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- 2. Ants to Analogues History Source of Insulin Goals and Purpose of Insulin Therapy Barriers to the use of Insulin Characteristics of insulin Current Concepts in Insulin Therapy Basal/Bolus Insulin Future of Insulin Conclusion
- 3. Have They Robbed Diabetes of Its Terror
- 4. History
- 5. HISTORY
- 7. Source of insulin Biosynthetic "human" insulin is now manufactured for widespread clinical use using genetic engineering techniques using recombinant DNA technology, which the manufacturers claim reduces the presence of many impurities, although there is no clinical evidence to substantiate this claim. Eli Lilly marketed the first such insulin, Humulin, in 1982. Humulin was the first medication produced using modern genetic engineering techniques in which actual human DNA is inserted into a host cell (E. coli in this case). The host cells are then allowed to grow and reproduce normally, and due to the inserted human DNA, they produce a synthetic version of human insulin
- 8. Purpose of Insulin Therapy Prevent and treat fasting and postprandial hyperglycemia Permit appropriate utilization of glucose and other nutrients by peripheral tissues Suppress hepatic glucose production Prevent acute complications of uncontrolled diabetes Prevent long term complications of chronic diabetes
- 9. WHAT!? Did you say INSULIN?! Barriers to the Use of Insulin
- 10. Patient Concerns About Insulin Fear of injections Perceived significance of need for insulin Worries that insulin could worsen diabetes Concerns about hypoglycemia
- 13. Barriers to Insulin Therapy : Common Medical Concerns Insulin therapy in type 2 diabetes might cause: Worsening Insulin Resistance? More Cardiovascular Risk? Weight Gain ? Hypoglycemia? 6-8
- 14. Insulin Sensitivity in Glucose Clamp Studies: Improved by Insulin Treatment Scarlett, et al. Diabetes Care. 1982;5:353-363; Andrews, et al. Diabetes. 1984;33:634-642; Garvey, et al. Diabetes. 1985;34:222-234. 57 80 53 87 40 67 0 20 40 60 80 100 Garvey Andrews Scarlett Baseline After Insulin Glucose Disposal % of Matched Control Values 6-9
- 15. Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Malmberg, et al. BMJ. 1997;314:1512-1515. All Subjects (N = 620) Risk reduction (28%) P = .011 Standard treatment 0 .3 .2 .4 .7 .1 .5 .6 0 1 Years of Follow-up 2 3 4 5 Low-risk and Not Previously on Insulin (N = 272) Risk reduction (51%) P = .0004 IV Insulin 48 hours, then 4 injections daily 0 .3 .2 .4 .7 .1 .5 .6 0 1 Years of Follow-up 2 3 4 5 6-11
- 16. Reassurance About Common Concerns Insulin Therapy in Type 2 DM Improves Insulin Sensitivity by Reducing Glucotoxicity Reduces Cardiovascular Risk Causes Modest Weight Gain Rarely Causes Severe Hypoglycemia Patients fears and concerns can be addressed by education 6-15
- 18. Dissociation of Regular Human Insulin Regular Human Insulin 10-3 M 10-3 M 10-5 M 10-8 M peak time 2-4 hr formulation capillary membrane hexamers dimers monomers
- 21. Characteristics of Insulin Insulin has 3 characteristics: Onset is the length of time before insulin reaches the bloodstream and begins lowering blood glucose. Peaktime is the time during which insulin is at maximum strength in terms of lowering blood glucose. Duration is how long insulin continues to lower blood glucose.
