Effective Treatment of Type 2 Diabetes

Faculty Disclosures Effective Treatment of Type 2 Diabetes Mellitus Dr. Milligan disclosed no relevant financial relationships with any commercial interests. Steven Milligan, MD Diplomat, American Board of Family Practice Fellow, AAPP Southern Colorado Family Medicine Pueblo, Colorado Learning Objectives SORT Discuss weight reduction, increased physical activity, and lifestyle changes in the management of type 2 diabetes mellitus (DM) Discuss the use of oral agents including biguanides, sulfonylureas, glinides, thiazolidinediones, glucagon-like like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors Discuss less common agents such as amylin agonists, alpha glucosidase inhibitors, and dopamine agonists Discuss the use of insulin in patients with type 2 DM Level 1: good-quality, patient-oriented evidence Level 2: limited-quality, patient-oriented evidence Level 3: other evidence such as consensus guidelines, extrapolations from bench research, usual practice, opinion, disease-oriented evidence (intermediate or physiologic outcomes only), or case series for studies of diagnosis, treatment, prevention, or screening SORT = Strength of Recommendation Taxonomy. Intensive Lifestyle Intervention Look AHEAD Study: 4-Year Results Diet modification/exercise/behavioral training Group support with in-person and telephone follow-ups Parameter Intensive Lifestyle Intervention (n = 2570) Support and Education (n = 2575) Weight loss (%) -6.5 65-0.88 088* Treadmill fitness (%) METS 12.74 1.96* HbA1c (%) -0.36-0.09* Systolic BP (mm Hg) -5.33-2.97* Diastolic BP (mm Hg) -2.92-2.48 HDL-C (mg/dl) 3.67 1.97* TGs (mg/dl) -25.56-19.75 *P<.0001; P =.012; P =.0006. Look AHEAD = Action for Health in Diabetes; METS = metabolic equivalents of task; HbA1c = hemoglobin A1c. BP = blood pressure; HDL-C = high-density lipoprotein cholesterol; TGs = triglycerides. Look AHEAD Research Group. Arch Intern Med. 2010;170(17):1566-1575. General Recommendations for Antihyperglycemic Therapy in Type 2 DM Healthy eating, weight control, increased physical activity Initial Drug Monotherapy Metformin Efficacy ( HbA1c) High Hypoglycemia risk Low Weight Neutral/loss AEs GI/lactic acidosis Costs Low Proceed to 2-drug combination if target HbA1c is not met after 3 months AEs = adverse effects; GI = gastrointestinal. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. Epub 2012 Apr 19. 1

General Recommendations for Antihyperglycemic Therapy in Type 2 DM* (continued) General Recommendations for Antihyperglycemic Therapy in Type 2 DM* (continued) 2-Drug Combination Efficacy ( HbA1c) High Metformin plus TZD High DPP-4 Inhibitor GLP-1 Receptor Agonist High Insulin (usually basal) Highest Hypoglycemia risk Moderate Low Low Low High Weight Gain Gain Neutral Loss Gain AEs Edema, HF Rare GI Sulfonylurea Intermediate Hypoglyemia Hypoglycemia Costs Low High High High Variable Proceed to 3-drug combination if target HbA1c is not met after 3 months *Order not meant to denote any specific preference. TZD = thiazolidinedione. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. Epub 2012 Apr 19. Metformin plus GLP-1 Receptor Agonist Insulin (usually basal) Sulfonylurea TZD DPP-4 Inhibitor plus plus plus plus plus TZD Sulfonylurea Sulfonylurea Sulfonylurea TZD or or or or or DPP-4 DPP-4 TZD TZD DPP-4 or or or or or GLP-1 GLP-1 Insulin Insulin GLP-1 or or Insulin Insulin Proceed to a more complex insulin strategy if combination therapy that includes basal insulin fails to achieve HbA1c target after 3-6 months *Order not meant to denote any specific preference. Inzucchi SE, et al. Diabetes Care. 2012;35(6):1364-1379. Epub 2012 Apr 19. Oral Hypoglycemics Biguanides:. Advantages Metformin Most available oral antidiabetic agents appear similarly effective for glycemic control (Level of Evidence 3) Limited evidence for clinical outcomes except for possible increased risk of CHF with glitazones Pioglitazone and metformin each associated with reduced CV morbidity in single trials (Level of Evidence 2) Insufficient evidence to support any conclusions about differences