Making Clinical Sense of Diabetes Medications. Types of Diabetes. Pathophysiology. Beta Cell Function & Glucagon

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Cameron Short
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1 Making Clinical Sense of Diabetes Medications Kathy Reily, RD, CDE Prince William Hospital Diabetes Program Coordinator Virginia Dietetic Association April 4, 2011 Types of Diabetes Type 1 DM = Beta Cell Destruction, absolute insulin deficiency Type 2 DM = Ranges from predominantly insulin resistance with relative insulin deficiency to predominantly insulin deficiency with insulin resistance Gestational DM (GDM) = glucose intolerance with onset during pregnancy Pre-Diabetes = Impaired Fasting Glucose (IFG) or Impaired Glucose Tolerance (IGT) Pathophysiology Insulin Deficiency + Insulin Resistance = Hyperglycemia Type 2 DM, Gestational DM, Pre- Diabetes Absolute Deficiency of Insulin = Hyperglycemia Type 1 DM Beta Cell Function & Glucagon Progressive Beta cell decline = inadequate insulin secretion 50% reduction in insulin secretion at Dx Glucagon is not suppressed during the post prandial period Hepatic glucose production is increased during the fasting period Relative contributions of postprandial ( ) and fasting ( ) hyperglycemia (%) to the overall diurnal hyperglycemia over quintiles of HbA 1c

Gestational DM (GDM) = glucose intolerance with onset during pregnancy Pre-Diabetes = Impaired Fasting Glucose (IFG) or Impaired Glucose Tolerance (IGT) Pathophysiology Insulin Deficiency + Insulin

2 Glycemic Targets ADA AACE FPG hr post prandial Bedtime glucose A1C <7% <6.5% Optimal Diabetes Medication Management Individualized patient goals, i.e. A1C Address patient concerns, i.e. hypo, weight gain, side effects, frequent SMBG Targeted drug response Avoid clinical inertia Oral Medications How and where they work Pancreas stimulate insulin production Liver decrease hepatic glucose production Muscles increase sensitivity Intestines/gut decrease absorption of CHO; gut hormones Other Question #1 Drugs in the sulfoynlurea class are the drug of choice for newly diagnosed Type 2 diabetes patients. a. True b. False Sulfonylureas Action: Stimulate insulin secretion Require functioning beta cells Efficacy: Reduce A1C 1-2%, decrease FPG 60 70mg/dl Work best in first 5-10 years of diabetes Risks: hypo, weight gain Sulfonylureas Glimepiride (Amaryl) Glipizide (Glucotrol and Glucotrol XL) Glyburide (Glynase, Micronase, DiaBeta) Dose qd-bid Avoid glyburide w/ CrCl <50

glucose production Muscles increase sensitivity Intestines/gut decrease absorption of CHO; gut hormones Other Question #1 Drugs in the sulfoynlurea class are the drug of choice for newly diagnosed

3 Meglinitides Nonsulfonylurea secretagogues Action: Fast, short action Short term insulin secretion, 1-4 hrs Take 0-15 min before meals and large snacks Tid-qid dosing Efficacy: Reduce A1C 1-2%, Decrease FGB, PPG Meglinitides (continued) Repaglinide (Prandin) Netaglinide (Starlix) Risks Hypoglycemia Moderate Wt Gain Question #2 Question #3 Which of the following is an important counseling point for patients taking Prandin? a. Take with first bite of meal b. Take on an empty stomach c. May cause GI upset d. If you skip a meal, skip Prandin Metformin is one of the best choices to target post prandial glucose elevations. a. True b. False Biguanides Biguanides (continued) Action: Decrease hepatic gluconeogenesis and Stimulate glucose uptake by muscle Primary action is to decrease FPG Dose with meals, qd-bid 500 mg 2550 mg qd Efficacy: Reduce A1C 1-2%, decrease FPG mg/dl, weight loss, may decrease cholesterol Metformin (Fortamet, Riomet, Glucophage, Glucophage XR, Glumetza) Risks Side effects of diarrhea, nausea, abdominal pain Lactic acidosis (rare) Metallic taste May reduce B-12 level Contraindicated if serum Cr > 1.4 mg/dl women, > 1.5 mg/dl men

point for patients taking Prandin? a. Take with first bite of meal b. Take on an empty stomach c. May cause GI upset d.