- 23. Types of Insulin Insulin Type (trade name) Onset Peak Duration Bolus (prandial) Insulins Rapid-acting insulin analogues (clear): • Insulin aspart (NovoRapid®) • Insulin glulisine (Apidra™) • Insulin lispro (Humalog®) • Insulin lispro U200 (Humalog® 200 units/mL) 10 - 15 min 10 - 15 min 10 - 15 min 10 - 15 min 1 - 1.5 h 1 - 1.5 h 1 - 2 h 1 - 2 h 3 - 5 h 3 - 5 h 3.5 - 4.75 h 3.5 - 4.75 h Short-acting insulins (clear): • Insulin regular (Humulin®-R) • Insulin regular (Novolin®geToronto) 30 min 2 - 3 h 6.5 h Basal Insulins Intermediate-acting insulins (cloudy): • Insulin NPH (Humulin®-N) • Insulin NPH (Novolin®ge NPH) 1 - 3 h 5 - 8 h Up to 18 h Long-acting basal insulin analogues (clear) • Insulin detemir (Levemir®) • Insulin glargine (Lantus®) • Insulin glargine U300 (Toujeo®) • Insulin glargine (BasaglarTM) 90 min 90 min Up to 6 h 90 min Not applicable Up to 24 h (detemir 16-24 h) Up to 24 h (glargine 24 h) Up to 30 h Up to 24 h (glargine 24 h)
- 26. Action profiles of Analogues
- 28. Dosing Approximately 40-50% of the total daily insulin dose is to replace insulin overnight, when you are fasting and between meals. This is called background or basal insulin replacement. The basal or background insulin dose usually is constant from day to day. The other 50-60% of the total daily insulin dose is for carbohydrate coverage (food) and high blood sugar correction.
- 29. Twice-daily Split-mixed Regimens Regular NPH B S L HS Insulin Effect B 6-23
- 30. 30/70 Dose Calculation Weight = 80 kg 80 kg x 0.3 U/kg = 24 U 2/3 in the AM = 16 Units 1/3 at supper = 8 Units
- 31. Multiple Daily Injections (MDI) NPH + Regular Regular NPH NPH at AM and HS + Regular AC NPH at HS + Regular AC Insulin Effect B S L HS B Insulin Effect B S L HS B Regular NPH 6-24
- 32. Insulin Therapy Options MDI therapy 0.5 units/kg = total daily dose 4x/day 40% NPH @ hs and 60% rapid acting analogue ac meals
- 33. The Basal/Bolus Insulin Concept Basal Insulin Suppresses glucose production between meals and overnight Nearly constant levels 50% of daily needs Bolus Insulin (Mealtime or Prandial) Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour 10% to 20% of total daily insulin requirement at each meal 6-20
- 34. Rapid-acting Analogues: Clinical Features Insulin profile more closely mimics normal physiology Convenient administration immediately prior to meals Faster onset of action Limit postprandial hyperglycemic peaks Shorter duration of activity Reduced late postprandial hypoglycemia But more frequent late postprandial hyperglycemia Need for basal insulin replacement revealed 6-27
- 35. Rapid-acting Insulin Analogues: Lispro and Aspart 400 350 300 250 200 150 100 Meal SC injection 50 0 0 30 60 Time (min) 90 120 180 210 150 240 Lispro Regular Human 500 450 400 350 300 250 150 50 200 100 0 0 50 100 Time (min) 150 200 300 250 Aspart Regular Human Plasma Insulin (pmol/L) Plasma Insulin (pmol/L) Meal SC injection Heinemann, et al. Diabet Med. 1996;13:625-629; Mudaliar, et al. Diabetes Care. 1999;22:1501-1506. 6-28
- 36. Multiple Daily Injections (MDI) NPH + Mealtime Lispro NPH at AM and HS + Lispro AC NPH at HS + Lispro AC Insulin Effect B S L HS B Insulin Effect B S L HS B Lispro NPH Lispro NPH 6-29
- 37. Profiles of Various Basal Insulins Glargine NPH Ultralente CSII n = 20 T1DM Mean ± SEM SC insulin 4.0 3.0 2.0 1.0 0 24 20 16 12 8 4 0 0 4 8 12 16 20 24 Time (h) mg/kg/min mol/kg/min µ
- 38. Bedtime Glargine vs NPH, With Mealtime Regular *P < .01 (change from baseline to endpoint within each group) **P < .02 (compared to NPH) Rosenstock, et al. Diabetes. 1999;48(suppl 1):A100. Baseline 8.5± 1 * * * * 8.8± 1 11.1±4 10.6± 4 Baseline 4 3 2 1 0 1 2 48 36 24 12 0 Nocturnal Hypoglycemia FPG (mmol/L) HbA1c (%) NPH Glargine ** Patients (%) 6-51
- 39. Insulin degludec (Tresiba) T1/2 : 25 hours Glucose-lowering duration : > 42 hours Time to steady-state : 3 days of once-daily dosing Peak : peakless Retained sequence of human insulin No amino acid substitutions Fatty acid (hexadecanedioic acid) coupled to lysine at B29 position via glutamic acid ‘spacer’ Lower risk of hypoglycemia True 24 hour insulin Can be coformulated with other proteins
- 40. WHEN TO START INSULIN ?