among oral medications in all-cause mortality, peripheral vascular disease, quality of life, and functional status Main advantages include no weight gain or hypoglycemia In the UKPDS, overweight patients randomized to metformin experienced improved macrovascular outcomes as well Associated with about 1% absolute reduction in HbA1c when used as monotherapy (Level 3 Metformin is the only anti-hyperglycemic i drug shown to reduce MI rates in monotherapy patients Adding metformin to a sulfonuylurea is associated with less weight gain than pioglitazone (Level 2 with similar or better glycemic control (Level 3 Extended-release metformin is as effective as immediate-release metformin for glycemic control (Level 3 CV = cardiovascular. UKPDS = UK Prospective Diabetes Stud y; MI = myocardial infarction. Biguanides: Disadvantages Metformin Many patients experience GI adverse effects, especially diarrhea Metformin efficacy for glycemic outcomes may not persist after 6-9 years (Level 3 Contraindicated if creatinine >1.5 mg/dl in men or >1.4 mg/dl in women due to increased risk of lactic acidosis (rare) Should not be prescribed in those with renal disease, liver failure, advanced CHF, metabolic acidosis, hemodynamic imbalance, or those undergoing radiology procedures with contrast Use of metformin in patients with HF is controversial Prescribing information lists HF requiring drug therapy as a contraindication (Grade C Recommendation) secondary to lack of evidence of safety rather than established harms In patients with HF and DM, metformin may be the only antidiabetic agent not associated with harm (Level 2 HF = heart failure. Sulfonylureas: Advantages Glyburide, Glipizide, Glimepiride Increase insulin secretion by the beta cell Therefore glucose no longer controls insulin output, which explains the main AE of the sulfonylureas, namely, hypoglycemia Moderately effective, with a HbA1c lowering potential of 1%-2%; also one of the least expensive options In the UKPDS, sulfonylureas were shown to reduce microvascular end points Initial doses of preferred agents include: Glimepiride 1-2 mg QD PO Glipizide 5 mg QD PO QD = once daily; PO = by mouth. 2

Sulfonylureas: Disadvantages Glyburide, Glipizide, Glimepiride Glinides: Advantages Repaglinide, Nateglinide Main disadvantages include hypoglycemia and weight gain Insulin levels rise with sulfonylurea therapy Hyperinsulinemia has been associated with increased CV risk, although there is no evidence that sulfonylureas increase such risk Ischemic preconditioning is the self-protective mechanism of cardiomyocytes to conserve metabolic demands during ischemia by opening potassium channels Sulfonylureas may impair this action, although the actual clinical importance of this potential effect is not known Cautions Glyburide may have a dose-response relationship with mortality (Level 2 Drug allergy risk may be associated with sulfa allergy (Level 2 Glyburide is associated with increased risk for hypoglycemia compared with other sulfonylureas (Level 2 American Diabetes Association. Diabetes Care. 2012; 35(Suppl 1):S11-S63. Nonsulfonylurea insulin secretagogues that share similar effects with traditional sulfonylureas Much quicker onset and shorter duration of action than sulfonylureas Insulin secretion is stimulated only after medication ingestion, to coincide with meals, with less risk of hypoglycemia and possibly less weight gain Glinides reduce HbA1c levels (Level 3 Repaglinide may cause fewer symptomatic hypoglycemic episodes than sulfonylureas in elderly patients (Level 2 Glinide analogs Repaglinide 0.5-2 mg within 15 minutes before meals 2-4 times daily (usual dose 1 mg) Nateglinide120 mg 1-30 minutes before meals 3 times daily Repaglinide and nateglinide are equally effective for most glucose homeostasis outcomes, but repaglinide may have greater HbA1c lowering than nateglinide (Level 3 Glinides: Disadvantages Repaglinide, Nateglinide TZDs: Advantages Pioglitazone, Rosiglitazaone More expensive with more frequent dosing Safety and efficacy in children younger than 18 years of age not established Pregnancy Category