4 Thiazolidenediones (TZDs) Action: Increase insulin sensitivity Insulin sensitizers Decrease insulin resistance Suppress hepatic glucose production Efficacy: Reduce A1C 0.5 1% Delayed onset ~ 6 weeks Without regard to meals Positive lipid effects Qd dosing TZDs (continued) Pioglitazone (Actos) Risks Rosiglitazone (Avandia) Weight gain Edema Not used in CHF, abnormal LFTs Monitor LFTs q 2 mos X 1 year FDA safety announcement -Avandia Alpha-Glucosidase Inhibitors AGIs (continued) Action: Delay digestion and absorption of CHO Inhibit intestinal enzyme slow breakdown of complex CHO Efficacy: Reduce A1C.5-1% Decrease FBG (20-30 mg/dl) and PPG (40-50 mg/dl) Acarbose (Precose) Miglitol (Glyset) Dose with 1 st bite each meal/large snack Slow titration Risks GI: diarrhea, gas, bloating Contraindicated with IBD or cirrhosis DPP-4 Inhibitors DPP-4 Inhibitors (continued) Sitagliptin (Januvia) Saxagliptin (Onglyza) Ingestion of food release of incretin hormones GLP-1 and GIP Beta & Alpha cell stimulation In DM, DPP-4 enzyme breaks down GLP-1 & GIP, so that the beta/alpha cells have decreased stimulation These inhibit the DDP-4 enzyme prolongs life of GLP-1 Clinical Effects Reduces A1C 1% Reduces PPG & FPG Glucose dependent* No hypo T2DM early years Risks Upper respiratory Stuffy nose Headache Dose adjustment for renal patients

LFTs Monitor LFTs q 2 mos X 1 year FDA safety announcement -Avandia Alpha-Glucosidase Inhibitors AGIs (continued) Action: Delay digestion and absorption of CHO Inhibit intestinal enzyme slow

5 Combination Meds Metaglip (metformin/glipizide) Glucovance (metformin/glyburide) Actosplus Met (pioglitazone/metformin) Duetact (pioglitazone/glimepiride) Janumet (sitagliptin/metformin) Avandamet (rosiglitazone/metformin) Avandaryl (rosiglitazone/glimepiride) Kombiglyze XR (metformin/saxagliptin) Incretin Mimetics Action: increase insulin secretion, B-cell growth/replication, slows gastric emptying, may decrease food intake, suppresses glucagon secretion Efficacy: Used with Type 2 Reduce A1C 0.5 1% Incretin Mimetics (continued) Exenatide (Byetta) Liraglutide (Victoza) Injectable prefilled pen Risks: nausea, not with CrCL< 30mg/dl, not with pancreatitis Liraglutide: thyroid tumor warning Question #4 Which medication(s) do not have the side effect of hypoglycemia? a. Januvia b. Metformin c. Exenatide d. Glyburide Amylinomimetc Action: Hormone amylin co-secreted by beta cells in response to meals Deficiencies relative to beta cell function Increases satiety Reduces food intake, appetite suppression Suppresses glucagon secretion Efficacy: Reduces A1C 1% Used with Insulin Type 1 & 2 pramlintide (Symlin) Amylinomimetic (continued) Dose T1DM 15 mcg 60mcg 4 step titration Dose T2 DM 60mcg 120 mcg 2 step titration Prefilled pens, vials Do not mix with insulin SQ abdomen or thigh Dosed prior to meal, meal must have cho Decrease IOB by 50% when starting Risk of hypo, nausea, headache

emptying, may decrease food intake, suppresses glucagon secretion Efficacy: Used with Type 2 Reduce A1C 0.

6 Dopamine Agonist Bromocriptine (Cycloset) Decreases A1C 0.7% Dopamine receptor agonist, exact mechanism unknown Used with diet & exercise in Type 2 DM Nausea, fatigue, dizziness Up to 6 tablets q am, titrate slowly Bile Acid Sequestrant Action: bile acid sequestrant colesevelam (Welchol) Type 2 DM on insulin Lowers A1C 0.5% Lowers LDL, FPG May Increase TG GI side effects (constipation, dyspepsia, nausea) Oral suspension or up to 6 tablets daily Insulin Therapy When is it time? Type 1 DM GDM Type 2 DM Glycemic goals not met Unable to tolerate oral meds Glucose toxicity Illness/surgery Goal = Mimic physiologic insulin Insulin Insulin Onset Peak Duration Lispro/apidra/aspart 5-15 min 1-2 hr <5 hr Regular min 2-4 hr 6-8 hr NPH 2-6 hr 4-14 hr hr Detemir 3-8hr flat 7-23 hr Glargine 1-2 hr flat hr Insulin Premixed Rapid 75/25 70/30 50/50 Premixed Regular 70/30 Limitations Bid dosing Insulin: Basal/Bolus Regimen Basal insulin targets FPG NPH, detemir (Levemir), glargine (Lantus) NPH Not ideal for basal therapy; bid dosing Pronounced peak Hypo Variability, onset and duration Detemir & glargine more physiologic for basal delivery Usually qd dosing, levemir bid dosing No peak/blunted peak