- 41. Typical Diagnosis of Diabetes Severity of Glucose Intolerance Years to Decades Normal Blood Glucose Natural History of Type 2 Diabetes Risk of Macrovascular Complications Insulin Resistance IGT Insulin Secretion Postprandial Glucose Risk of Microvascular Complications Frank Diabetes NGT Worsens with Time
- 42. Indications for Insulin Use in Type 2 Diabetes Pregnancy (preferably prior to pregnancy) Acute illness requiring hospitalization Perioperative/intensive care unit setting Postmyocardial infarction High-dose glucocorticoid therapy Inability to tolerate or contraindication to oral antiglycemic agents Newly diagnosed type 2 diabetes with significantly elevated blood glucose levels (pts with severe symptoms or DKA) Patient no longer achieving therapeutic goals on combination antiglycemic therapy
- 43. Starting With Basal Insulin: Advantages 1 injection with no mixing Slow, safe, and simple titration Low dosage Limited weight gain Effective improvement in glycemic control 6-37
- 44. Changing from Other regimens to Basal/Bolus Insulin ~50% Basal* Total Daily Dose (~70-75% of prior insulin regimen TDD) ~50% Bolus* Usually divided into 3 premeal doses *Range: 40 to 60%
- 45. An Example: Mr. M: 58 yo with history type 2 diabetes for 8 years In addition to oral meds, he is on 70/30 insulin: 30 u AM and 15 u PM Current Total Daily Dose = 45 u of 70/30 However, he has been having difficulty with wide glycemic excursions After discussing his options in detail, he is willing to begin basal/bolus regimen: New TDD= 45 u x .75 = 33.75 = 34 u Basal = 17 u Lantus at bedtime Bolus = 17 u total / 3 = 5.6 u = 5 u Humalog with meals
- 46. Insulin Sensitivity Factor 1 unit of insulin will blood glucose by: mg/dl EXAMPLE TDD is 34 units 1500 Rule: 1500 ÷ 34 = 44 1 unit of Regular bg 44 mg/d 1800 Rule: 1800 ÷ 34 = 53 1 unit of Humalog bg 53 mg/dl
- 47. Starting with Basal Insulin Continue oral agent(s) at same dosage (eventually stop secretegogue) Add single, evening insulin dose (around 10 U) Glargine (bedtime or anytime?) NPH (bedtime) 70/30 (evening meal) or 75/25 Adjust dose by fasting BG Increase insulin dose weekly as needed Increase 4 U if FBG >140 mg/dL Increase 2 U if FBG = 120 to 140 mg/dL Treat to target (usually <120 mg/dL) 6-59
- 48. Starting With Basal Insulin: Advantages 1 injection with no mixing Slow, safe, and simple titration Low dosage Limited weight gain Effective improvement in glycemic control 6-37
- 49. Advancing Bolus/ Adding Bolus Insulin Indicated when FBG acceptable but HbA1c not at goal and/or Postprandial BG not at goal (<140mg/dl) Insulin options To Glargine, add mealtime Regular or Lispro To bedtime NPH, add morning NPH and mealtime Regular or Lispro To suppertime 70/30, add morning 70/30 or 75/25 Oral agent considerations Usually stop secretagogue Continue metformin and TZD for additional glycemic and other benefits 6-60
- 50. Dosage Changes Change insulin dose so that peak of action corresponds to most abnormal value (pre- meal) If all values are abnormal - start with fasting glycemia followed by lunch, supper and bedtime Change the dose by increments of 1-4 U Not more than twice/week Monitor for PATTERNS in hypoglycemia
- 51. The Future of Insulin Inhaled Insulin: Exubra, others Oral / Buccal Insulin: Oralin New basal insulin New Rapid Acting Insulin Analogue Other: Closed Loop Systems (Artificial pancreas) 6-54
- 52. Summary: Insulin Therapy Replaces complete lack of insulin in type 1 diabetes Supplements progressive deficiency in type 2 diabetes Basal insulin added to oral agents can be used to start Full replacement requires basal-bolus regimen Hypoglycemia and weight gain are main medical risks New insulin analogues and injection devices facilitate use
- 53. Case Study Patient K.G., DM for 15 years BMI = 26 Meds: Metformin 1000 mg BID and Gluconorm 2 mg bid Vildagliptin BID HbA1C = 8.5%, FBS 188 PPbs 201 Post MI What is the next step?