C Multiple potential drug interactions Avoid combination of repaglinide plus gemfibrozil TZDs are insulin sensitizers that augment insulin action in muscle and somewhat in the liver Pioglitazone and rosiglitazone are FDA approved for monotherapy or in combination with metformin, sulfonylureas, repaglinide, or insulin Associated with 1%-1.25% decrease in HbA1c levels (Level 3 Effectiveas add-on therapy to reduce HbA1c, but little evidence to support increased efficacy compared with other drugs as monotherapy (Level 3 Pioglitazone not clearly shown to improve clinically relevant outcomes, but may reduce risk of MI and stroke (Level 2 TZDs include: Pioglitazone: usual dose 15-30 mg/day, with maximum of 45 mg/day (30 mg/day if in combination with other diabetic medications) Rosiglitazone: withdrawn in Europe and use restricted in United States TZDs = thiazolidinediones; FDA = US Food and Drug Administration. TZDs: Disadvantages Pioglitazone, Rosiglitazaone GLP-1 Receptor Agonists: Advantages Exenatide, Liraglutide, Bydureon Major concerns remain regarding weight gain and edema, the latter likely due to renal effect on increase sodium reabsorption Boxed warning includes risk of HF with TZDs (Level 2 Effect on CV risk is a highly controversial topic Pioglitazone may reduce risk of MI and stroke (Level 2 Rosiglitazone may be associated with increased risk of myocardial ischemic events (Level 2 and is not recommended (Grade B Recommendation) Possibly associated with increased risk for fractures (Level 2 Liver function tests recommended before starting, then periodically; discontinue if ALT persistently >3 times upper limit of normal There is ongoing research by the FDA regarding the possible association between pioglitazone use and bladder cancer; currently the FDA does not recommend any changes ALT = alanine aminotransferase. Simpson SH, et al. CMAJ. 2006. 17;174(2):169-174. May improve glycemic control (Level 3 Mean reductions in HbA1c from 0.47%-1.56% Associated with increased weight loss in overweight or obese patients with type 2 diabetes (Level 2 Associated with significantly greater weight loss (mean difference -6.2 lbs) in analysis of 18 trials of adults with type 2 diabetes Also associated with significantly greater improvement in BP, plasma concentrations of cholesterol, and glycemic control 3 formulations are available Exenatide injected BID Liraglutide injected QD Extended-release exenatide that is injected once weekly (Approved 2/2012) BID = twice daily. Shyangdan DS, et al. Cochrane Database Syst Rev. 2011; (10):CD006423. Vilsbøll T, et al. BMJ. 2012;344:d7771. US Food and Drug Administration. FDA MedWatch. http://www.fda.gov/safety/ MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm258826.htm. Accessed June 19, 2012. 3

GLP-1 Receptor Agonists: Disadvantages Exenatide, Liraglutide DPP-4 Inhibitors: Advantages Sitagliptin, Saxagliptin, Linagliptin Associated with GI adverse effects (Level 2 Liraglutide Boxed Warning regarding risk of thyroid C-cell tumors Found to cause thyroid C-cell tumors in rodents at clinically relevant exposures Contraindicated in patients with personal or family history of medullary thyroid carcinoma or MEN 2 Associated with possible increased risk of pancreatitis Exenatide Adverse effects include hypoglycemia when added to sulfonylurea (but not when added to metformin), nausea, vomiting, diarrhea Acute pancreatitis has been reported in 36 cases Avoid exenatide if creatinine clearance <30 ml/minute MEN 2 = multiple endocrine neoplasia syndrome type 2. Shyangdan DS, et al. Cochrane Database Syst Rev. 2011; (10):CD006423. US Food and Drug Administration. FDA MedWatch. http://www.fda.gov/safety/medwatch/safetyinformation/ SafetyAlertsforHumanMedicalProducts/ucm258826.htm. Accessed June 19, 2012. Newer drug class for managing patients with type 2 DM Although no effect has been demonstrated on gastric emptying or on satiety, these agents augment insulin output and decrease glucagon secretion Weight neutral Effect on HbA1c is modest (0.5%-1%), although when compared with other agents they fare reasonably well Adverse effects appear to be few with the DPP-4 inhibitors No hypoglycemia Possible beta-cell preservation (theoretical) Aschner P, et al. Diabetes Care.2006;(29):2632-2637. Horie Y, et al. Trials. 