Natural History of Type 2 Diabetes

Transcription

1 Key Points About Insulin to Discuss Today We should be using insulin earlier in the natural history of type 2 diabetes How early and how do we know when to start insulin? Barriers to insulin therapy Goals of therapy: Definitions and individualization Different insulin formulations, their characteristics and uses Initiating and advancing insulin therapy: Strategies that work Natural History of Type 2 Diabetes Severity of Glucose Intolerance NGT IGT Frank Diabetes Risk of Macrovascular Complications Insulin Resistance Risk of Microvascular Complications Insulin Secretion Postprandial Glucose Normal Blood Glucose Worsens with Time 1 Years to Decades Typical Diagnosis of Diabetes Advancing Therapies With Stages of T2DM ADA/EASD 216 General Recommendations Beta-Cell Function (%, HOMA) HOMA = homeostasis model assessment. Based on data from UKPDS 16. Diabetes. 1995;4(11): Metformin and Lifestyle Combination Therapy (orals and injectables) Insulin Intensive or in Combination 2 Type 2 Type 2 Diabetes Diabetes Phase I Phase II Phase III Years From Diagnosis Criteria for Advancing to the Next Stage? HbA1c Level Not at Target 3 If HbA1c goal not reached after 3 months triple therapy: Adapted from ADA. On oral therapy: move to injectables Diabetes On GLP-1 RA: add basal insulin Care. On optimal basal insulin: add GLP-1 RA or mealtime insulin 216;39(1):S1 Refractory: consider adding TZD or SGLT2 inhibitor -S111. Individualizing HbA1c Targets for People with T2DM Implications of DCCT, UKPDS, ACCORD, ADVANCE on Glycemic Control Intensive glycemic control microvascular risk Role in reducing macrovascular risk is less clear HbA1c % doesn t mortality per se, but HbA1c doesn t tell the whole story Variations in glycation HbA1c doesn t tell you about patterns Hypoglycemia can create life-threatening risks Severe hypoglycemia can occur in people with higher HbA1c levels Treatments with lower risk of hypoglycemia can have significant advantages ADA. Diabetes Care. 216;39(1):S1-S111. Adapted from Garber, et al. Am J Med. 213;126:

2 Prevalent Racial/Ethnic Differences Related to Diabetes Medications Caucasian (n=23) If my doctor told me that I would benefit from taking more medications, I would be willing to take more If my doctor asked me to change my medication regimen, it would make me worry more about my health I worry about the expense of my medications or glucose-monitoring supplies I worry about becoming dependent on my medications I worry about side effects from my medications Huang ES et al. Diabetes Care. 29;32: African American (n=279) } P=.8 Latino (n=167) } } } } P< Patients responding affirmatively (%) P<.1 P<.1 P<.1 Patient Barriers to Insulin Initiation Barriers Sense of failure Insulin causes complications Loss of independence Perception of Insulin Ineffectiveness Addressing the Barriers Need for insulin due to β-cell dysfunction is inevitable Discuss the eventual use of insulin with patients early Do not use insulin as threat, but as solution Acknowledge the patient s fear Provide information about the provider s experiences of the effectiveness and safety of insulin Empower patient to take control of BG Provide self-management education on monitoring and selfadjustment Use insulin pens & insulin regimens to maximize flexibility Give limited trial with appropriate insulin doses Monitor for symptom improvement Patient to monitor for improved glucose at time of primary insulin effect (e.g. AM for basal insulin; postprandial) Adapted from Funnell MM. Clinical Diabetes. 