Type 2 Diabetes Mellitus - Role of Insulin Gayotri Goswami, MD, FACE Assistant Clinical Professor of Medicine Division of Endocrinology & Metabolism November 9, 2009

Accounts for 90-95% of all diabetes mellitus cases Caused by a combination of complex metabolic disorders that result from co-existing defects of multiple organ sites such as insulin resistance at the adipose tissue and muscle, a progressive decline in pancreatic insulin secretion and unopposed glucagon action causing unrestrained hepatic glucose production

Before the appearance of clinical symptoms a degree of hyperglycemia may be present, causing pathologic and functional changes in various target tissue Most affected individuals are obese with varying degrees of insulin resistance while the non obese may have a percentage of visceral fat which can also cause insulin resistance

Stages of Type 2 Diabetes Related to Beta-Cell Function 100 75 Beta­Cell Function (%) 50 Type 2 Phase 1 IGT Type 2 Phase 3 25 Postprandial Hyperglycemia Stages of Type 2 Diabetes Related to Beta-Cell Function Beta-cell Function from 0 to 6 years post-diagnosis appear as data points extracted from UKPDS data Hyperglycemia in Type 2 diabetes is associated with a decline in Beta-cell function. Insulin deficiency ultimately causes reduced insulin-mediated glucose uptake from muscle, exaggerated glucose production from the liver, and increased free fatty acid mobilization from adipose tissue. The result initially is postprandial hyperglycemia, which later is followed by fasting hyperglycemia. Insulin resistance, whether genetic or acquired, can contribute to the development of Type 2 diabetes by increasing the requirements for insulin, thus leading to insulin insufficiency in those individuals whose ß cells have limited secretory reserve. Key words: Type 2 Beta cell UKPDS 16. Overview of 6 years’ therapy of type 2 diabetes: a progressive disease. UKPDS. Diabetes. 1995;44:1249-1258. Adapted from Lebovitz HE. Insulin secretagogues: old and new. Diabetes Reviews. 1999;7(3). Type 2 Phase 2 ­12 ­10 ­6 ­2 2 6 10 14 Years from Diagnosis Adapted from Lebovitz HE. Diabetes Reviews. 1999;7(3).

Contributions of FPG and PPG to Overall Glycemia in T2DM 290 patients not on insulin and divided into 5 gps 38 patients were investigated by CGMS A1c is a function of both FPG and PPG- 1) Bonora et al Diabetes Care, 2001:24 2) Rohlfing et al.Diabetes Care,2002;25:275-278 <7.3 7.3- 8.4 8.5 - 9.2 9.3- 10.2 >10.2 FPG = fasting plasma glucose. PPG: Post prandial glucose Adapted with permission from Monnier L et al. Diabetes Care. 2003;26:881-885.

Targets for Glycemic Control* Normal Goal American Diabetes Association1 A1C (%) Preprandial plasma glucose (mg/dL) Peak postprandial plasma glucose (mg/dL) <6.0 <110 <7.0 70-130 <180 European Diabetes Policy Group2 Postprandial glucose (mg/dL) <6.5 <135 American Association of Clinical Endocrinologists3 <140 Targets for Glycemic Control The American Diabetes Association (ADA), European Diabetes Policy Group (EDPG), and American Association of Clinical Endocrinologists (AACE) have all issued recommended guidelines for glycemic control. The ADA suggests that glycosylated hemoglobin A1C (A1C) levels should be maintained at <7.0%, which is higher than that recommended by the EDPG and AACE (6.5%). The ADA guidelines for preprandial plasma glucose allows for a range from 90 to 130 mg/dL, but the EDPG and AACE recommend that glucose levels stay below 110 mg/dL. (For self-monitoring, EDPG recommends <100 mg/dL.) The EDPG and AACE also recommend lower postprandial glucose levels (<135 mg/dL and <140 mg/dL, respectively) compared with the ADA recommendations of <180 mg/dL. References American Diabetes Association. Standards of medical care in diabetes 2006. Diabetes Care. 2006;29(suppl 1):S4-S42. Feld S. AACE Diabetes Guidelines. Endocr Pract. 2002;8(suppl 1):40-82. European Diabetes Policy Group 1999. A desktop guide to type 2 diabetes mellitus. Diabet Med. 1999;16:716-730. Category: Diabetes Keywords: glycemic control, A1C, PPG, FPG, goals *More stringent goal of <6.0% should be considered for individual patients. Generally, A1C goal for each patient is an A1C as close to normal as possible without significant hypoglycemia. A1C = glycosylated hemoglobin A1C. 1. ADA. Diabetes Care. 2006;29(suppl 1):S4-S42. 2. European Diabetes Policy Group 1999. Diabet Med. 1999;16:716-730. 3. Feld S. Endocr Pract. 2002;8(suppl 1):40-82.