2009;10:82. Drucker D, et al. Diabetes Care. 2007;30(6):1335-1343. Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):s1- s53. Nathan DM, et al. Diabetes Care. 2009;32(1):193-203. Kendall D, et al. Am J Med. 2009;122(6A):s37-s50. Rosenstock J, et al. Diabetes Obes Metab. 2008;10:376-386. Vella A, et al. Diabetes. 2007;56:1475-1480. DPP-4 Inhibitors: Disadvantages Sitagliptin, Saxagliptin, Linagliptin Alpha-Glucosidase Inhibitor: Advantages Acarbose, Miglitol Costly compared with other therapies URI symptoms Urticaria URI = upper respiratory infection. Aschner P, et al. Diabetes Care.2006;(29):2632-2637. Horie Y, et al. Trials. 2009;10:82. Drucker D, et al. Diabetes Care. 2007;30(6):1335-1343. Handelsman Y, et al. Endocr Pract. 2011;17(Suppl 2):s1- s53. Nathan DM, et al. Diabetes Care. 2009;32(1):193-203. Kendall D, et al. Am J Med. 2009;122(6A):s37-s50. Rosenstock J, et al. Diabetes Obes Metab. 2008;10:376-386. Vella A, et al. Diabetes. 2007;56:1475-1480. Inhibit alpha-glucosidase enzymes in intestinal brush-border and pancreatic alpha-amylase Delays postprandial glucose absorption, and as a result, carbohydrate absorption is slowed and postprandial glucose spikes are attenuated Acarbose and miglitol are FDA approved as adjunct to diet to improve glycemic control in patients with type 2 DM Initial dose 25 mg 3 times daily at beginning of each main meal May increase dose at 4-8 week intervals to 50-100 mg 3 times daily Reported to improve glycemic control and insulin levels, but no significant effect on lipids or body weight, and unknown effect on morbidity and mortality (Level 3 Low risk of hypoglycemia Alpha-Glucosidase Inhibitor: Disdvantages Acarbose, Miglitol Dopamine-2 Agonists: Advantages Bromocriptine GI adverse effects specifically flatulence, diarrhea, and abdominal discomfort has limited the widespread use of these agents in the United States They remain more popular in Japan and Germany Frequent dosing required Reduction in HbA1c is small (0.5%-0.8%) Contraindicated if diabetic ketoacidosis, intestinal disease, or (for acarbose) cirrhosis Drug interactions may occur with pramlintide (contraindicated), digoxin, digestive enzyme supplements, intestinal adsorbents, ranitidine, and propranolol HandelsmanY, et al. Endocr Pract. 2011;17(Suppl 2):s1-s53. Nathan DM, et al. Diabetes Care. 2009; 32:196. Van de Laar F, et al. Diabetes Care. 2005;28:166-175. Bromocriptine FDA approved in 2009 for type 2 DM Initial dose 0.8 mg within 2 hours after waking in morning with food Increase by 0.8 mg weekly to maximum tolerated dose up to 4.8 mg/day Efficacy May reduce incidence of CV disease (Level 2 As monotherapy has minimal effect on: HbA1c (0.6%-0.7%) (Level 3 Fasting plasma glucose (Level 3 Weight (Level 2 Addition of bromocriptine to sulfonylurea may reduce HbA1c and fasting plasma glucose (Level 3 but may increase weight (Level 2 4

Dopamine-2 Agonists: Disadvantages Bromocriptine Contraindications are uncontrolled hypertension, syncopal migraines, and sensitivity to ergot alkaloids Pregnancy Category B, but can also interfere with lactation Serious adverse effects include Sudden episodes of falling asleep Symptomatic hypotension (initially) and hypertension (week 2) Seizures and stroke Pleural and pericardial effusions, pleural and pulmonary fibrosis (high-dose, long-term therapy) Confusion and psychosis Multiple potential drug interactions Dodd ML, et al. Arch Neurol. 