27;25(1): Peyrot M, et al. Primary Care Diabetes. 21;4(Suppl 1):S11-S18. Patient Barriers to Insulin Initiation Barriers Fear of injections Fear of hypoglycemia Weight gain Cost Addressing the Barriers Insulin needles are very small; Use 4-mm 32-G needles Less painful than finger sticks for BG testing Insulin pen is usually less intimidating Have patient give a saline injection in office Educate: with basal (esp. analog) insulin, low incidence Teach patient to recognize and treat (Rule of 15) Initially increase glucose monitoring to reassure Meet with dietitian before initiation of insulin Start with basal insulin which is associated with less gain Mention options of combinations with metformin and GLP-1 RAs Basal Insulin is usually less expensive than adding multiple other non-generic medications Adapted from Funnell MM. Clinical Diabetes. 27;25(1):36-38, Peyrot M, et al. Primary Care Diabetes. 21;4(Suppl 1):S11-S18. Physician Barriers to Insulin Initiation Barriers Clinical inertia Suboptimal insulin knowledge Fear of hypoglycemia Weight gain GLP-1 = glucagon-like peptide-1. Adapted from Funnell MM. Clinical Diabetes. 27;25(1): Derr RL, et al. Diabetes Spectrum. 27; 2(3): Addressing the Barriers Use systems to facilitate chronic disease care EMR reminders to support real-time treatment and monitor results Education on insulin selection, initiation, and titration Incidence is low, especially with basal analogs Experience reassures Review glucose log to identify patterns of hypoglycemia Have patient meet with dietitian before initiation of insulin More physiologic insulin delivery may minimize weight gain Minimize with metformin and GLP-1 RAs Patient Reported Reasons for Missing Insulin Injections Dread taking injections Insulin injections negatively affect activities Injections interfere with eating or exercise Often worry about hypoglycemia Need to plan daily activities around injections Grunberger G. Diabet Obes Metab. 213;15(suppl 1): Percent of respondents Physicians Beliefs Regarding Insulin Therapy I wish there was an insulin treatment that would cover patients in case they forgot a dose* I believe that I must manage safety and efficacy but it is difficult to optimally manage both with insulin I would treat my patients more aggressively if there was no concern about hypoglycemia* A significant number of patients do not have adequate blood glucose levels with insulin treatment* Peyrot M, et al. Diabetic Medicine. 212;29: Primary Care Percentage (%) Specialist p< p< p<.5 2

3 Team Approach to Insulin Initiation Keys To Insulin Initiation In Primary Care Pharmacist Dietitian Physician Patient Certified Diabetes Educator Nurse/ Nurse Practitioner/ Physician Assistant Allow patients to self-titrate. Customize insulin care plan for each patient and provide written instructions on protocol. Use insulin pens for accurate insulin adjustment and delivery. Teach patients how to utilize and interpret results of Self-monitoring of blood glucose (SMBG) values. Consider structured glucose testing rather than random glucose testing for all patients. Prepare patients to recognize and treat hypoglycemia. Unger J. