Diabetes Medications: An Overview Eric L. Johnson, M.D. Assistant Professor Department of Community and Family Medicine University of North Dakota School of Medicine and Health Sciences Assistant Medical Director Altru Diabetes Center Altru Health System Grand Forks, ND Objectives • Assess knowledge of usual diabetes medications • Implement proper medication use per guideline management • Improve knowledge of side effects and contraindications of diabetes medications Diabetes Mellitus • Type 1: Usually younger, insulin at diagnosis • Type 2: Usually older, often oral agents at diagnosis • Type “1.5” (Latent Autoimmune), mixed features • Gestational: Diabetes of Pregnancy U.S. Prevalence of Diabetes 2010 • Diagnosed: 26 million people—8.3% of population (90%+ have Type 2) • Undiagnosed: 7 million people • 79 million people have pre-diabetes CDC 2011 Diabetes Diagnosis Category FPG (mg/dL) 2h 75gOGTT A1C Normal <100 <140 <5.7 140-199 5.7-6.4 >200 >6.5 Prediabetes 100-125 Diabetes >126** Or patients with classic hyperglycemic symptoms with plasma glucose >200 ** On 2 separate occasions Diabetes Care 34:Supplement 1, 2011 Natural History of Type 2 Diabetes Obesity IFG* Uncontrolled Hyperglycemia Diabetes Glucose (mg/dL) 350 – Postmeal Glucose 300 – 250 – Fasting Glucose 200 – 150 – 100 – Relative Function (%) 50 – 250 – Insulin Resistance 200 – 150 – 100 – -cell Function -Cell Failure 50 – 0– -10 -5 0 5 10 Years of Diabetes 15 20 25 *IFG=impaired fasting glucose. Copyright® 2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission. 30 The Ominous Octet Islet -cell Decreased Incretin Effect Impaired Insulin Secretion Increased Lipolysis Islet a-cell Increased Glucose Reabsorption Increased Glucagon Secretion Increased HGP Neurotransmitter Dysfunction Decreased Glucose Uptake Goals of Glucose Management Targets for glycemic (blood sugar) control in most non-pregnant adults A1c (%) Fasting (preprandial) plasma glucose Postprandial (after meal) plasma glucose ADA AACE <7* ≤6.5 70-130 mg/dL <110 mg/dL <180 mg/dL <140 mg/dL *<6 for certain individuals • American Diabetes Association. Diabetes Care. 2010;33(suppl 1) • Implementation Conference for ACE Outpatient Diabetes Mellitus Consensus Conference Recommendations: Position Statement at http://www.aace.com/pub/pdf/guidelines/OutpatientImplementationPositionStatement.pdf. Accessed January 6, 2006. • AACE Diabetes Guidelines – 2002 Update. Endocr Pract. 2002;8(suppl 1):40-82. A1C ~ “Average Glucose” A1C % 6 6.5 7 7.5 8 8.5 9 9.5 10 eAG mg/dL 126 140 154 169 183 197 212 226 240 mmol/L 7.0 7.8 8.6 9.4 10.1 10.9 11.8 12.6 13.4 Formula: 28.7 x A1C - 46.7 - eAG American Diabetes Association Diabetes Medications Diabetes Medications • Many new medications in last decade • Three main categories – Oral agents (pills)- many different kinds old and new – Insulin- newer, more modern insulins – Newer, non-insulin injectable medications • Choices allow individualization of treatment plan • Different medications, different indications, different situations Glucose-lowering Potential of Diabetes Therapies* Treatment FPG HbA1C Sulfonylureas 50-60 mg/dl 1-2% Metformin 50-60 mg/dl 1-2% a-Glucosidase Inhibitors (Precose) 15-30 mg/dl 0.5-1% Repaglinade (Prandin) 60mg/dl 1.7% Thiazolidinediones 40-60 mg/dl 1-2% Gliptins (Januvia,Onglyza) targets ppd 0.5 - 0.8% *based on package insert data as monotherapy Glucose-lowering Potential of Injection Diabetes Therapies* Treatment FPG HbA1C Exenatide (Byetta) targets ppd 1-1.5% Liraglutide (Victoza) targets