle-with-diabetes-teams-up-with-drug-company/17Diabetes vs. Obesity 2008

Centers for Disease Control and Prevention: National Diabetes Surveillance System. Available online at: http://apps.nccd.cdc.gov/DDTSTRS/default.aspx. Retrieved 1/20/201218Treating DiabetesFirst Line ClassesSulfonylureasBiguanidesSulfonylureas (Second Generation)Glipizide (Glucatrol, Glucatrol XL)Glimepiride (Amaryl)Glyburide (Diabeta, Micronase)-ionized Glyburide (Glynase) also available-ionized doses to regular GlyburideYes Virginia, there is a First generation Sulfonylurea Rarely usedChlorpropamide (Diabinese)TolazamideTolbutamidePreference for a specific Sulfonylurea?Second generation?Glipizide because of short half-life?Glimeperide because of a study showing less hypoglycemia in the elderly?1PMID: 19952550/PMID: 8675920 Annals study & Glimeperide 19952550/867592023BiguanidesMetformin (Glucophage)Metformin ER (Fortamet/Glumetza/Glucophage XR)Riomet -liquid cherry flavored MetforminAre there different generations of Biguanides?Originally introduced in the 1950s, the first biguanides (Phenformin) had a very high frequency of lactic acidosis & were removed from the market.Some critics will argue there is not enough evidence of lactic acidosis1Metformin has a much lower incidence of lactic acidosis but still enough to warrant a Black Box warning. (9 cases per 100000 person years)21. PMID 20393934. 2. PMID:1037224325Are there other first line meds?Sitagliptin (Januvia) is a DPP4 previously used as an adjunct that has now been approved as a monotherapy. Insulin. Very poor control/renal failure/etc but thats a whole nother presentation.

So which medicine have we started in the past??Sulfonylurea or Metformin?Cardiac concerns?Old study (1970) with first generation sulfonylurea Tolbutamide showed increased cardiovascular mortality.1 Some belief that this still persists with all sulfonylureas including second generation.2 1. PMID: 992232. 2. PMID :222501692= Recent Annals study28Are they Overweight/Obese?Sulfonylureas increase insulin release from the pancreas & thus can cause weight gainAre they Overweight/Obese?Metformin helps with weight loss by:-reduction of GI absorption of glucose.-stimulation of anerobic glycolysis. (lactic acid)-inhibition of gluconeogenesis.-stimulation of glucose uptake in the liver.-increasing insulin receptors.

Dosing=Start low & go slow.Start Sulfonylureas at lower doses & increase slowly due to concern of hypoglycemia.Start Metformin at lower doses & increase slowly due to concern of GI side effects. May even start with PM or HS dosing, then increasing to BID. (To sleep through the bloating sensation) Also consider the extended release formula.Max dose Sulfonylurea varies medicine to medicineMax daily dose Metformin2550mg/dayRenal failure?Metformin contraindicated due to concerns of lactic acidosis. Metformin should be held in anticipation of procedures when IVP dye is used.Sulfonylureas are excreted by the kidneys & may build up in the bloodstream, thus causing hypoglycemia.Rare adverse anemiasMetformin- Megaloblastic anemiaSulfonylureas- Aplastic anema, hemolytic anemia & pancytopeniaCostMost first line options on $4/month $10/3month lists or even free depending on the pharmacy.

Example: Walmart $4 ListDiabetesChlorpropamide 100mg tab* . . . . . . . . . . . . . . 30 . . . . . 90Glimepiride 1mg tab . . . . . . . . . . . . . . 30 . . . . . 90Glimepiride 2mg tab . . . . . . . . . . . . . . 30 . . . . . 90Glimepiride 4mg tab . . . . . . . . . . . . . . 30 . . . . . 90Glipizide 5mg tab . . . . . . . . . . . . . . . . 30 . . . . . 90Glipizide 10mg tab* . . . . . . . . . . . . . . . 60 . . . . . 180Glyburide 2.5mg tab . . . . . . . . . . . . . . . . . . . . 30 . . . . . 90Glyburide 5mg tab (blue) . . . . . . . . . . . .30 . . . . . 90Glyburide 5mg tab (green) . . . . . . . . . . . 30 . . . . . 90Glyburide, micronized 3mg tab . . . . . . . . . . . . 30 . . . . . 90Glyburide, micronized 6mg tab . . . . . . . . . . .. 30 . . . . . 90Metformin 500mg tab . . . . . . . . . . . . . . . . . . . . 60 . . . . . 180Metformin 850mg tab . . . . . . . . . . . . . . . . . . . . 60 . . . . . 180Metformin 1000mg tab* . . . . . . . . . . . . . 60 . . . . . 180Metformin 500mg ER tab* . . . . . . . . . . . 60 . . . . . 180