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy. 211;4: ZismanA, et al. ADA Scientific Sessions. San Diego, CA P When to Consider Insulin in a Person with Type 2 Diabetes When a combination of non-insulin antihyperglycemic medications are unable to achieve HbA1c target High fasting or postprandial glycemia Unacceptable side effects of other medications Advanced hepatic or renal disease Special considerations (steroids, infection, pregnancy) Hyperglycemia in a hospitalized patient Severely uncontrolled diabetes* Patient : LaDonna What to do when insulin doesn t work 53-year-old African American woman with long-standing T2DM (since age of age 39) presents for yearly follow-up. Has tried multiple oral antihyperglycemic agents (OHA) over the past decade, none of which has brought her HbA1c below 8.5%. Basal insulin was added to her OHA 2 years ago, but has never got her to her glycemic target. Current Meds: metformin 1 mg bid glargine 1 units bid lispro 25 units before each meal. Her AM fasting glucose averages 19mg/dl Bedtime glucose averages 25mg/dl Nathan DM, et al. Diabetes Care. 29; volume 32, Inzucchi SE, et al. Diabetes Care. 212;35(6): ADA Diabetes Care. 214:37(Suppl 1):S14-S8. * Random Glucose > 3 mg/dl, HbA1c > 1%, Ketonuria, Symptomatic polyuria/polydipsia, weight loss LaDonna: Continued Physiologic Insulin Secretion She has stopped regular home glucose monitoring (HGM) because the numbers never change and she often falls asleep at night without taking bedtime dose. AM readings usually aren t any different when she misses a dose. Employed as bus driver and has three children and one grandchild living at home. Spends free time caring for her family. She can t recall ever weighing less than her current 24 pounds, but other than having high sugars she doesn t feel distressed by her weight. Her husband and three children are all obese as well. Plasma Insulin Breakfast Lunch Dinner Bolus, Mealtime, Prandial Insulin 4: 8: 12: 16: 2: 24: 4: Time Basal Insulin Adapted from Kruszynska Y, et al. Diabetologia. 1987; 3:16. 3

4 Ultra-Rapid-acting: Inhaled human insulin Types of Insulin 216 ADA/EASD Position Statement Initiation and Adjustment of Insulin Regimens: Basal Insulin (Analog or NPH) Rapid-acting analogs: Aspart, Glulisine, Lispro Short-acting Regular human insulin (soluble) Intermediate-acting NPH human insulin Long-acting basal insulin analogs: Detemir, Glargine; U3 Glargine, Degludec Human insulin 7/3: premix NPH/regular Time (hours) Premixed Analogs: Insulin lispro mix 75/25, 5/5 Biphasic insulin 19 aspart 7/3 Adapted from Hirsch I. N Engl J Med. 25;352: ADA. Diabetes Care. 216;39(1):S1-S111. Selecting an Insulin Regimen Start by assessing patient lifestyle, willingness to start insulin, blood glucose data, appropriate targets Give the option of a 3-month trial Any insulin will improve glucose control May start with a basal insulin regimen, optimize dose, and intensify with prandial coverage if needed Advantages of Basal Insulin Analogs Over Human NPH Insulin Longer-acting (up to 24 hours or more) Once-daily administration Less variability from day to day Flatter biological activity (less peak) Lower risk of nocturnal and overall hypoglycemia Less weight gain (insulin detemir, U3 Glargine) Hirsch IB. N Engl J Med. 25;352(2): Meneghini L. et al. Diabetes Obes Metab. 27;9(6): Monami M, et al. Diabetes Res Clin Pract. 28;81(2): HbA1c Addition of Basal Insulin to Oral Therapy: Treat-to-Target Trial 756 Patients with Type 2 Diabetes on 1 or 2 Oral Agents Glycemic Control Over Time 9.% 8.5% Glargine 8.% NPH 7.5% 7.% 6.5% 6.% Weeks of Treatment Riddle MC, et al. Diabetes Care. 23;26: Cumulative Number of Events (Documented PG 56 mg/dl) PG = plasma glucose Hypoglycemia Time (days) Observational, Open-Label, Treat-to-Target Study: Insulin Detemir vs NPH Insulin Added to Oral Therapy HbA1c Level (%) HbA1c & Weight Changes Detemir NPH *P <.1 Weeks +2.6 lb* +6.2 lb 7% of patients achieved HbA1c < 7% Hermansen K, et al. Diabetologia. 24;47(Suppl 1):A273. Hermansen K, et al. Diabetes Care. 26;29(6): Hypoglycemic Events per Patient per Year Risk of Hypoglycemia P <.1 Overall Detemir + OAD NPH + OAD P <.1 Nocturnal 4