ppd 1-1.5% Pramlintide (Symlin) targets ppd 1-2% Insulin Limited by hypoglycemia 1.5-3.5% *based on package insert data as monotherapy ADA/EASD consensus algorithm to manage type 2 Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%. Tier 1: Well-validated core therapies Lifestyle and MET + intensive insulin Lifestyle and MET + basal insulin At diagnosis: Lifestyle + MET Lifestyle and MET+ SUa Step 1 Step 2 Step 3 Tier 2: Less well-validated studies Lifestyle and MET + pioglitazone No hypgglycemia No edema/CHF Bone loss Lifestyle and MET + GLP-1 agonistb No hypoglycemia No Weight loss Nausea/vomiting aSU other than glyburide or chlorpropamide. bInsufficient Lifestyle and MET + pioglitazone + SUa Lifestyle and MET + basal insulin clinical use to be confident regarding safety. MET: metformin; SU: sulfonylurea. Nathan et al. Diabetes Care 2009;32(1): 193-203 Key Points of Medication Selection in Type 2 • Metformin at diagnosis unless a contraindication • Second line agents- basal insulin or many other meds Oral Diabetes Medications Sulfonylureas • Oldest oral medications • Stimulate pancreas to secret more insulin • Effective, inexpensive • Glyburide, Glipizide, Glimiperide Caveats with Sulfonylureas • • • • • • Hypoglycemia (particularly in elderly) Premature B-cell exhaustion? Caution in liver disease, renal disease Weight gain Rash Avoid if anaphylactic to sulfa Metformin • • • • • • • Improves insulin resistance Reduced Hepatic Glucose production Effective, inexpensive Extremely low incidence of hypoglycemia Weight neutral or weight loss Positive effects on lipid profiles Long term use may result in better CVD outcomes • Can be combined with virtually all other DM meds Caveats with Metformin • • • • • • • • Liver Disease Renal Disease GI upset Heavy Alcohol Use Intravascular Dye Studies (IVP, Angio,etc) CHF Not for persons over 80 Can result in B12 deficiency Thiazolidinediones (TZD’s) • Pioglitazone (Actos) • Rosiglitazone (Avandia) • Improves insulin resistance • Extremely low incidence of hypoglycemia Caveats with TZD’s • • • • • CHF (or if hx/risk?) Patients already dealing with edema Potential weight gain Renal disease-fluid overload Current TZD’s rare liver disease, not recommended in active liver disease • Heart disease risk? (Rosiglitazone-new restrictions) Gliptins(DPP-IV) • DPP-IV inhibitors • Sitagliptin (Januvia) • Saxagliptin (Onglyza) • Oral agents • Weight neutral or weight loss • Can use with Metformin, Sulfonylurea, TZD, or insulin (sitagliptin) Gliptins’ Caveats, Benefits Caveats: • Hypoglycemia if used with sulfonyurea or insulin • Nausea, rash Benefits: Few drug interactions; can be renally dosed “Niche” Drugs • Colesevelam (Welchol) - adjunct to lower A1c and LDL - limited efficacy, cost • Repaglinide (Prandin), Nateglinide (Starlix) - may replace SU if sulfa allergy - Prandin may be useful in CKD • Acarbose (Precose), Miglitol (Glyset) - limited efficacy, GI intolerance, cost • Bromocriptine (Cycloset) - limited efficacy? Will be marketed • Salsalate -older NSAID, may lower blood sugar, no indication yet Non-Insulin Injectable Medications Glucagon-like Peptide-1 (GLP-1) • • • • • • Gut hormone Stimulates pancreas to secret insulin Suppresses glucagon action Many target organs Weight regulation Caution in renal or hepatic impairment GLP-1 • • • • • Exenatide (Byetta) GLP-1 mimetic Liraglutide (Victoza) GLP-1 analog Both available in pen injectors (easy) Modest weight loss Combined with other agents except DPP-IV inhibitors or insulin (exenatide