- 54. case study 22 yrs old MALE type 2 DM. acanthosis + strong family history no complications of DM HbAIC 10.2 fbs-201 ppbs-349 fairly good pancreatic beta cell reserve.
- 55. Case Study Patient RD DM for 8 years BMI = 22 Meds: Metformin 1000 mg BID and GLICLAZIDE 80 mg bid Vildagliptin BID Insulatard 12 units at night. HbA1C = 7.5%, FBS 201 PPbs 182 Post CABG, What is the next step?
- 56. Somogyi Effect Hyperglycemia secondary to asymptomatic hypoglycemia (especially at night) If the insulin is increased in evening, the problem worsens Check capillary glycemia around 3 a.m. to eliminate hypoglycemia In this case, reduce the h.s. NPH
Editor's Notes
- Romanian, R. C. Paulesco In 1908, a young internist in Berlin, Georg Ludwig Zuelzer created a pancreas extract named acomatrol. his laboratory was turned over to the German military during World War I.
- Recombinant DNA production
- Slide 6-8 Barriers to Insulin Therapy Common Concerns Insulin has been used therapeutically in patients with diabetes for more than 70 years and has an almost unlimited power to reduce plasma glucose. The major barriers to insulin use are a perceived increase of cardiovascular risk, weight gain, and the risk of hypoglycemia. Although a true cause/effect relationship has not been established between hyperinsulinemia and atherosclerosis, the development of weight gain during exogenous insulin therapy is a well-known phenomenon. The cycle of worsening insulin resistance, greater insulin requirements, and hyperinsulinemia is typical in diabetes. Central obesity, hypertension, and dyslipidemia are strongly associated with hyperinsulinemia and contribute substantially to the cardiac risk profile. Whether therapy with insulin actually increases (or decreases) cardiovascular risk is currently debated. The risk of mild to severe hypoglycemic reactions is increased with intensive insulin therapy and is dependent on numerous factors, including duration of diabetes, duration of insulin therapy, and degree of glycemic control, as well as prior hypoglycemic episodes. The following slides will present some of the published data bearing on these concerns.
- Slide 6-9 BARRIERS TO INSULIN THERAPY Insulin Sensitivity in Glucose Clamp Studies Improved by Insulin Treatment Because insulin dosage correlates with insulin resistance in epidemiologic studies, and because insulin can cause weight gain that is also associated with insulin resistance, it has been feared that treatment with insulin may worsen insulin resistance. Three studies done with similar methods have directly tested this concern. Each study shown here examined the insulin sensitivity of peripheral tissues, mainly muscle, using the glucose-insulin clamp method, before and after restoration of good glycemic control in type 2 diabetes patients with aggressive insulin treatment. In each case the treatment period was short (2 to 4 weeks) and relatively high insulin dosage was required (>100 U daily). The figure shows the insulin sensitivity of tissues before and after treatment, expressed as a percentage of the mean value for insulin sensitivity of a nondiabetic control group that was matched in age, gender, and weight to the diabetic subjects. The three studies had remarkably similar results, with insulin sensitivity before treatment reduced by half, compared to the nondiabetic values, indicating marked insulin resistance. After treatment, insulin sensitivity improved toward the nondiabetic values, though some insulin resistance persisted, as would be expected. This improvement is presumably due to reduced “glucotoxicity” accompanying improved control of plasma glucose. Whether the improvement of insulin sensitivity persists when insulin treatment is continued was not tested in these studies. However, these studies show that, at least in the short term, successful insulin treatment reduces rather than worsens insulin resistance. Scarlett JA, Gray RS, Griffin J, Olefsky MJ, Kolterman OG. Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care. 1982;5:353-363; Andrews WJ, Vasquez B, Nagulesparan M, et al. Insulin therapy in obese, non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes. 1984;33:634-642; Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985;34:222-234.
