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Diabetes Medications Update Eric L. Johnson, M.D. Assistant Medical Director Altru Diabetes Center Altru Health System Associate Professor Department of.

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Presentation on theme: "Diabetes Medications Update Eric L. Johnson, M.D. Assistant Medical Director Altru Diabetes Center Altru Health System Associate Professor Department of."— Presentation transcript:

1 Diabetes Medications Update Eric L. Johnson, M.D. Assistant Medical Director Altru Diabetes Center Altru Health System Associate Professor Department of Community and Family Medicine University of North Dakota School of Medicine and Health Sciences Grand Forks, ND

2 Disclosures Off label use of some medications will be discussed

3 Objectives Assess knowledge of usual diabetes medications Implement proper medication use per guideline management Improve knowledge of side effects and contraindications of diabetes medications

4 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

5 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

6 Diabetes Diagnosis Category FPG (mg/dL) 2h 75gOGTT A1C Normal <100 <140 <5.7 Prediabetes 100-125 140-199 5.7-6.4 Diabetes >126** >200 >6.5 Or patients with classic hyperglycemic symptoms with plasma glucose >200 ** On 2 separate occasions Diabetes Care 35:Supplement 1, 2012

7 *IFG=impaired fasting glucose. Copyright ® 2000 International Diabetes Center, Minneapolis, USA. All rights reserved. Adapted with permission. Natural History of Type 2 Diabetes Years of Diabetes Glucose (mg/dL) 50 – 100 – 150 – 200 – 250 – 300 – 350 – 0 – 50 – 100 – 150 – 200 – 250 – -10-5051015202530 Relative Function (%) Fasting Glucose Postmeal Glucose ObesityIFG*Diabetes Uncontrolled Hyperglycemia Insulin Resistance  -cell Function  -Cell Failure

8 The Ominous Octet Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect DeFronzo Diabetes 2008

9 Targets for glycemic (blood sugar) control in most non-pregnant adults ADAAACE A1c (%) <7*≤6.5 Fasting (preprandial) plasma glucose 70-130 mg/dL<110 mg/dL Postprandial (after meal) plasma glucose <180 mg/dL<140 mg/dL American Diabetes Association. Diabetes Care. 2012;35(suppl 1) 2011 *<6 for certain individuals Goals of Glucose Management

10 More stringent (<6.5) appropriate: -No significant CVD -Short duration -Long life expectancy American Diabetes Association. Diabetes Care. 2012;35(suppl 1)

11 Goals of Glucose Management Less stringent (<8) appropriate: History of severe hypoglycemia Limited life expectancy Advanced complications or comorbid conditions Longstanding difficult to control diabetes American Diabetes Association. Diabetes Care. 2012;35(suppl 1)

12 Goals of Glucose Management Hypoglycemia must be considered “Many factors, including patient preferences, should be taken into account when developing a patient's individualized goals” American Diabetes Association. Diabetes Care. 2012;35(suppl 1)

13 A1C ~ “Average Glucose” American Diabetes Association A1C eAG % mg/dL mmol/L 61267.0 6.51407.8 71548.6 7.51699.4 818310.1 8.519710.9 921211.8 9.522612.6 1024013.4 Formula: 28.7 x A1C - 46.7 - eAG

14 Diabetes Medications

15 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

16 Glucose-lowering Potential of Diabetes Therapies* Treatment FPG  HbA1C  Sulfonylureas50-60 mg/dl1-2% Metformin50-60 mg/dl1-2%  -Glucosidase Inhibitors (Precose) 15-30 mg/dl0.5-1% Repaglinade (Prandin)60mg/dl1.7% Thiazolidinediones40-60 mg/dl1-2% Gliptins (Januvia,Onglyza)targets ppd0.5 - 0.8% *based on package insert data as monotherapy

17 Glucose-lowering Potential of Injection Diabetes Therapies* Treatment FPG  HbA1C  Exenatide (Byetta) targets ppd1-1.5% Liraglutide (Victoza) targets ppd 1-1.5% Pramlintide (Symlin) targets ppd1-2% InsulinLimited by1.5-3.5% hypoglycemia *based on package insert data as monotherapy