has basal insulin data) GLP-1 Caveats • Nausea, vomiting • Pancreatitis • Medullary thyroid carcinoma in rodents (liraglutide) • Hypoglycemia combined with sulfonyurea Pramlintide-Synthetic Amylin (Symlin) • Amylin secreted by normal pancreas along with insulin to regulate blood glucose • Enhances Postprandial control. Used in Type 1 and Type 2 patients • Used as adjunct to insulin • Available in pen injector • Possible significant hypoglycemia Combination Drug Therapy • Consider early if failing monotherapy • Generally additive or synergistic effects • Triple or quadruple non-insulin drug therapy -limited benefit in many -safe for many • Insulin is often a better,more potent choice Insulin Therapies Insulin Therapy • All Type 1 patients at diagnosis • All type 2 patients will require insulin if they live long enough -7 to 10 years post diagnosis -A1C >9% -Function of many non-insulin meds based on presence of native insulin Beta-cell function declines as diabetes progresses Beta-cell function decline over time 100 Diagnosis 75 Beta-cell function (%) 50 Beta-cell decline exceeds 50% by time of diagnosis IGT Insulin initiation Postprandial 25 Type 2 Diabetes Hyperglycemia 0 12 8 4 0 Years from diagnosis Lebovitz H. Diabetes Rev 1999;7:139-153. 4 8 12 Insulin Therapy • Modern insulins safer and more predictable • Most insulin types come in pen injectors • Pen injectors easy to use, to teach, less cumbersome than vials/syringes Rapid Acting Insulin • • • • Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra) (Human Regular) • Taken with meals and snacks • “Bolus” insulin Long-Acting Insulin • Detemir (Levemir) • Glargine (Lantus) • Human NPH (N) • Taken 1 or 2 times daily • “Basal” insulin Insulin Time Action Curves 140 Rapid (Lispro,Glulisine, Aspart) Insulin Effect 120 100 Short (Regular) 80 Intermediate (NPH) 60 40 Long (Detemir,Glargine) 20 0 0 2 4 6 8 Hours 10 12 14 16 18 20 adapted from R. Bergenstal, IDC Basal Insulin in Type 2 Diabetes • • • • • • Glargine (Lantus), Detemir (Levemir) Good, potent add-on for improved A1C Second line agent for many patients A1C >9, diabetes longer than 5 to 7 years AACE: ? Weight benefit with Detemir Pen injectors easy Basal Insulin in Type 2 Diabetes • Some oral meds may be continued -metformin, maybe TZD, maybe SU, maybe gliptin (sitagliptin) • Glargine (Lantus) or Detemir (Levemir) started at 10 units at HS • Increase 3 units every 3 to 5 days until fasting blood sugars <110 (or <140) • Most type 2 on 50-80+ units/day Adding Bolus Insulin in Type 2 Diabetes • • • • Lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) Pen injectors • Why is bolus insulin important in Type 2? Fasting and Postprandial Glycemic Excursions as a Function of A1C 80 Postprandial hyperglycemia Contribution (%) Fasting hyperglycemia 60 40 20 0 1 (<7.3) 2 3 4 (7.3–8.4) (8.5–9.2) (9.3–10.2) Monnier L et al. Diabetes Care. 2003;26:881-885. A1C (%) Quintiles 5 (>10.2) Adding Bolus Insulin in Type 2 Diabetes • 1 injection basal/1 injection bolus good 2 injection programbetter than split basal • 90/10 rule (90% basal, 10% bolus) • Start with largest meal of the day • Add other meal doses later • Usually stop TZD, always stop SU • Easy with pens Premix Insulins • 70/30, 75/25, 50/50 • Combine R or rapid acting with NPH or an “NPH-like” component • Certain applications may be appropriate • Limitation: change 2 insulins at once Case Studies Case #1 • 42 y/o Hispanic female with hx of GDM 6 years ago, term 10 lb 5 oz male infant • Not seen for follow-up in 