2005;62(9):1377-1381. DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995. Record No. 238040 Bromocriptine. http://search.ebscohost.com/login.aspx?direct= true&site=dynamed&id=116678. Accessed July 1, 2012. Amylin Agonists Pramlintide Newer injectable agent An analogue of the beta-cell peptide, amylin Effects include the suppression of glucagon, slowing of gastric emptying, and increased satiety Pramlintide Administered 3 times daily Mainly used in patients with type 1 DM on intensive insulin regimens who are not able to achieve adequate glucose control Approved for similarly treated patients with type 2 DM, but rarely used Bile Acid Sequestrants Colesevelam Insulin Colesevelam has been available to treat hyperlipidemia for years Colesevelam hydrochloride reduces glucose and lipid levels in uncontrolled type 2 DM (Level 3 Colesevelam hydrochloride reduced: Mean HbA1c by 0.54% (P<.001) Mean fasting plasma glucose by 13.9 mg/dl (P=.01) Total cholesterol by 7.2% (P<.001) LDL-C by 15.9% (P<.001) Non-HDL-C by 10.3% (P<.001) No significant differences in TGs or HDL-C Colesevelam may improve glycemic control (reducing HbA1c by about 0.5%) in patients with inadequately controlled diabetes (Level 3 Colesevelam vs placebo at 16 weeks Mean change in HbA1c -0.41% vs 0.09% (P<.001) Mean change in LDL-C -12.3% vs 0.5% (P<.001) Median change in TGs 22.7% vs 0.3% (P<.001) LDL-C = low-density lipoprotein cholesterol. Bays HE, et al. Arch Intern Med. 2008;168(18):1975-1983. Goldberg RB, et al. Arch Intern Med. 2008;168(14):1531-1540. Many different formulations are available Short acting/rapid acting: bolus insulin (regular, aspart, lispro, glulisine) Intermediate acting: NPH Long acting: basal insulin (glargine, detemir) Premixed (eg, 70/30 or 75/25) The optimal regimen for each patient may be different and should be based on his/her needs and capacities Generally, the earlier in the disease course, the less aggressive the regimen needs to be In late-stage patients, intensive regimens as might be used in patients with type 1 DM may be required, since significant insulin deficiency has occurred There are many barriers to insulin therapy Patients often fear injections and insulin therapy is also viewed as more complex by both patients and clinicians The main disadvantages include weight gain and hypoglycemia NPH = neutral protamine Hagedorn. DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995. Record No. 115979 Glucose lowering medications for type 2 diabetes; [updated 2012 Mar 21] http://search.ebscohost.com/login.aspx?direct =true&site=dynamed&id=115979. Accessed July 1, 2012. Insulin as Initial Therapy Insulin as Initial Therapy for Type 2 DM Insulin therapy is effective and well tolerated in patients with newly diagnosed type 2 DM (Level 2 No significant difference between treatments in hypoglycemic events, compliance, HbA1c, weight gain, or quality of life All patients in insulin group reported willingness to continue insulin therapy Lingvay I, et al. Diabetes Care. 2009;32(10):1789-1795. Outcome CSII MDI Oral Agents Patients reaching glycemic target (%) 97.1 95.2 83.5 Mean time to glycemic target (days) 4 5.6 9.3 Glycemic remission at 1 year (%) 51.1 44.9 26.7 Glycemic remission at 1 year in ITT* (%) 49.6 42.7 22.3 Glycemic remission at 1 year (%) 49.6 42.7 38.8 Intensive insulin therapy for 2-3 weeks in patients with newly diagnosed type 2 DM may support glycemic remission for 1 year (Level 3 CSII group: Initial dose 0.4-0.5 units/kg/day, given as 50% basal/50% bolus MDI group: Premix 70/30 3 times daily; human insulin NPH at bedtime Oral hypoglycemic agents group had initial strategy based on body mass index: Combination of gliclazide and metformin used if glycemic target not reached with single oral hypoglycemic agent or if fasting plasma glucose 11.1 mmol/l (200 mg/dl) at baseline *ITT analysis assuming all dropouts failed to achieve glycemic remission. Worst-case ITT analysis assumes insulin dropouts failed but oral agent dropouts reached glycemic remission. CSII = continuous subcutaneous insulin infusion; MDI = multiple daily insulin injections; ITT = intention to treat. Weng J, et al. Lancet. 2008;371(9626):1753-1760. 5