“Although insulin therapy has not traditionally been implemented early in the course of Type 2 diabetes, there is no reason why it should not be…” Key Words: Insulin Type 2 Nathan DM. NEJM. Oct 24, 2002;347(17):1342-1349.

Metabolic Management of type 2 DM Nathan et al, A Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care,29:759-764,2006

Insulin Insulin is composed of 2 polypeptide chains the A and B linked together by disulphide bonds Among most species the A chain consists of 21 AA and the B of 30 AA Although the AA sequences differ in species there are certain segments of the molecule that are highly conserved

Insulin Most affective agent, when used in adequate doses to decrease any level of A1c to therapeutic goal Relatively large doses are used in Type 2 insulin resistant patients when compared to Type 1 Has beneficial effects on TG and HDL but can cause weight gain Important side effect is hypoglycemia (can be reduced by education, peakless and short acting insulins) Risk of hypoglycemia increases as we get more aggressive

Ideal insulin therapy One which replicates physiologic insulin secretion Maintains near-normal glycemia Minimizes long term complications Improves quality of life

Physiologic Blood Insulin Secretion Profile 75 Breakfast Lunch Dinner 50 Plasma Insulin (µU/mL) 25 Physiologic Blood Insulin Secretion Profile Physiologic insulin secretion has two components: basal insulin + bolus insulin to cover PPG excursions. Basal or bolus insulin alone is not physiologic therapy. There is a basal level of insulin secretion, and then a surge of insulin secretion (bolus) to cover mealtime needs. This is what occurs in people without diabetes. Ideally, every patient with diabetes would be managed with a therapy that would mimic the normal physiologic profile as closely as possible. This typically requires what we call “intensive insulin therapy” or MDI (multiple daily injections). The goals are to: Maintain near-normal glycemia Minimize long-term complications, both microvascular and macrovascular Improve quality of life Key words: Physiologic Insulin profile White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36. 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Adapted from White JR, Campbell RK, Hirsch I. Postgraduate Medicine. June 2003;113(6):30-36.

Ideal Basal/Bolus Insulin – elementary principal Slide 3-23 Ideal Basal/Bolus Insulin – elementary principal 75 50 25 Breakfast Lunch Dinner Glucose Bolus Insulin Base Insulin Plasma Insulin (U/mL) Ideal Basal/Bolus Insulin Absorption Pattern Ideally, what is needed is: A short-acting insulin with immediate onset and a shorter duration of action; and A long-acting insulin that provides consistent insulin availability—sufficient to prevent interruptions in basal insulin levels. Currently these two preparations are in development (short-acting insulin aspart and long-acting insulin glargine), and it is anticipated that they will be available in 2000. 4:00 8:00 12:00 16:00 20:00 24:00 4:00 8:00 Time Skyler J, Kelley’s Textbook of Internal Medicine 2000.