18 ADA/EASD consensus algorithm Type 2 MET: metformin; SU: sulfonylurea. Nathan et al. Diabetes Care 2009;32(1): 193-203 a SU other than glyburide or chlorpropamide. b Insufficient clinical use to be confident regarding safety. No No hypoglycemia Weight loss Nausea/vomiting Lifestyle and MET + intensive insulin Lifestyle and MET + basal insulin Lifestyle and MET+ SU a At diagnosis: Lifestyle + MET Step 1Step 2Step 3 Lifestyle and MET + pioglitazone NoNo hypgglycemia edema/CHF Bone loss Lifestyle and MET + GLP-1 agonist b Lifestyle and MET + pioglitazone + SU a Lifestyle and MET + basal insulin Tier 2: Less well-validated therapies/studies Tier 1: Well-validated core therapies 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%.


20 Key Points of Medication Selection in Type 2 Metformin at diagnosis unless a contraindication Second line agents- basal insulin or many other meds Advance therapy as disease progresses ADA/EASD will have a new guideline in 2012

21 Oral Diabetes Medications

22 Sulfonylureas Oldest oral medications Stimulate pancreas to secret more insulin Effective, inexpensive Glyburide, Glipizide, Glimiperide

23 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

24 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

25 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

26 Thiazolidinediones (TZD’s) Pioglitazone (Actos) Rosiglitazone (Avandia) Improves insulin resistance Extremely low incidence of hypoglycemia The role of TZD’s is rapidly diminishing

27 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-restrictions) Bladder cancer? Pioglitazone (Actos)

28 Gliptins(DPP-IV) DPP-IV inhibitors Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Tradjenta) Oral agents Weight neutral or weight loss Can use with Metformin, Sulfonylurea, TZD, or insulin (sitagliptin)

29 Gliptins’ Caveats, Benefits Caveats: Hypoglycemia if used with sulfonyurea or insulin Nausea, rash Benefits: Few drug interactions; can be renally dosed

30 “Niche” Drugs Colesevelam (Welchol) - adjunct to lower A1c and LDL 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? Mechanism uncertain Salsalate-older NSAID, may lower blood sugar, no indication yet

31 Non-Insulin Injectable Medications

32 Glucagon-like Peptide-1 (GLP-1) Gut hormone Stimulates pancreas to secret insulin Suppresses glucagon action Many target organs Weight regulation

33 GLP-1 Medications 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 Exenatide approved for combo use with insulin

34 GLP-1 Caveats Nausea, vomiting Pancreatitis Medullary thyroid carcinoma in rodents (liraglutide) Hypoglycemia combined with sulfonylurea Caution in renal or hepatic impairment

35 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

36 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

37 Prediabetes Lifestyle measures are treatment of choice to prevent progression to type 2 diabetes Many meds have some prediabetes data Metformin may be considered in those with prediabetes especially for: BMI >35 kg/m Age <60 years Women with prior GDM or PCOS ADA Diabetes Care. 2012;35(suppl 1)

38 Insulin Therapies

39 Intensifying Treatment Beta-cell function (%) Beta-cell decline exceeds 50% by time of diagnosis 4­4­4­12­8­80812 0 50 100 75 25 Type 2 Diabetes IGT Years from diagnosis Postprandial Hyperglycemia Diagnosis Insulin initiation Lebovitz H. Diabetes Rev 1999;7:139-153. Beta-cell function declines as Type 2 diabetes progresses

40 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

41 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

42 Long-Acting Insulin Detemir (Levemir) Glargine (Lantus) (Human NPH (N) ) Taken 1 or 2 times daily “Basal” insulin

43 Rapid Acting Insulin Aspart (Novolog) Lispro (Humalog) Glulisine (Apidra) (Human Regular) Taken with meals and snacks “Bolus” insulin

44 Insulin Time Action Curves 0 20 40 60 80 100 120 140 0246810121416 Insulin Effect Hours 1820 Intermediate (NPH) Long (Detemir,Glargine) Short (Regular) Rapid (Lispro,Glulisine, Aspart) adapted from R. Bergenstal, IDC

45 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

46 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

47 Adding Bolus Insulin in Type 2 Diabetes Lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) Pen injectors Why is bolus insulin important in Type 2?