Insulin Add-On for Suboptimal Control Regular Insulins Insulin alone (in 2 or more daily doses) is at least as effective as combination of insulin plus oral hypoglycemic agents for glycemic control (Level 3 Combination i of insulin and sulfonylurea l may improve glycemic control and lower insulin dose compared with insulin alone (Level 3 Regular insulin available over-the-counter Human recombinant Recombinant DNA origin Timing of effect Onset 30-60 minutes Peak 1.5-2 hours Duration 5-12 hours Short-Acting Insulin Continuous Short-Acting Insulin Insulin aspart Insulin lispro Insulin glulisine Addition of short-acting insulin may reduce HbA1c in patients with inadequately controlled type 2 DM (Level 3 There is increased risk of hypoglycemia and weight gain (Level 2 Short-acting insulin analogs might reduce number of hypoglycemic episodes compared with regular human insulin in most patients with DM (Level 2 Short-acting insulin analogs reduced HbA1c by 0.1% in patients with type 1 DM, no difference in patients with type 2 DM Short-acting insulin analogs reduced overall mean hypoglycemic episodes per patient-month by 0.2 in patients with both type 1 and type 2 DM (not statistically significant) Siebenhofer A, et al. Cochrane Database Syst Rev. 2006 Apr 19;(2):CD003287. Mixed data on continuous SC lispro infusions May be no more effective than multiple daily insulin injections for glycemic control (Level 2 50 patients with type 1 DM randomized to continuous SC insulin lispro infusion vs basal QD insulin glargine plus mealtime insulin lispro and followed for 24 weeks No significant differences between treatments in number of hypoglycemic events, mean HbA1c, fasting blood glucose, and self-monitored plasma glucose levels Associated with greater glycemic control and reduced hypoglycemia compared with multiple daily insulin injections (Level 2 39 patients with controlled type 1 DM were randomized to continuous SC insulin lispro infusion vs multiple daily injections with insulin lispro and insulin glargine for 4 months Continuous SC insulin infusion associated with lower blood glucose levels, fewer hyperglycemic episodes, and greater patient satisfaction Bolli GB, et al. Diabetes Care. 2009;32(7):1170-1176. Bruttomesso D, et al. Diabet Med. 2008;25(3):326-332. Intermediate-Acting Insulins Long-Acting Insulin Insulin isophane suspension (NPH), available overthe-counter Human recombinant Recombinant DNA origin Timing of effect Onset 1-2 hours Peak 4-8 hours Duration 10-20 hours Insulin detemir: Onset 1 hour, no peak, duration 20 hour Insulin glargine: Onset 1-2 hours, no peak, duration 24 hours Long-acting insulin may be slightly more effective than oral agent as add-on therapy for reduction of HbA1c and fasting plasma glucose levels, but may increase rate of hypoglycemic events (Level 3 Insulin glargine might be associated with better quality of life (Level 2 Long-acting insulin analogs appear to have similar effects on HbA1c but it is unclear if possible reductions in severe hypoglycemia warrant increased costs (Grade C Recommendation) Glargine and detemir may have less symptomatic and nocturnal hypoglycemia than NPH insulin or insulin lispro (Level 2 No differences in HbA1c levels (Level 3 6

Which Insulin Do I Use? Dosing Regimens for Type 2 DM Type 2 DM Treatment of choice: NPH insulin BID Second choice: glargine at night or detemir BID, continue oral hypoglycemic agent and add premeal insulin, as needed Alternative: premixed insulin before breakfast and dinner Selecting insulin therapy based on individual blood glucose profiles Patients with fasting hyperglycemia and daytime euglycemia Treatment of choice: NPH or detemir insulin at night Second choice: short-acting insulin at dinner if bedtime blood glucose > 40 mg/dl (>7.7 mmol/l), based on expert opinion Patients with postprandial hyperglycemia and fasting euglycemia with type 2 DM and partial failure of oral hypoglycemia agents, end-stage liver disease, or end-stage kidney disease Treatment of choice: NPH or detemir insulin in morning Second choice: rapid- or short-acting insulin before 1 or more meals, based on expert opinion Special populations Older frail persons with type 2 DM (Grade C Recommendation) Treatment of choice: glargine in morning Second choice: NPH or detemir insulin BID DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995. Record No. 116678 Titration of Insulin Dose; [updated 2012 Mar 21]. http://search.ebscohost.com/ login.aspx?direct=true&site=dynamed&id=116678. Registration