*Prices may be higher in CA, HI, MN, MT, PA, TN and WI.Example: Target $4 ListDiabetesCHLORPROPAMIDE 100 MG* - Tablet 30 90 GLIMEPIRIDE 1 MG - Tablet 30 90 GLIMEPIRIDE 2 MG - Tablet 30 90 GLIMEPIRIDE 4 MG - Tablet 30 90 GLIPIZIDE 5 MG - Tablet 30 90 GLIPIZIDE 10 MG* - Tablet 60 180 GLYBURIDE 2.5 MG - Tablet 30 90 GLYBURIDE 5 MG - Tablet 30 90 GLYBURIDE MICRO 3 MG - Tablet 30 90 GLYBURIDE MICRO 6 MG - Tablet 30 90 METFORMIN 500 MG - Tablet 60 180 METFORMIN 850 MG - Tablet 60 180 METFORMIN 1000 MG* - Tablet 60 180 METFORMIN ER 500 MG* - Tablet 60 180 More on strategy laterSecond-line/Add on TherapyAlpha-glucosidase inhibitorsBeta cell stimulatorsTZDsGLP-1sDPP4sOthers

Alpha-glucosidase inhibitorsAcarbose (Precose)Miglitol (Glyset)

Prolong digestion of carbohydrates & reduce peak glucose levels by blocking oligosaccharide binding to the brush border.Taken with first bite of the meal & has additive effects when combined with sulfonylurea.Side effects: -GI related. Worse with Acarbose (including elevated LFTs & ileus)Oral Beta cell stimulatorsRepaglinide (Prandin) technically a MeglitinideNateglinide (Starlix) technically amino acid derivative

Action similar to sulonylureas, working in a glucose dependent fashion but still with the risk of hypoglycemia. Have a very short half-life & must be taken with meals.Some consideration as first line therapy in renal failureSide effects:- URI symptoms & GI side effects. Rare cardiac ischemia with Prandin & rare accidental injury with StarlixThiazolidinediones (TZDs/Glitazones)Pioglitazone (Actos)Rosiglitazone (Avandia)

Very good for additional control.Agonists of PPARgamma.Work at the tissue level to increase insulin sensitivity.Side effects:-may cause or worsen heart failure-rare hepatotoxicity-fractures (in women only)1-Bladder cancer21. PMID: 17363747. 2. PMID: 21515844.42

43Incretin Mimetics (GLP-1s)Exanatide (Byetta)Liraglutide (Victoza)Lixisenatide (Lyxumia) soon to be released

Works as a glucogon-like peptide (GLP-1) to increase glucose dependent insulin secretion, decrease excessive glucagon secretion, slow gastric emptying & decrease appetite.$$$ & bid injections. If willing to do injections why not just do insulin??Side effects: -Suppresses appetite -Associated with pancreatitis -Rarely associated with acute renal failure -Injection site concerns?