- Slide 6-11 BARRIERS TO INSULIN THERAPY Cardiovascular Risk Mortality After MI Reduced by Insulin Therapy in the DIGAMI Study Patients at high risk of cardiovascular disease are often thought to be inappropriate candidates for treatment with insulin because of the belief that hypoglycemia, hyperinsulinemia, or other metabolic effects of insulin might provoke or worsen the outcome of major cardiovascular events. This figure shows data from the Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) trial. This Swedish trial studied the short-term and long-term effects of intensive insulin treatment of patients with diabetes who were enrolled in the trial at the time of a myocardial infarction. The subjects were immediately randomized to continued management according to the judgment of their physicians, or to intravenous infusion of insulin and glucose for 48 hours followed by a four-injection regimen subsequently for as long as 5 years. Other aspects of management of the infarction included treatment with b-blockers, angiotensin-converting enzyme inhibitors, fibrinolytic agents, and aspirin in high proportions of both groups. The rationale underlying the study was the old observation that, in animal experiments and studies of small numbers of humans, infarct size and outcome are improved by insulin-glucose infusion, in part because of suppression of otherwise elevated free fatty acid levels in plasma. The figure shows the cumulative total mortality rates in the whole population of 620 subjects randomized to the two treatments, as well as the rates for a predefined subgroup of subjects who were judged likely to survive the initial hospitalization and were not previously using insulin. The whole population showed an 11% actual and a 28% relative risk reduction with intensive insulin treatment after 5 years, and the subgroup showed a 15% actual and a 51% relative risk reduction. Most of the benefit was apparent in the first month of treatment and presumably was partly due to immediate intravenous infusion of insulin; however, the survival curves tended to separate further over time, suggesting an ongoing benefit from intensive treatment. This study suggests that insulin is an entirely appropriate treatment for patients with type 2 diabetes and high cardiovascular risk, especially at the time of myocardial infarction. Malmberg K, Rydén L, Hamsten A, Herlitz J, Waldenström, Wedel H, and the DIGAMI study group. Effects of insulin treatment on cause-specific one-year mortality and morbidity in diabetic patients with acute myocardial infarction. Eur Heart J. 1996;17:1337-1344; Nattrass M. Managing diabetes after myocardial infarction: time for a more aggressive approach. BMJ. 1997;314:1497; Malmberg K, and the DIGAMI study group. Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. BMJ. 1997;314:1512-1515.
- Slide 6-15 BARRIERS TO INSULIN THERAPY Reassurance About Common Concerns The preceding slides have presented findings that offer reassurance about the risk-benefit ratio of using insulin for type 2 diabetes. Slide 9 shows that intensive treatment with insulin actually improves the insulin sensitivity of peripheral tissues, at least in the short term, by reducing the glucotoxic effects of hyperglycemia. Slide 10 shows that insulin treatment improves triglyceride levels, fosters a trend toward better HDL levels, and has no effect on LDL levels or blood pressure. Slide 11 shows an impressively reduced mortality with immediate and sustained intensive insulin treatment following myocardial infarction, suggesting that in this setting the benefits outweigh any theoretical cardiovascular hazards. Slide 12 shows the weight gain found in the UKPDS with various treatments, confirming that insulin causes the most weight gain but also that the mean gain is relatively modest, about 10 lb during 10 years for both less obese and more obese patients. Slide 13 shows that concurrent use of metformin markedly reduces weight gain when insulin treatment is started or intensified. Slide 14 shows more data from the UKPDS confirming that both mild and severe hypoglycemia are more common with insulin treatment than with other treatments, but that the rate of severe hypoglycemia is quite low. Buse JB. Overview of current therapeutic options in type 2 diabetes. Diabetes Care. 1999;22(suppl 3):C65-C70; Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22(suppl 3):C71-C75; UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853.