5 Initiation and Adjustment of Insulin Regimens: Basal Insulin (Analog or NPH) Start once-a-day long-acting insulin analog or NPH bedtime or morning Starting dose: 1 units or.2 units/kg Titrate against FPG until in target range (7-13 mg/dl) Increase dose typically by 2 units every 3 days Can increase dose by 4 units every 3 days if BG >18 mg/dl If hypoglycemia occurs or if BG <7 mg/dl: Reduce dose by 4 units, or by 1% if dose >6 units Continue regimen, recheck HbA1c level every 3 months Inzucchi SE et al. Diabetes Care 212;35: Yes HbA1c at goal after 2-3 months? Premixed No Intensify Basal-Bolus Insulin Glargine: Patient Self-Titration vs Physician Adjusted Frequent contacts with patients (12 in 24 weeks) Mixed-specialty and general medicine clinics Patients to adjust dose by 2 units Q3 days vs weekly adjustments by physicians HbA1c Level HbA1c Level (%) Patient- Adjusted 7.9 Physician- Adjusted Baseline 24 Weeks Incidence of Hypoglycemia (%) Davies M, et al. Diabetes Care. 25;28(6): Hypoglycemia Patient-Adjusted Physician-Adjusted Severe Symptomatic Nocturnal U-3 Insulin Glargine* More concentrated insulin Reduced rate of absorption Flatter, more prolonged pharmacokinetic and pharmacodynamic profiles Less variability; Half-life ~23 h, duration <= 36 h, steady state 4 days *FDA approved Feb US FDA. Drugs@FDA. Pharmacodynamics of U3 Glargine vs U1 Glargine GIR (mg/kg -1 min -1 )* SC Injection U1.4 U/kg -1 U3.4 U/kg Time (hours) The U-3 glargine has a flatter more prolonged effect The time it takes for 5% of the effect of a single injection U-1 = 12.1 hours U-3 = 16.7 hours *GIR = glucose infusion rate. Tillner J, et al. Poster 92P 73 rd ADA Scientific Sessions June 21-25, 213, Chicago, IL. Accessed March 21, 214. U3.6 U/kg -1 U3.9 U/kg -1 U-3 Insulin Glargine vs U-1 Insulin Glargine in T2DM Cumulative Number of Confirmed or Severe Hypoglycemic Events/Participant Hypoglycemia GLAR-1 GLAR Time, weeks Weight Change GLAR-1 GLAR-3 P =.15 Equivalent HbA1c reduction for U-3 glargine and U-1 glargine Mean Weight Change, kg 28-week, open-label, treat-to-target, RCT; N = 818; BL weight, 98. kg to 98.7 kg; mean BMI = 34.8 kg/m 2 ; hypoglycemia defined in accordance with ADA criteria (assistance needed or confirmed BG 7 mg/dl). Yki-Jarvinen H, et al. Diabetes Care. 214;37: Insulin degludec: steps in biologic action Long multihexamer chains assemble Insulin degludec injected Jonassen et al. Pharm Res 212;29: [ Phenol; Zn 2+ ] Phenol from the vehicle diffuses quickly, and insulin degludec links up via single side-chain contacts Zinc diffuses slowly causing individual hexamers to disassemble, releasing monomers Monomers are absorbed from the depot into the circulation Immediately after injection Slow release following injection 5

6 Half-life of insulin degludec is twice as long as that of insulin glargine The mean half-life of insulin degludec is 25.4 hours compared with insulin glargine, which has a half-life of 12.1 hours 1 Pharmacokinetic profiles obtained following last dose -> serum IDeg concentration decreased slowly over time and was detectable for at least 12 h Insulin degludec concentration reaches steady state in 3 days 2 12 IDeg serum concentration Proportion of Day 6 level (%) Type 1 diabetes Days since first dose 12 Proportion of Day 4 level (%) Type 2 diabetes Days since first dose Flat