48 Fasting and Postprandial Glycemic Excursions as a Function of A1C Monnier L et al. Diabetes Care. 2003;26:881-885. 0 20 60 80 2 (7.3–8.4) 3 (8.5–9.2) 4 (9.3–10.2) 5 (>10.2) 1 (<7.3) 40 Contribution (%) A1C (%) Quintiles Postprandial hyperglycemia Fasting hyperglycemia

49 Adding Bolus Insulin in Type 2 Diabetes 1 injection basal/1 injection bolus good 2 injection program- better than split basal 90/10 rule (90% basal, 10% bolus) Start with largest meal of the day Add other meal doses later (MDI-different formulas) Often stop TZD, always stop SU Easy with pens

50 Other Insulins Premix 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 U-500 Sometimes in severe insulin resistance

51 Severely Insulin Resistant 200-300+ units total daily dose Obesity Lipodystrophies Donohue and Rabson–Mendenhall Syndrome Type a Insulin Resistance Syndrome and HAIR-AN Garg NEJM 2004 Semple et al Clin Endocrinol. 2010

52 Severely Insulin Resistant Consider occult infections (UTI, abcess, sinus, etc) Consider other inflammatory conditions (periodontal disease, etc)

53 Severely Insulin Resistant Options: U-500 Add Symlin Add GLP-1 (exenatide now FDA approved with insulin) Change/add “insulin sensitizing” agents Bariatric Surgery Sometimes pump- better absorption, maybe lower daily dose

54 Medication Combinations Sulfonylureas: Virtually any in type 2 Metformin: Virtually any in type 2 TZD: Virtually any in type 2 Gliptins (DPP-IV): metformin, TZD, insulin (sitagliptin),sulfonylureas Insulin: metformin, TZD, sulfonylurea, amylin, sitagliptin Amylin: only in insulin regimens Exenatide/Liraglutide: metformin, sulfonyureas, TZD

55 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: Case by case as discussed

56 Future Medications SGLT (sodium-glucose co-transporter) 1/2 inhibitors (i.e., Dapagliflozin) GPR (G-protein receptors) Ultralong acting insulins (i.e., degludec) Ultralong acting GLP-1 (i.e., bydureon) New P-PARS

57 Typical Type 2 Timeline Metformin at diagnosis Add something else Consider insulin if: -Duration >5 years -A1C>9

58 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

59 Acknowledgements Jim Brosseau, M.D., M.P.H. Altru Diabetes Center William Zaks, M.D., Ph.D., Altru Diabetes Center Altru Diabetes Center Team Melissa Gardner, Department of Family and Community Medicine, UNDSMHS

60 Contact Info/Slide Decks/Media e-mail Facebook search “North Dakota Diabetes” on Facebook Phone 701-739-0877 cell Slide Decks (Diabetes, Tobacco, other) iTunes Podcasts (Diabetes) (Free downloads) or iTunes>> search UND Medcast ( WebMD Page: (under construction) Diabetes e-columns (archived):

61 Case Studies

62 Case Study 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)

63 Case Study Metformin 500 mg prescribed twice daily, titrated to 1000mg BID ASA 81 mg daily Lisinopril 10 mg daily Simvistatin 40 mg daily Fish Oil 1000mg BID

64 Case Study Referred to Diabetes Educator and Dietician Recommend developing graduated exercise plan (exercise prescription) Six months after diagnosis, A1C = 6.8% (target <7%)

65 Case Study Three years later, patient’s A1C has risen to 8.4% (target <7%) Blood pressure and cholesterol effectively treated Now what?

66 Case Study 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

67 Case Study 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?

68 Case Study 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

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