- 16
- Slide 6-23 INSULIN TACTICS Twice-daily Split-mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split-mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times.
- Slide 6-24 INSULIN TACTICS Multiple Daily Injections (MDI) NPH + Regular Another strategy, shown in this slide, consists of two injections of NPH (or lente) insulin daily plus two or three injections of regular insulin with meals. The second injection of NPH is given at bedtime, to confer less risk of nocturnal hypoglycemia while providing enough insulin to control overnight fasting glucose levels. This is often called a multiple daily injection (MDI) regimen. It is widely used for type 1 diabetes patients but is also appropriate for type 2 diabetes patients whose endogenous levels are declining. The match of insulin levels to endogenous needs is better with this approach than with twice-daily NPH and regular, but still not very good.
- Slide 6-20 MIMICKING NATURE WITH INSULIN THERAPY The Basal/Bolus Insulin Concept Insulin is capable of restoring glycemia to nearly normal in most patients with type 2 diabetes. The basal/bolus insulin concept attempts to mimic, with insulin therapy, the patterns that normally control glucose in persons without diabetes. Basal insulin suppresses glucose production so that the levels remain nearly constant between meals and overnight. Basal insulin meets about half of the patient’s daily need for insulin and may be sufficient when considerable endogenous insulin remains. Bolus insulin (10% to 20% of the total daily insulin requirement given at each meal) limits hyperglycemia after meals. This tends to smooth the peaks of glucose that occur in response to these meals. Frequent glucose monitoring aids in determining the candidates for basal or mealtime regimens. Ideally, each component of insulin replacement therapy should come from a different type of insulin with a specific profile to fit the patient’s needs. Practical methods to accomplish this basal/bolus strategy will be illustrated later in this module. Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3:308-334; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.
- Slide 6-27 INSULIN TACTICS Short-acting Analogues: Lispro and Aspart Clinical Features Two quick-acting insulin analogues, insulin lispro and insulin aspart, have absorption profiles that more closely match normal mealtime patterns. Small alterations in their molecular structure relative to human insulin reduce their tendency to aggregate into pairs (dimers) or groups of six (hexamers) molecules, thus speeding their absorption after subcutaneous injection. Because of this property, they can be given immediately before meals. This timing is much more convenient for patients than waiting 20 to 40 minutes after the injections to begin eating. Their quick onset of action matches normal mealtime peaks of plasma insulin better than does human regular insulin. Clinical studies have shown that these properties lead to less prominent peaks of glucose after meals and less late postprandial hypoglycemia. However, rapid waning of the effects of mealtime lispro and aspart leads to greater dependency on adequate basal insulin levels between meals and overnight.
- Slide 6-28 INSULIN TACTICS Short-acting Insulin Analogues: Lispro and Aspart Plasma Insulin Profiles This figure shows two separate experiments displaying the plasma insulin profiles after injection of insulin lispro and insulin aspart in comparison to that of human regular insulin. The experiment with lispro, shown on the left, included 10 patients with type 1 diabetes, and the experiment with aspart shows findings from 18 healthy subjects. Both of these analogues have very rapid onset of action, which allows them to be taken immediately before meals. Both reach a peak about 1 hour after injection, with a decline in baseline levels in 4 hours, closely matching normal insulin patterns. The delayed and extended profile of human regular insulin is seen in both studies, with significant elevations above baseline persisting well beyond 4 hours after injection. Heinemann L, Heise T, Wahl LC, et al. Prandial glycaemia after a carbohydrate-rich meal in type I diabetic patients: using the rapid acting insulin analogue [Lys(B28), Pro (B29)] human insulin. Diabet Med. 1996;13:625-629; Mudaliar SR, Strange P, Lindberg FA, et al. Insulin aspart (B28 asp-insulin): a fast-acting analog of human insulin. Diabetes Care. 1999;22:1501-1506.