time-action profile in type 2 diabetes at steady state Time since injection (hours) Variability in glucose-lowering effect over 24 hours at steady state 3 Day-to-day variability (coefficient of variation %) GIR (mg/kg/min) 2 IDeg IGlar IDeg variability is four-fold 16 lower than IGlar Area under the GIR curve (time interval, hours) o This info is repeated on the next slide. Why is it separate here? Overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes with IDeg vs. IGlar [RR:.83[.74;.94](95%) (CI) and RR:.68[.57;.82](95%) (CI) T1DM population, nocturnal confirmed hypo significantly lower with IDeg vs. IGlar during maintenance treatment (RR:.75[.6;.94](95%) (CI) ). Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. 1. Heise et al. Diabetes Obes Metab 212;14:944 5; Heise et al. Diabetes 212;61(Suppl. 1):A259; 3. Heise et al. Diabetes Obes Metab 212;14: Hypoglycemia: Insulin Degludec vs Insulin Glargine metaanalysis Overall hypoglycemia Nocturnal hypoglycemia However, basal insulin plus oral agents may still not achieve target glycemia in many type 2 diabetes patients o Overall T2DM population, significantly lower rates of overall confirmed and nocturnal confirmed episodes with IDeg vs. IGlar [RR:.83[.74;.94](95%) (CI) and RR:.68[.57;.82](95%) (CI) ). o T1DM population, nocturnal confirmed hypo significantly lower with IDeg vs. IGlar during maintenance treatment (RR:.75[.6;.94](95%) (CI) ). o Reduction in hypoglycaemia with IDeg vs. IGlar was more pronounced during maintenance treatment in all populations. Ratner et al. Diabetes, Obesity and Metabolism 213;15: 175 When It May Be Time to Stop Titrating Basal Insulin Therapy in T2DM? Individual is not meeting glycemic targets on basal insulin 1,2 HbA1c still not at goal with.5 U/kg/day of daily basal insulin HbA1c not at goal despite target fasting plasma glucose (FPG) with basal insulin usually due to increased PPG Large glucose drops overnight or between meals (suggesting excessive amounts of basal insulin) Nocturnal hypoglycemia 1,2 When further increases in basal insulin result in hypoglycemia Options When Basal Insulin + Oral Antihyperglycemic Agents Do Not Achieve Target Glycemia? Add GLP-1 RA or DPP-4 inhibitor Add SGLT2 inhibitor Substitute premix insulin Add bolus, mealtime (prandial) insulin Add inhaled technosphere insulin 1. Inzucchi S, et al. Diabetes Care. 212;35: ADA. Practical Insulin: A Handbook for Prescribing Providers. 3rd ed. 211:

7 d LaDonna: Non-insulin strategies for glycemic control Today s HbA1c in the office is 9.2%. What is a realistic evidence-based target for her HbA1c to have clinical impact? 1. Below 8.5% 2. Below 8.% 3. Below 7.% % Non-Insulin Approaches to Lowering Glucose SGLT2 Inhibitors GLP-1 RAs Bariatric Surgery Weight loss Medications Non-insulin Approaches GLP-1 RA: (exenatide, liraglutide, albiglutide, dulaglutide, lixisenatide*) Injectable class that improves glycemic control through multiple mechanisms Enhance insulin secretion & inhibit glucagon release in a glucose dependent manner Longer acting GLP-1 RAs have greater impact on FPG & less effect on PPG levels Weight loss & improved CV risk profile DPP-4 Inhibitors: (sitagliptin, linagliptin, saxagliptin, alogliptin) Oral agents with moderate HbA1c improvement, esp. when combined with metformin Weight neutral Adjustments for renal impairment except linagliptin SGLT2 Inhibitors: (canagliflozin, dapagliflozin, empagliflozin) Oral agents with HbA1c improvement Reduced SBP / DBP and weight loss Significant renal impairment limits use *lixisenatide not FDA aproved Campbell JE, et al. Cell Metab. 