and login required. Accessed July 1, 2012. Intermediate- or long-acting insulin may be sufficient for patients with type 2 DM Initial dose of 10-15 units at bedtime, with dose adjusted in 3- day intervals Increase 1-2 units for every 20 mg/dl of fasting blood glucose over 100 mg/dl Preprandial supplemental rapid-acting insulin often needed Initial dose 5-10 units according to individual sensitivities and amount of carbohydrates ingested Further adjustments made on the basis of the individual s response DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995. Record No. 116678 Titration of Insulin Dose; [updated 2012 Mar 21]. http://search.ebscohost.com/login.aspx?direct= true&site=dynamed&id=116678. Accessed July 1, 2012. Dosing Regimens for Type 2 DM (continued) Alternative protocol estimates insulin requirement at 0.6 units/kg/day 1/2 dose given as basal insulin 1/6 dose given as initial pre-prandial rapid acting insulin Dosage adjusted by: Calculating "insulin-to-carbohydrate" ratio (total preprandial rapid-acting insulin dose/day divided by total carbohydrate intake/day) and adjusting for change in carbohydrate intake Supplemental insulin dose ("correction factor") added to correct for preprandial blood glucose levels Correction factor estimates insulin sensitivity (expected decrease in blood glucose level [in mg/dl] in response to 1 unit of insulin) DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995. Record No. 116678 Titration of Insulin Dose; [updated 2012 Mar 21]. http://search.ebscohost.com/login.aspx?direct=true&site=dynamed&id =116678. Accessed July 1, 2012. Support for Patients Starting Insulin Therapy Initiating insulin therapy in groups appears as effective as individual initiation Comparing group vs individual initiation (INITIATE Trial) Mean HbA1c 8.8% vs 8.7% at baseline Mean HbA1c 6.8% vs 6.9% at 24 weeks (not significant) Mean insulin dose 56 vs 62 units at 24 weeks (not significant) Mean total time spent initiating patients 2.2 vs. 4.2 hours No significant differences in rates of hypoglycemia or treatment satisfaction Weekly contact associated with modest improvement in glycemic control in patients with type 2 DM starting insulin glargine (Level 3 HbA1c levels at 24 weeks decreased by 1.5% with active insulin titration vs by 1.3% with usual insulin titration 38% active vs 30% usual titration patients had HbA1c levels < 7% (NNT 9) Active insulin titration associated with higher rates of hypoglycemia (6 vs 3.7 confirmed episodes per patient-year, NNH 5.2) NNT = number needed to treat; NNH = number needed to harm. Yki-Järvinen H, et al. Diabetes Care. 2007;30(6):1364-1369. Bergenstal RM, et al. Diabetes Care. 2008;31(7):1305-1310. How to Modify Insulin Regimens Titration Schedule for Basal Insulin Carbohydrate count-based and simple algorithm-based insulin dose adjustments associated with similar glycemic control in patients with type 2 DM (Level 3 No differences in HgbA1c changes or levels but the carbohydrate count group had lower daily mean gluisine dose and trend toward less weight gain Fasting plasma glucose titration target of 70-90 mg/dl may be associated with greater frequency of achieving HbA1c <7% than 80-110 mg/dl target (Level 3 Fasting plasma glucose titration targets for adjustment of basal insulin QD Achievement of HbA1c levels <7% in 64.3% vs 54.5% (NNT 11) Mean decrease from baseline in HbA1c levels -1.2% vs -0.9% Blonde L, et al. Diabetes Obes Metab. 2009;11(6):623-631. Umpierrez GR, et al. Diabetes Care. 2007;30(9):2181-2186. Based on fasting blood glucose levels for 3 consecutive days >180 mg/dl ( 9.9 mmol/l): increase basal insulin by 8 units 160-180 mg/dl (8.8-9.9 mmol/l): increase basal insulin by 6 units 140-159 mg/dl (7.7-8.75 mmol/l): increase basal insulin by 4 units 120-139 mg/dl (6.6-7.65 mmol/l): increase basal insulin by 2 units 100-119 mg/dl (5.5-6.65 mmol/l): increase basal insulin by 1 unit 80-99 mg/dl (4.4-5.45 mmol/l): maintain current dose 60-79 mg/dl (3.3-4.34 mmol/l): decrease basal insulin by 2 units <60 mg/dl (<3.3 mmol/l): decrease basal insulin by 2 units DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995. Record No. 116678 Titration of Insulin Dose; [updated 2012 Mar 21]. http://search.ebscohost.com/ login.aspx?direct=true&site=dynamed&id=116678. Accessed July 1, 2012. 7