- Slide 6-29 INSULIN TACTICS Multiple Daily Injections (MDI) NPH + Mealtime Lispro This schematic slide shows the profiles resulting from two kinds of multiple-injection regimens in which insulin lispro is substituted for human regular insulin. The peaks of lispro more closely match the normal profile, but the 4-hour duration of lispro leaves lunch and late evening poorly covered by insulin with the two-mealtime-injection regimen on the left. With NPH at bedtime and lispro with meals, as shown on the right, clear gaps of coverage of basal requirements are evident as well.
- The goal of diabetes treatment is maintenance of long-term near-normoglycemia to prevent the onset and/or progression of long-term complications. Different insulins have different mechanisms of action, with differing abilities to meet this treatment goal. Glargine is a peakless insulin with a long duration of action (nearly 24 hours). Because of these features, it is associated with less nocturnal hypoglycemia and lower postprandial glucose levels. Glargine also has a lower intersubject variability than NPH and ultralente, and it closely mimics continuous subcutaneous insulin infusion (CSII), the gold standard of basal insulin replacement. Lepore M, Pampanelli S, Fanelli C, et al. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000;49:2142-2148.
- Slide 6-51 INSULIN TACTICS Advancing With Multiple Daily Injections Bedtime Glargine vs NPH, With Mealtime Regular A multicenter, randomized, parallel group study was conducted to compare insulin glargine with NPH in patients with type 2 diabetes who were previously treated with insulin-only therapy. The 518 patients were randomized to receive insulin glargine once daily at bedtime or NPH once daily at bedtime or twice daily in the morning and at bedtime based on the patient’s prestudy insulin regimen. In addition, the patients were allowed to use preprandial regular insulin as part of their daily regimen. At baseline, the mean HbA1c was 8.5% and mean FPG was 11.1 mmol/L (196 mg/dL). Similar reductions were observed in HbA1c (–0.41% in the insulin glargine group compared with –0.59% in the NPH group). Compared with baselines, patients receiving insulin glargine achieved a significant reduction in FPG of 1.72 mmol/L (–31 mg/dL) and the NPH groups achieved a reduction of 1.17 mmol/L (–21 mg/dL). Of note, the risk of nocturnal hypoglycemia was reduced by 25% in the patients receiving insulin glargine (31.3% vs 40.2%; P < .02). Rosenstock J, Schwartz S, Clark C, Edwards M, Donley D. Efficacy and safety of HOE 901 (insulin glargine) in subjects with type 2 DM: a 28-week randomized, NPH insulin-controlled trial. Diabetes. 1999;48(suppl 1):A100.
- Explain each component (line) as it is animated. Type 2 diabetes begins with insulin resistance (impaired glucose tolerance), which is linked to macrovascular disease. Beta cell function accelerates to compensate, however, it eventually begins to deteriorate, resulting in insulin deficiency and elevated glucose. In response to deteriorating beta cell function and subsequent loss of first-phase insulin response, postprandial glucose increases, which is associated with the initiation of macrovascular complications. While fasting glucose levels remain normal during the initial stages of this cycle. They eventually rise, initiating the development of microvascular complications. Main Message(s) While physicians often look at fasting glucose as an indication of control, we can see that the postprandial glucose is the initial driver of hyperglycemia and microvascular complications. Because beta cell deterioration is progressive and persistent, all patients who live long enough will eventually need insulin therapy. With the increasing prevalence of type 2 diabetes among younger adults, we will see many patients living with diabetes for many years.