213;17(6): Garber AJ. Diabetes Care. 211;34 Suppl2:s279-s284. Cross LB, Brunell S. Am J Pharm Benefits. 213:5(6):e139-e15. Yale J, et al. Diabetes Obes Metab. 213;15: Ghosh RK, Ghosh SM, Chawla S, Jour. Clin.Pharm 52; 4; , April 212 Heap G. Decision Resources. Drugwatch Blog. January 214. Deacon CF and Holst JJ. Expert Opin Pharmacother. 213;14: GLP-1 RAs vs Prandial Insulin Added to Basal Insulin DULA is approved with prandial insulin; EXN QW is not approved with any insulin 4,5 LIRA QD 1,a ASP QD 1,a EXN BID 2,b LIS TID 2,3,b,c ALBI QW 3,c P = Noninferior 1.5 Noninferior Δ HbA1c, % Outcome LIRA vs ASP 1 EXN BID vs LIS 2 ALBI vs LIS 3 Δ Weight, kg 2.8 d d.7 d.8 Hypo, EPY e 1. d Nausea, % LIRA > ASP, first 2 wk a Added to DEG (26 wk; N = 177); DEG is not approved by 1. Mathieu C, et al. Diabetes Obes Metab. 214;16: the US FDA. 2. Diamant M, et al. Diabetes Care. 214;37: b Added to GLAR (3 wk; N = 637). 3. Rosenstock J, et al. Diabetes Care. 214;37: c Added to GLAR (26 wk; N = 566). 4. Eli Lilly and Co. Trulicity (dulaglutide) prescribing information. d P <.5 between groups. e Rates of severe hypoglycemia were low across groups. 5. US FDA. Drugs@FDA. Emerging Basal Insulin GLP-1 RA Fixed-Ratio Coformulations HbA1c < 7%, % 81 6 d 65 d 84 8 Δ HbA1c, % Δ BW, kg 5 5 DEG-LIRA 1,a,b DEG 1,a,b LIRA 1,b GLAR-LIXI 2,a,c GLAR 2,c Noninferior to DEG Superior Superior to LIRA to GLAR severe hypoglycemic episodes per group Lower rate of hypoglycemia for LIRA vs DEG or DEG-LIRA (overall and nocturnal) 1 Lower rate of hypoglycemia for GLAR-LIXI than for GLAR (overall) 2,e Current GLP-1 RAs should not be mixed with or injected adjacent to insulin 3 a Not US FDA approved. 1. Gough SC, et al. Lancet Diabetes Endocrinol. 214;2: b 26-week open-label, treat-to-target RCT; N = 1663 (insulin naïve). 2. Rosenstock J, et al. Diabetologia. 214;57(suppl 1) [abstract 241]. c 24-week open-label, treat-to-target RCT; N = 323 (insulin naïve). 3. US FDA. Drugs@FDA. d P <.1 vs DEG-LIRA; e P <.1 vs GLAR-LIXI However, many type 2 diabetes patients will require the addition of a prandial insulin to achieve glycemic goals 7

8 Initiation & Adjustment of Insulin Therapy: Prandial Insulin (Analog or Regular or Premix) Role for Premixed Insulin Advantages Both basal and prandial components in a single insulin preparation Can cover insulin requirements through most of day Disadvantages Not physiologic Requires consistent meal and exercise pattern, Cannot separately titrate individual insulin components 1 risk for nocturnal hypoglycemia 2,3 risk for fasting hyperglycemia if basal component does not last long enough 3 Often requires accepting higher HbA1c goal (<7.5% or 8%) 2,3 ADA. Diabetes Care. 216;39(1):S1-S Inzucchi S. et al. ADA, EASD Position Statement. Diabetes Care. 212;35; Janka HU, et al. Diabetes Care. 25;28: Fritsche A, et al. Diab Obes Metab. 21;12: INITIATE: Basal Analog vs Premixed Analog HbA1c Level (%) Change in HbA1c Level From Baseline to Study End Baseline Endpoint P < % 7.4% Insulin Glargine + OADs 2.4% 9.7% Raskin P et al. Diabetes Care. 25;28(2): % Biphasic Insulin Aspart 7/3 2.8% Episodes per Patient Year Documented Hypoglycemic Episodes (<56 mg/dl) P <.5.7 Insulin Glargine + OADs 3.4 Biphasic Insulin Aspart 7/3 Total units = 51.3 ± 26.7 with glargine plus OADs vs ± 39.5 with premixed insulin Adding Prandial Insulin to Basal Therapy Further Improves HbA1c Davies M et al Diabetes Obes Metab. 28 May;1(5): Potential advantages of rapid acting insulin analogs Largest decrease in HbA1c after 1 st & 2 nd prandial insulin dose 3 2 Earlier onset & peak of biologic activity Shorter duration of action Less biologic variability = = = Lower post prandial glucose Less late prandial hypoglycemia Less glycemic fluctuations More convenient administration May need to adjust basal dose & distribution 8.9% 8.7% 1 Insulin injection Time (hours) Change was adjusted for baseline HbA1c Meneghini L, et al. Endocrine Practice 211; 17: p=ns 8