Dipeptidyl peptidase-4 inhibitors(DPP4s) Sitagliptin (Januvia)Saxagliptin (Onglyza)Linagliptin (Tradjenta) recently releasedBy blocking DPP4, incretins including GLP-1 are increased & effect is similar to incretin mimetics.Side effects: -URI symptoms -pancreatitis

Cancers with GLP-1s/DPP4sWith known risk for pancreatitis in Exanatide & Sitagliptin, a review also found an increased risk for pancreatic cancer with these medicinesAlso thyroid cancer in ExanatidePMID: 21334333346

PMID: 21334333347Bile acid sequestrantsColesevelam (Welchol)

Cholesterol medicine shown to improve glucose control/lower A1C.Side effects:-GI (including obstructions starting at the esophagus & ending with fecal impaction)-Oral blisters/severe rashAmylin analoguesPramlintide (Symlin)

Increased risk of hypoglycemia (especially with insulin)The elephant in the roomINSULINCombination medsToo many to count!!!!If on multiple medicines, see if there is an option.Only Sulfonylureas & Beta cell stimulators (& insulin/amylin) can cause hypoglycemia. However, additional medicines may enhance the hypoglycemia caused by sulfonylureas.Future medicine optionsWeekly/Depot Byetta shots.More me too drugs such as DPP4 meds Vildagliptin & Alogliptin.Bromocriptine mesylate (Cycloset) is a dopamine agonist on the market with unknown mechanism of improved diabetic control. More meds like this soon?Other PPAR agonists. PPAR alpha, beta, or combinations with gamma. (TZDs only gamma)

Future medicine optionsDapaglifozinWorks as a SGLT2 inhibitor. Works at sodium-glucose cotransporter 2 in kidneys to prevent glucose being reabsorbed & thus to be lost to the urine.Increased incidence of UTIsIncreased incidence of bladder cancer?Increased incidence of breast cancerPMID: 22262072Even more combination medsJuvisync (Januvia & Simvastatin) approved recentlyWhich medicine do we start?Recent systematic review in the Annals of Internal Medicine..overall guideline quality was poor with respect to the rigor of the guideline development process, particularly in use of systematic methods to identify evidence. In addition, most guidelines were susceptable to bias because they lacked a description of editorial independence from funders and guideline developers failed to report potential conflicts of interest.

PMID: 22213492Recent systematic review in the Annals of Internal Medicine11 guidelines met the inclusion criteria. Seven guidelines agreed with the conclusion that metformin is favored as the first-line agentThe American Diabetes Association has also recently clarified its preference for metformin

Which medicine to add on?New England Journal of Medicine interactive clinical decisions survey January 2008Patient on Metformin & Glipizide with fasting morning glucose of 110-140 & HbA1C of 8.1%Adding Pioglitazone, NPH before bedtime or Exanatide twice dailyPMID: 1827288858Results6455 votes castPioglitazone 1625 votesExanatide twice daily 1587 votesNPH before bedtime 3243 votesStaying up to dateDont forget to check the American Diabetes Associations website in the beginning of every January for updates on recommendations.QuestionA patient with poorly controlled DM2 comes in the office for a follow-up & yearly physical. The patient notes that if they were placed on insulin, they would no longer be able to work in their current profession & they would be fired What is your patients job?A. NurseB. TeacherC. CarpenterD. Truck driverE. ChefAnswer

D. Truck driverDiabetes & drivingBut wait a minute!!From the Instructions for the Medical Examiner section of the Medical Examination Report for Commercial Driver Fitness Determination:CMV drivers who do not meet the Federal diabetes standard may call (202) 366-1790 for an application for a diabetes exemptionDiabetes Exemption Team (202) 366-4001Insulin & Truckers Timeline1986: ADA & others petitioned to grant waivers on a case-by-case basis1993: Waiver program granted for those with safe driving history & endocrinologist/ophthalmologist approval. 1996: Appeals court ruled the program illegal (Advocates for Highway and Auto Safety v Federal Highway Administration)2003: Federal waiver process established with an exemption for for interstate commerceNow: Most states are adopting similar process to Federal rule for their CDLshttp://www.fmcsa.dot.gov/facts-research/research-technology/tech/TB-02-01-1.htm66ADA GuidelinesAn entire section for Diabetes & Driving...people with diabetes should be assessed individually, taking into account each individual's medical history as well as the potential related risks associated with driving.Potential medical-legal ramifications

Todays Goals1. To recognize the importance of knowledge of treatment of diabetics by reviewing the increasing prevalence of type 2 Diabetes2. To review the numerous classes of medicines currently used for oral management of Diabetes3. To recognize strategies used for treatment of Diabetes 4. To discuss Diabetes & drivingThank You!