Loss of Early Insulin Release Leads to Postprandial Hyperglycemia Plasma Insulin Plasma Glucose 60 360 270 40 (mg/dL) (mU/L) 180 20 90 Loss of Early Insulin Release Leads to Postprandial Hyperglycemia Mitrakou and colleagues conducted a study to assess the contribution of the liver, muscle and diminished splanchnic glucose uptake to postprandial hyperglycemia in 10 patients with Type 2 diabetes following a 1 gm/kg oral glucose tolerance test (OGTT) (maximum 75 gm dose). The first graph presents insulin levels and the second graph shows glucose levels. As insulin level is lower in patients with diabetes it explains high glucose levels. The graphs on this slide show that patients with diabetes have a blunted and delayed response to insulin with higher and prolonged glucose excursions compared with nondiabetic subjects. In addition, in contrast to normal subjects, there was an initial rise, rather than fall, in postprandial glucagon (data not shown). The authors concluded that impaired suppression of endogenous hepatic glucose production was the primary cause of postprandial hyperglycemia. Mitrakou A, et al. Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes. 1990;39:1381–1390. –1 1 2 3 4 5 –1 1 2 3 4 5 Hours After Glucose Ingestion Healthy Subjects Patients With Type 2 Diabetes Mitrakou A, et al. Diabetes. 1990;39:1381–1390.

Components of a daily regimen Basal: maintains interprandial and overnight glycemic control Bolus /Nutritional/Prandial: controls the post meal glucose surge

What are insulin analogs? An insulin analog is an altered form of insulin. Through genetic engineering of the underlying DNA,the amino acid sequence of insulin is changed to alter its absorption, distribution, metabolism and excretion.

INSULINS Peak (duration) hrs RAPID-ACTING INSULIN ANALOGS Humalog (lispro) 1-2 (2-6) Novolog (aspart) 1-2 (2-6) Glulisine (epidra) 1-2 (2-6) SHORT-ACTING - Regular 2 - 4 (3-6) INTERMEDIATE-ACTING NPH (Neutral Protamine Hegedron) 6-12 (10-24) LONG ACTING Lantus / glargine none (10-24) Levemir / detemir - Insulin detemir has a slight peak and is used BID Genetically engineered new insulins by changing the order of amino acids that make up human insulin, absorbed faster and quicker onset of action LANTUS forms microprecipitates after being injected S/Q

Fixed dose insulin mixes HUMULIN (NPH/REG) 70/30 50/50 HUMALOG (Prot-lispro/free lispro) 75/25 NOVOLIN (NPH/REG) NOVOLOG MIX (Prot-aspart/aspart)

Insulin delivery devices

Long Acting Analogs

Lantus (Glargine)- formulary Two positively charged arginine molecules are added to the C-terminus of the B-chain, asparagine at position 21 in the A-chain is replaced by glycine              

Lantus Upon injection into the subcutaneous space(pH 7.4), the acidic (4.0) glargine solution is neutralized and it forms an amorphous suspension resulting in delayed absorption and an extended duration of action. Reduced incidence of hypoglycemia compared with NPH

Levemir (Detemir) To the Lysine AA at position B29 a fatty acid (myristic acid ) is bound. After it is absorbed it binds to albumin through the fatty acid at position B29 and the slowly dissociates from this complex.                                                                                       .

NPH- formulary Neutral Protamine Hegedron: is a suspension of crystalline zinc insulin combined with a polypeptide protamine Intermediate acting and the most commonly used basal insulin Half life is 8 hours and reaches a peak concentration at 4-6 hrs

Short Acting Analogs

Lispro (Humalog)- formulary Lysine and proline residues on the C-terminal end of the B-chain are reversed Insulin Glulisine (Apidra) The AA asparagine at position B3 is replaced by lysine and the lysine in position B29 is replaced by glutamic acid

Aspart (Novolog) The AA , B28, which is normally proline , is substituted with an aspartic acid residue

Human Insulin Time-Action Patterns Normal insulin secretion at mealtime Change in serum insulin Theoretical representation of expected insulin release in nondiabetic subjects Baseline Level Human Insulin Time-Action Patterns Key Words: Insulin profile Time (hours) SC injection

Human Insulin Time-Action Patterns Normal insulin secretion at mealtime Regular insulin (human) Change in serum insulin Theoretical representation of profile associated with Regular Insulin (human) Baseline Level Human Insulin Time-Action Patterns Characteristics of regular insulin (mealtime) Should inject 30 minutes before meals Risk of early postprandial hyperglycemia Risk of late postprandial hypoglycemia Key words: Insulin profile Regular Human Insulin Time (hours) SC injection

Analog Insulin Time-Action Patterns Normal insulin secretion at mealtime Change in serum insulin Theoretical representation of expected insulin release in nondiabetic subjects Baseline Level Analog Insulin Time-Action Patterns Key words: Insulin profiles Time (hours) SC injection