9 STEPwise Study Conclusions Ladonna: Looking for new options Overall HbA1c reduction of 1.2% Greatest HbA1c reductions achieved with the 1 st & 2 nd bolus injections (~ 1.% combined) Glycemic control comparable in both groups Prandial insulin doses between units per meal Similar rates of hypoglycemia, which increased with number of prandial injections Similar weight gain of 2 3 kg Her Endocrinologist felt that even higher doses of insulin would help and suggested one daily degludec u2 and three times daily U5 before meals. She cant reach her endocrinologist and asks you to explain her meds to her Meneghini, et al. Endocr Pract. 211;17: Who needs high-concentrated insulin? Patients injecting U-1 insulin Requiring > 2units/day Requiring multiple injections to administer single dose > 6 8 units using insulin pens > 1 units using syringes Patients using CSII with U-1 insulin Basal requirements > 3 units/hour (> 75 units/day basal insulin) Total requirements > 15 units/day Concentrated Insulin: Safety Hypoglycemia Severe hypoglycemia can occur up to hours after initial injection of U-5 Incidence is rare if U-5 Regular used appropriately Reported experience notes decreasing frequency of hypoglycemia over time and limited no severe hypoglycemia in several case series Errors 1 Administration and dispensing most common errors May be associated with hypoglycemia or hyperglycemia Pregnancy Pregnancy Category B Three case reports of use starting at weeks weeks gestation all resulted in healthy deliveries. 2, 3, 4 1 Segal et al. Am J Health-Syst Pharm 21;67: , 2 Okeigwe et al. J Perinatol 213;33(3):235-8, 3 Zuckerwise et al. Obstet Gynecol 212;12:439-42, 4 Hatipoglu et al. Endocr Pract 26;12(5):542-4 Dosing Recommend starting doses be in a multiple of 5 to simplify patient education Empiric dose adjustments 1 2% reduction if HbA1c < 8% 1 2% increase if HbA1c > 1% Administer 3 minutes before meals Vary amounts based on glucose trends (SMBG) or carbohydrate content of meals Inhaled Technosphere Insulin Inhalation powder formulation of human insulin and fumaryl diketopiperazine (FDKP) 1 FDKP is excreted in urine unchanged 1 Approved by US FDA in June Segal et al. Am J Health-Syst Pharm. 21;67: Image: 1. Nuffer W, et al. Ann Pharmacother. 215;49: US FDA. Drugs@FDA. 9

10 Limitations / Contraindications Limitations: Inhaled insulin is not a substitute for long acting insulin. Not recommended for the treatment of diabetic ketoacidosis Not recommended in patients who smoke or who have stopped smoking in last 6 months. Making Prandial Insulin Work: How much do I give? Glycemic excursions HGM patterns Carb counting Correction factors Contraindications: During episodes of hypoglycemia In patients who have chronic lung disease such as COPD or asthma etabolicdrugsadvisorycommittee/ucm39865.pdf Paired Glucose Testing Can Provide Valuable Information to Patients Post-meal Delta Value >5 mg/dl >1 mg/dl <5 mg/dl Interpretation Not enough insulin used to cover carbs Insulin lag time not utilized Illness (flu) Snacking between the meal and 2-hour check time Forgot to give insulin (especially if delta >2 