Medications Used in the Treatment of Diabetes Mellitus Kelly Green Boesen, Pharm D, BCPS, CDE

Type 1 DM Treatment Insulin! Best results is to mimic normal physiology as close as possible Long acting insulin, meal-time coverage with rapid acting insulin Insulin pump therapy Testing Type 1 DM Treatment

Type 2 DM Treatment First line therapy often metformin +/- sulfonylureas +/- TZD +/- DPP-4 inhibitor +/- GLP-1 agonist +/- basal insulin Addition of other agents based on response Combinations that are not optimal: Sulfonylureas and meglitinides (same basic mechanism of action) GLP-1 agonist and DPP-4 inhibitors (work on same pathway, GLP-1 agonists work better at this pathway) Sulfonylureas and rapid acting insulin Over 3 oral medications and not at goal Type 2 DM Treatment

Antihyperglycemic therapy in type 2 diabetes: general recommendations (15). Antihyperglycemic therapy in type 2 diabetes: general recommendations (15). The order in the chart was determined by historical availability and the route of administration, with injectables to the right; it is not meant to denote any specific preference. Potential sequences of antihyperglycemic therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. *See ref. 15 for description of efficacy categorization. †Consider starting at this stage when A1C is ≥9%. ‡Consider starting at this stage when blood glucose is ≥300–350 mg/dL (16.7–19.4 mmol/L) and/or A1C is ≥10–12%, especially if symptomatic or catabolic features are present, in which case basal insulin + mealtime insulin is the preferred initial regimen. §Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (15). American Diabetes Association Dia Care 2015;38:S41-S48 ©2015 by American Diabetes Association

Approach to starting and adjusting insulin in type 2 diabetes (15). Approach to starting and adjusting insulin in type 2 diabetes (15). FBG, fasting blood glucose; GLP-1-RA, GLP-1 receptor agonist; hypo, hypoglycemia; mod., moderate; PPG, postprandial glucose; #, number. Adapted with permission from Inzucchi et al. (15). American Diabetes Association Dia Care 2015;38:S41-S48 ©2015 by American Diabetes Association

Type 2 DM Treatment Insulin therapy usually added to oral medications Usually continue metformin to help with resistance Usually add basal insulin first If patients have high resistance, will see insulin dosing over 50 units/day No maximal dosing on insulin Insulin causes weight gain Many patients will need insulin therapy at some point Type 2 DM Treatment

Hypoglycemia Known to cause: Possibly when used with above: Insulin Sulfonylureas (Glipizide, Glyburide) Meglitinides (Nateglinide, Repaglinide) Possibly when used with above: DPP-4 inhibitors (Alogliptin, Linagliptin, Sitagliptin, Saxagliptin) GLP-1 Agonists (Exenatide, Liraglutide, Albiglutide) May be precipitated with taking medications and skipping meals Hypoglycemia

Insulin Principals Basal/bolus Combination of long acting/rapid acting insulin to achieve as close to normal physiology Insulin Principals

Insulin Principals

Rapid-Acting Insulin Lispro (Humalog) Aspart (Novolog) Glulisine (Apidra) Onset: 5-15 minutes Peak: 45-75 minutes Duration of effect: 2-4 hours Meal-time coverage, typically used in combination with long acting, sometimes used to reduce a high blood sugar outside of meal-times. Can be dosed 15 minutes prior to a meal or within 15 of eating a meal. Rapid-Acting Insulin

Short-Acting Regular (R) (Humulin R or Novolin R) Onset: 30 minutes-1 hour Peak: 2-4 hours Duration: 5-8 hours Meal-time coverage, typically used in combination with long acting, sometimes used to reduce a high blood sugar outside of meal-times. Dosed 30 minutes before a meal. Short-Acting

Intermediate-Acting NPH (N) (Humulin N, Novolin N, isophane) Onset: 2 hours Peak: 4-12 hours Duration: 18-28 hours Used to cover basal needs, often used in combination with short or rapid acting insulin Intermediate-Acting

Type of Insulin / Brand Name Onset Peak Duration Reason LONG-ACTING Insulin glargine (Lantus) 2 hours No peak 20-24 hr Covers basal insulin needs up to 24 hours, often used in combination with rapid acting insulin. Insulin detemir (Levemir) 3-9 hours Up to 24h Long-Acting

Pre-mixed (SA: short-acting, IA: intermediate-acting) Humulin 70/30 Novolin 70/30 Onset: SA: 30 minutes, IA: 2 hours Peak: SA: 2-4 hours, IA: 4-12 hours Duration: SA: 5-8 hours, IA: 18-28 hours 70% of the dose is NPH, 30% of the dose is regular Pre-mixed (SA: short-acting, IA: intermediate-acting)

Pre-mixed (SA: short-acting, IA: intermediate-acting) Novolog 70/30 Humalog 70/30 Onset: SA: 5-15 minutes, IA: 2 hours Peak: SA: 45-75 minutes, IA: 4-12 hours Duration: SA: 2-4 hours, IA: 18-28 hours 70% of the dose is intermediate acting, 30% of the dose is rapid acting Pre-mixed (SA: short-acting, IA: intermediate-acting)