Titration Schedule for Preprandial Insulin Titration Schedule for Premixed Insulins Based on fasting blood glucose levels for 3 consecutive days >180 mg/dl ( 9.9 mmol/l): increase rapid-acting insulin by 3 units/injection 160-180 mg/dl (8.8-9.9 mmol/l): increase rapid-acting insulin by 2 units/injection 140-159 mg/dl (7.7-8.75 mmol/l): increase rapid-acting insulin by 2 units/injection 120-139 mg/dl (6.6-7.65 mmol/l): increase rapid-acting insulin by 1 unit/injection 100-119 mg/dl (5.5-6.65 mmol/l): maintain current dose 80-99 mg/dl (4.4-5.45 mmol/l): decrease rapid-acting insulin by 1 unit/injection 60-79 mg/dl (3.3-4.34 mmol/l): decrease rapid-acting insulin by 2 units/injection <60 mg/dl (<3.3 mmol/l): decrease rapid-acting insulin by 4 units/injection DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995 -.Record No. 116678 Titration of Insulin Dose; [updated 2012 Mar 21]. http://search.ebscohost.com/login.aspx?direct=true&site=dynamed&id =116678. Accessed July 1, 2012. Based on fasting blood glucose levels for 3 consecutive days >180 mg/dl (>9.9 mmol/l): increase predinner insulin dose by 6 units 141-180 mg/dl (7.76-9.9 mmol/l): increase predinner insulin dose by 4 units 111-140 mg/dl (6.11-7.7 mmol/l): increase predinner insulin dose by 2 units 80-110 mg/dl (4.4-6.05 mmol/l): maintain current dose 60-79 mg/dl (3.3-4.35 mmol/l): decrease predinner insulin dose by 2 units < 60 mg/dl (< 3.3 mmol/l): decrease predinner insulin dose by 4 units Based on predinner glucose levels for 3 consecutive days >180 mg/dl (>9.9 mmol/l): increase prebreakfast ininsulinsulin dose by 6 units 141-180 mg/dl (7.76-9.9 mmol/l): increase prebreakfast insulin dose by 4 units 111-140 mg/dl (6.11-7.7 mmol/l): increase prebreakfast insulin dose by 2 units 80-110 mg/dl (4.4-6.05 mmol/l): maintain current dose 60-79 mg/dl (3.3-4.35 mmol/l): decrease prebreakfast insulin dose by 2 units <60 mg/dl (<3.3 mmol/l): decrease prebreakfast insulin dose by 4 units DynaMed [Internet]. Ipswich (MA): EBSCO Publishing. 1995. Record No. 116678 Titration of Insulin Dose; [updated 2012 Mar 21]. http://search.ebscohost.com/login.aspx?direct=true&site=dynamed&id =116678. Accessed July 1, 2012. Insulin Use in Hospitals Insulin Use in Hospitals (continued) Basal-bolus of glargine and glulisine associated with improved glycemic control compared with SSI regimen during hospital stay in patients with type 2 DM admitted on oral medications or low-dose insulin (Level e 3 Comparing basal-bolus vs SSI (RABBIT 2 Trial) Blood glucose target <140 mg/dl reached in 66% vs 38% (NNT 4) Mean daily glucose during hospital stay 166 mg/dl vs 193 mg/dl No significant difference in hypoglycemic events Patients with SSI who maintained blood glucose >240 mg/dl had significant improvement in glycemic control after switching to basal-bolus regimen (P<.05) SSI = sliding scale insulin. Umpierrez GR, et al. Diabetes Care. 2007;30(9):2181-2186. In patients with type 2 DM hospitalized for general surgery on oral medications or low-dose insulin ( 0.4 units/kg) randomized to basal-bolus regimen vs SSI Comparing basal-bolus vs SSI (RABBIT 2 Surgery Trial) Mean daily glucose during hospital stay 157 mg/dl vs 176 mg/dl Post-surgical complications in 8.6% vs 24% (NNT 7) Post-surgical wound infections in 3% vs 10% (NNT 15) Length of stay in intensive care 1.23 days vs 3.19 days Hypoglycemia (<70 mg/dl) in 23.1% vs 4.7% (NNH 5) Severe hypoglycemia (<40 mg/dl) in 3.8% vs 0 (NNH 26) Umpierrez GR, et al. Diabetes Care. 2011;34(2):256-261. SSI Use in Hospitals Sliding scale and usual regimens did not have significant differences in randomized trial No differences in rates of: Any glycemic events (35.9% vs 36%) Hyperglycemia (34.6% vs 33.3%) Hypoglycemia (9% vs 8%) Significant differences in mean length of hospitalization (5.4 vs 4.2 days) Dickerson LM, et al. Ann Fam Med. 2003;1(1):29-35. 8