mg/dl) Insulin has expired or is denatured Insulin antibodies forming Insulin-to-carb mismatch Too much insulin (watch for hypoglycemia) Alcohol use (decreases gluconeogenesis) Insulin stacking: consider this option when the delta is NEGATIVE at 2 hours! Simple Algorithm vs Carbohydrate Counting For Mealtime Insulin Adjustment HbA1c % Simple Algorithm Group Carb-Count Group Baseline Insulin dose (U/kg/d) Simple Algorithm: 1.9 Carb Counting: 1.7 P <.2 Bergenstal R, et al. Diabetes Care. 28;31: Weight gain (kg): Simple Algorithm: 3.6 Carb Counting: 2.4 P =.6 How Often Does Hypoglycemia Occur in Diabetes? When Does Hypoglycemia Occur With Diabetes? Frequency of NSHE, % Daily to about 1/wk 1/mo to several times/mo Only a few times/y or very rarely T1DM T2DM 4.2 Awake and at work 2% Awake but not at work 3% During sleep at night 5% 1/5 of all nonsevere hypoglycemia occurs nocturnally NSHE, nonsevere hypoglycemic events. Survey 49 US patients with T1DM (n = 2) and with T2DM (n = 29). Brod M, et al. Value Health. 211;14: NSHE, nonsevere hypoglycemic events. Survey 49 US patients with T1DM (n = 2) and with T2DM (n = 29). Brod M, et al. Value Health. 211;14:

11 Practical Tips for Treating Hypoglycemia Patient, family, and friends should be aware of hypoglycemia signs and symptoms Have a plan to manage hypoglycemia (eg, Rule of 15) Test BG, if possible Treat hypoglycemia with 15 grams of sugar or carbohydrates (eg, ½ cup juice, 2-3 glucose tablets) Wait 15 minutes and test BG again Take additional 15 grams if necessary Follow treatment of hypoglycemia with protein Resume activity when feeling better and BG > 1 mg/dl Guidelines for Preventing Hypoglycemia AACE 1-4 Address in each patient contact If problematic, adjust regimen by: Reviewing/applying diabetes self-management Frequent SMBG Flexible, appropriate insulin regimens Individualized glycemic goals Ongoing professional guidance and support Consider each of the known risk factors for hypoglycemia ADA 5 Reevaluate SMBG skills periodically Avoid aggressive targets in advanced disease Limit alcohol intake 1 drink/day in adult women 2 drinks/day in adult men Add carbohydrate before exercising if BG < 1 mg/dl Strict avoidance of hypoglycemia for several weeks partly resolves repeated severe hypoglycemia, hypoglycemia unawareness 1. Cryer PE, et al. J Clin Endocrinol Metab. 29;94: ADA. Hypoglycemia (low blood glucose). SMBG, self-monitoring of blood glucose. 2. Cooperberg BA, et al. Diabetes Care. 28;31: Raju B, et al. J Clin Endocrinol Metab. 26;91: Taplin CE, et al. J Pediatr. 21;157: ADA. Diabetes Care. 216;39(1):S1-S111. Key Points About Insulin Take Home Points We should be using insulin earlier in the natural history of type 2 diabetes How early and how do we know when to start insulin? Barriers to insulin therapy Goals of therapy: Definitions and individualization Different insulin formulations, their characteristics and uses Initiating and advancing insulin therapy: Strategies that work 63 Insulin therapy may be considered if HbA1c level is >8.% and blood glucose levels are not controlled on multiple oral anti-diabetes agents (OADs). In most situations, first address the fasting blood sugars with basal insulin. Monitor blood glucose and optimize insulin doses. Continue OADs or adjust dosages if necessary. Start bolus insulin at the largest meal or the one with the highest postprandial blood glucose levels (usually breakfast). Fixed prandial insulin doses are effective and safe for basal/bolus therapy in type 2 diabetes. Encourage and empower your patients! 11