Pre-mix Other combination products First number is intermediate acting, second is fast acting. Usually dosed twice daily prior to am and pm meal Humulin/Novolin products use regular as the fast-acting. Dosing occurs 30 minutes before the meal. Humalog/Novolog use a rapid-acting. Dosing occurs 5-15 minutes before meal. Pre-mix

Evaluating Insulin Efficacy Fasting glucose readings are reflective of basal insulin coverage Pre-lunch, Pre-dinner, Pre-bedtime readings reflect how well the previous meal-time was covered with short acting insulin 2-hour post prandial readings reflect meal-time coverage Evaluating Insulin Efficacy

Type 2: Other DM Medications Sulfonylureas Biguanides Meglitinides Thiazolidinediones (TZD) Dipeptidyl pepsidase-4 inhibitors (DPP-4 inhibitors) GLP-1 agonists Alpha-Glucosidase Inhibitors Sodium-Glucose Co-Transporter-2 (SGLT-2) Inhibitors Type 2: Other DM Medications

Sulfonylureas Glipizide (Glucotrol®), Glyburide (Micornase®) Increases insulin secretion from pancreatic beta cells, usually in response to food intake A1c reduction of 1-2% Some controversy over causing increased CV risk, acceleration of beta cell destruction First began using for treatment in the 1950’s Possible weight gain Sulfonylureas

Sulfonylureas Should see overall blood glucose numbers decreasing Full effect takes about 7 to 10 days to see When adding basal insulin, this is sort of like meal-time coverage Sulfonylureas

Biguanides Metformin (Glucophage®) Not a hypoglycemic agent Decreases hepatic gluconeogenesis Decreases intestinal absorption of glucose Improve insulin sensitivity in skeletal muscle Possible weight loss Should see overall lowering of blood glucose A1c reduction of 1-2% Biguanides

Biguanides Monitoring Periodic renal function Needs to be dose adjusted or stopped for renal impairment GI side effects are the most common, can be alleviated with slow titration Must be stopped for 48 hours after any scan if contrast given Biguanides

Meglitinides Nateglinide (Starlix®), Repaglinide (Prandin®) Short acting insulin secetragogues, stimulates insulin release from pancreatic beta cells Dosed 3 times a day with the meal Drug interactions Meal-time coverage A1c reduction of 0.5-1.5% Meglitinides

Thiazolidinediones (TZD) Pioglitazone (Actos®), Rosiglitazone (Avandia®) Not hypoglycemic Improved insulin sensitivity of muscles Cause fluid retention/swelling, contraindicated in heart failure Require LFT monitoring Not used as widely due to associated CV risk with May take weeks to months for full effect A1c reduction of 0.5-1.4% Thiazolidinediones (TZD)

Dipeptidyl pepsidase-4 inhibitors (DPP-4 inhibitors) Alogliptan (Nesina®), Linagliptin (Tradjenta®), Sitagliptan (Januvia®), Saxagliptin (Onglyza®) Slows inactivation of incretin hormone (GLP-1), increases insulin release and decreases glucagon secretion Results in lower circulating glucose Weight neutral A1c reduction 0.5-0.8% Dipeptidyl pepsidase-4 inhibitors (DPP-4 inhibitors)

Dipeptidyl pepsidase-4 inhibitors (DPP-4 inhibitors) Monitor renal function periodically Side effects include: Upper respiratory tract infections Arthralgias Dipeptidyl pepsidase-4 inhibitors (DPP-4 inhibitors)

Exenatide (Byetta®), Liraglutide (Victoza®), Albiglutide (Tanzeum®) Increased insulin production and release when glucose is elevated Slows gastric emptying Weight loss, reduced food intake Subcutaneous injection A1c reduction 0.5-1.5% GLP-1 agonists

GLP-1 agonists Warnings about pancreatitis Most common side effects are GI related, can be alleviated with slow titration GLP-1 agonists

Alpha-Glucosidase Inhibitors Acarbose (Precose®), Miglitol (Glyset®) Result in a reduction of carbohydrate absorption Reduces post-prandial blood glucose elevation Taken with each meal GI side effects Meal-time coverage A1c reduction 0.5-1.0% Alpha-Glucosidase Inhibitors

Sodium-Glucose Co-Transporter-2 (SGLT-2) Inhibitors Canagliflozin (Invokana®), Dapagliflozin (Farxiga®), Empagliflozin (Jardiance®) Blocks reabsorption of glucose in the kidneys to increase excretion through the urine UTI’s, yeast infections, hyperkalemia, DKA Possible weight loss A1c reduction 0.5-1.0% Sodium-Glucose Co-Transporter-2 (SGLT-2) Inhibitors

Other DM Treatment Daily aspirin therapy based on CV risk Treatment of HTN (use of ACEI/ARBs for renal protection) Treatment of Dyslipidemia Statins Fish oil Possibly gemfibrozil Neuropathy TCA’s (amitriptyline, nortriptyline) Gabapentin, Pregabalin (Lyrica®) Narcotics?? Vaccines (influenza, pneumococcal, Hepatitis B) Other DM Treatment