sequestrant colesevelam (Welchol) Type 2 DM on insulin Lowers A1C 0.

7 Basal/Bolus Regimen Bolus insulin targets meals/snacks and post prandial glucose Rapid acting (more physiologic) Lispro (Hulmalog) Aspart (Novolog) Glulysine (Apidra) Short acting Regular insulin Delayed peak, longer duration Risk of hypo Variability Insulin Step 1: if FPG/PPG/A1C above target: Add glargine/detemir qd (HS) Step 2 Add rapid insulin to main meal Step 3 Add rapid insulin to next largest meal Step 4 Add rapid insulin to last meal Insulin Injection sites Abdomen preferred site Rotate within Room temp storage of vial/pen Storage duration of vial/pen Delivery devices Syringe Pen Pump Case Study #1 S.B. is a 42 yo AAF, 5 year hx Type 2 DM. PMH includes HTN, Ht 61 inches, wt 163 #; labs A1C 10.2%, HDL 55 mg/dl, LDL 83 mg/dl, TG 111, TC 167, SCr 0.9. Meds: lisinopril, metformin 1000 mg bid, glyburide 5 mg bid, asa 81 mg qd. Q: Which of the following is the most effective approach to improve SBs glycemic control? Case Study #1 a. Increase glyburide to 20 mg bid b. Add pioglitazone 15 mg po qd c. Add exenatide 5 mcg sc bid d. None of the above Case Study #2 T.L. is a 72 yo Caucasian male with 15 year hx DMT2. Meds: glipizide 10 mg bid, precose 25 mg tid ac, simvastatin. FBG , tests BG only in the am. BP 143/63, 6 ft 1 in, 220 #, SCr 1.7, HDL 26, LDL 79, TG 182, TC 120. A1C 8.2%. He reports he often forgets to take the precose. Q: Which of the following is the most effective approach to improve TLs glycemic control?

largest meal Step 4 Add rapid insulin to last meal Insulin Injection sites Abdomen preferred site Rotate within Room temp storage of vial/pen Storage duration of vial/pen Delivery devices Syringe Pen

8 Case Study #2 a. Add metformin 1000 mg bid b. Switch precose to starlix 60 mg tid c. Decrease precose, add januvia 50 mg qd d. Add glargine 10 units at bedtime Case Study #3 J.R. is a 40 yo AAM, 20 yr hx DMT2. Patient currently taking Lantus 20 units HS, glimepiride 4 mg qam, metformin 1000 mg bid, atenolol, lisinopril, pravachol, asa 81 mg. SMBG FBG 180s, before dinner or HS up to 200s- 300s. Ht: 5 8, wt 177#. Review of diet indicates patient is not overeating. A1C 11.2, LDL 98, HDL 41, TG 144, TC 177. Q: Which of the following is the most effective approach to improve JRs glycemic control? Case Study #3 a. Increase glimepiride to 8 mg qd b. Add actos 30 mg qd c. Increase Lantus 1 unit daily until FBG less than d. Add apidra 3 units ac

SMBG FBG 180s, before dinner or HS up to 200s- 300s. Ht: 5 8, wt 177#. Review of diet indicates patient is not overeating. A1C 11.2, LDL 98, HDL 41, TG 144, TC 177.

Noninsulin Diabetes Medications Summary Chart Medications marked with an asterisk (*) can cause hypoglycemia MED GROUP DESCRIPTOR

Noninsulin Diabetes Medications Summary Chart Medications marked with an asterisk (*) can cause MED GROUP DESCRIPTOR INSULIN SECRETAGOGUES Sulfonylureas* GLYBURIDE* (Diabeta) (Micronase) MICRONIZED GLYBURIDE*