- Slide 6-37 INSULIN TACTICS Starting With Basal Insulin Advantages Patients who no longer respond adequately to oral agents will benefit from combination therapy that consists of maintaining the use of oral antidiabetic agents together with insulin therapy. The advantages of adding basal insulin to prior treatment with oral agents include the following: (1) only one insulin injection may be required each day, with no need for mixing different types of insulin; (2) the use of insulin pens can enhance patient acceptance of the treatment; (3) titration can be accomplished in a slow, safe, simple fashion; and (4) eventually combination therapy requires a lower total dose of insulin. The result is effective improvement in glycemic control while causing only limited weight gain.
- Slide 6-59 PRACTICAL GUIDELINES Starting Basal Insulin The most critical approach to the management of type 2 diabetes patients with persistent hyperglycemia despite combination oral therapy is to use a simple, straightforward strategy that will facilitate initiation of insulin therapy. The increasing use of insulin pens will certainly simplify the administration of insulin, and its use can be demonstrated to patients in “real time” during their visit to the physician’s office. It is very important that patients continue the oral agents at the same dosage and eventually reduce this dose when appropriate. Conservatively, a single insulin dose of around 10 U of NPH given at bedtime or 70/30 insulin given at the evening meal is a standard initial approach to treatment. Basal insulin glargine has the potential to facilitate and extend the use of this insulin strategy because of its long duration of action, peakless flat profile, more predictable response, and reduced risk of hypoglycemia. Insulin glargine is given once daily at bedtime, but based on its insulin kinetics, it could theoretically be given at any time. The insulin dose should be adjusted according to the fasting SMBG level. The insulin dose can be increased on a weekly basis as needed. It should be increased by 4 U if the fasting blood glucose (FBG) is greater than 140 mg/dL, and by 2 U if the FBG is 120 to 140 mg/dL. The treat-to-target level is usually an FBG < 120 mg/dL.
- Slide 6-37 INSULIN TACTICS Starting With Basal Insulin Advantages Patients who no longer respond adequately to oral agents will benefit from combination therapy that consists of maintaining the use of oral antidiabetic agents together with insulin therapy. The advantages of adding basal insulin to prior treatment with oral agents include the following: (1) only one insulin injection may be required each day, with no need for mixing different types of insulin; (2) the use of insulin pens can enhance patient acceptance of the treatment; (3) titration can be accomplished in a slow, safe, simple fashion; and (4) eventually combination therapy requires a lower total dose of insulin. The result is effective improvement in glycemic control while causing only limited weight gain.
- Slide 6-60 PRACTICAL GUIDELINES Advancing Basal/Bolus Insulin Clinical judgment should prevail when determining whether an advance to a basal/bolus insulin regimen is indicated, especially when the fasting blood glucose is acceptable, but this should be considered when the HbA1c is >7% or >7.5% suggesting postprandial hyperglycemia, and/or the SMBG before dinner is >180 mg/dL. There are three main insulin options. The first option is to add morning NPH and mealtime regular or lispro to the initial regimen of bedtime NPH insulin. The second option is to add morning 70/30 to suppertime 70/30 insulin. The third option is to add mealtime regular or lispro to bedtime insulin glargine. In terms of options for the oral agent, the sulfonylurea may be stopped, but some patients may develop wide fluctuations in blood glucose levels that require resumption of the sulfonylurea. For some patients, metformin can be continued to provide weight control, or glitazone can be continued to achieve glycemic stability.
- Slide 6-54 Insulin Tactics: The Future This slide shows some of the treatment approaches involving combination therapy with new insulin preparations that may prove viable in the future. They include the use of combination oral agents + basal insulin glargine, combination oral agents + bolus inhaled insulin, and basal insulin glargine + bolus inhaled insulin. The combination oral agents may consist of a sulfonylurea plus an insulin sensitizer, such as a glitazone or metformin, which also helps control weight gain. Basal insulin glargine has the advantage of providing prolonged action that may last up to 24 hours, with the relatively constant supply of basal insulin resulting from the continuous release of insulin from the injection site. Compared to injections, bolus inhaled insulin may provide mealtime insulin in a less invasive route of administration, which most patients would probably prefer.
- The Somogyi effect is often best illustrated by a log book or case example.