3 years • FBS done at annual pap/px is 149 Does this patient have type 2 diabetes? What next? Case #1 • Diagnosis of diabetes generally requires two abnormal values • Patient at high risk for type 2 • GDM is a pre-diabetes condition Repeat FBS three days later……. Case #1 • Repeat FBS 135 • Dx: type 2 diabetes (FBS >126 on two separate occasions) • What should be done next for this patient? Case #1 • Patient had tubal ligation after last delivery • Start metformin 500mg BID, advance to 850-1000 mg BID • Most newly-diagnosed patients should start metformin (current ADA recommendation) Case #1 • Diabetes Educator and Dietician • SBGM with appropriate targets • Check fasting lipids, monitor Blood Pressure Case Study#2 • 54 y/o white male • Diagnosed with type 2 diabetes after 2 fasting blood sugars of 154 and 142 • Also has high blood pressure and cholesterol disease (common in type 2) Case Study #2 • Metformin 500 mg prescribed twice daily, titrated to 1000mg BID • ASA 81 mg daily • Referred to Diabetes Educator and Dietician for meal planning • Recommend developing graduated exercise plan (exercise prescription) • Six months after diagnosis, A1C = 6.8% (target <7%) Case Study #2 • Three years later, patient’s A1C has risen to 8.4% (target <7%) • Blood pressure and cholesterol effectively treated • Now what? Case Study #2 • Choices include – Adding a basal insulin once daily – Adding any other oral agent – Adding exenatide twice daily or liraglutide once daily • Any of these are good choices • Choice may be made on individual factors Case Study #2 • Patient chose additional oral agent (sitagliptin), but others would be OK • A1C: 6 months later = 7.4% (target <7%) 3 years later = 8.1% (target <7%) Now what? Case Study #2 • Sitgliptin, metformin continued • Basal insulin started with titration • Eventually added bolus insulin with largest meal (90/10 rule) • Likely will add bolus with other meals over time Medication Combinations • • • • • Sulfonylureas: Virtually any in type 2 Metformin: Virtually any in type 2 TZD: Virtually any in type 2 Gliptins: metformin, TZD, insulin (sitagliptin) Insulin: metformin, TZD, sulfonylurea, amylin, sitagliptin • Amylin: only in insulin regimens • Exenatide/Liraglutide: metformin, sulfonyureas, TZD Medication Indications • Type 1 Diabetes: Insulin, amylin (amylin only in combination with insulin) • Type 2 Diabetes: All oral agents, exenatide, liraglutide, amylin, insulin (amylin only in combination with insulin) • Prediabetes: none (yet), case by case, i.e., PCOS Summary • • • • Diabetes is common Understand Medications and Indications Type 1 diabetes: Insulin regimen (pumps) Type 2 diabetes: Lots of choices, but nearly all will need insulin eventually Acknowledgements • North Dakota Department of Health, Karalee Harper • Centers for Disease Control • Office of Continuing Medical Education, UNDSMHS, Mary Johnson • Department of Family and Community Medicine, UNDSMHS, Melissa Gardner • Brandon Thorvilson, UNDSMHS IT • Disclosure: Novo Nordisk Speaker’s Bureau Contact Info/Slide Decks/Media e-mail eric.l.johnson@med.und.edu ejohnson@altru.org Phone 701-739-0877 cell Slide Decks (Diabetes, Tobacco, other) http://www.med.und.edu/familymedicine/slidedecks.html iTunes Podcasts (Diabetes) (Free downloads) http://www.med.und.edu/podcasts/ or iTunes>> search UND Medcast soon) WebMD Page: (under construction) http://www.webmd.com/eric-l-johnson Diabetes e-columns (archived): http://www.ndhealth.gov/diabetescoalition/DrJohnson/DrJohnson.htm (updated