Analog Insulin Time-Action Patterns Normal insulin secretion at mealtime Rapid-Acting Insulin Analog Change in serum insulin Theoretical representation of profile associated with rapid-acting Insulin Analog Baseline Level Analog Insulin Time-Action Patterns Key words: Insulin profiles Time (hours) SC injection

Analog Insulin Time-Action Patterns Normal insulin secretion at mealtime QD (basal) Analog Insulin Change in serum insulin Theoretical representation of profile associated with Basal Analog Insulin Baseline Level Analog Insulin Time-Action Patterns QD (basal) analog insulin alone provides limited coverage against early hyperglycemia Basal analog insulin alone does not cover postprandial glucose excursions Key Words: Insulin profile Basal Analog Time (hours) SC injection

Human Insulin Time-Action Patterns Normal insulin secretion at mealtime Human Premix 70/30 (70% NPH & 30% Regular) Theoretical representation of profile associated with Human Premix 70/30 Change in serum insulin Baseline Level Human Insulin Time-Action Patterns Characteristics of Human Premix 70/30 are the same as NPH and Regular Human Insulin because it contains 70% NPH and 30% Regular Human Insulin. Because it is a mix of these 2 insulins, there is an additive effect which creates a broader peak. Characteristics of NPH insulin (basal) No control of early hyperglycemia Increased risk of late hypoglycemia Characteristics of regular insulin (mealtime) Should inject 30 minutes before meals Risk of early postprandial hyperglycemia Risk of late postprandial hypoglycemia Key words: Insulin profile Human Premix 70/30 Regular Human Insulin NPH Human Time (hours) SC injection

Analog Insulin Time-Action Patterns Normal insulin secretion at mealtime Insulin Analog Premix Change in serum insulin Theoretical representation of profile associated with Insulin Analog Premix Baseline Level Analog Insulin Time-Action Patterns Key words: Insulin profiles Time (hours) SC injection

Advantages of rapid acting insulin analogs Restores the early insulin peak in combination with meal ingestion Prevents the hyperinsulinemia resulting from the late absorption of regular insulin and thereby protects against hypoglycemia

OPTIONS……… Once daily background or basal insulin if fasting BG is elevated but glucose values remain stable during the day A simple and practical approach is to implement once daily basal insulin and continue OAD therapy, titrating according to FBG * INSIGHT(Implementing New Strategies with Insulin Glargine for Hyperglycemic Treatment – Gerstein et al 2006.Diab.Med.23:736-742

OPTIONS……… Once daily or twice daily pre-mixed insulin analogue, orally administered drugs may or may not be continued Basal bolus therapy…..first initiate basal along with 1 bolus injection before the largest meal and eventually at each meal if needed

OAD and Insulin Proven to be effective in a review of 20 RCT Provides comparable glycemic control to insulin monotherapy Reduction in total daily insulin requirements Reduces weight gain and helps glycemic control by peripheral insulin sensitization and inhibiting hepatic gluconeogenesis

Dosing Glargine is effectively administered either in the morning or evening, provided the timing of injection is consistent each day Detemir is administered both once and twice daily NPH is usually administered twice daily, in the morning and at bedtime Detemir: may require twice daily in those needing increasing doses to reach goal as shown in the 4T trial and the Glargine/Detemir head to head trial

Dosing Short acting analogs are given 5-15 minutes before a meal while Apidra or Glulysine can be given upti 20 minutes after start of a meal RI is given atleast 20-30 minutes before a meal A short acting analog can be started as 10% of the TDD (basal insulin can then be decreased by 10%) and can be added to the heaviest meal

What doses to start with…….. With HbA1c <8%, begin 0.1U/Kg body weight HbA1c 8-10%, start 0.2U/kg body weight HbA1c >10%, start 0.3U/Kg body weight 10 units /day With pre-mixes can divide the total dose by 2 if used twice a day With insulin glargine, adjust dose every 3-7 days until target fasting dose is reached Bergenstal Endocrine Practice,Jan 2006

Titration Forced weekly titration (physician led) Treat to Target Trial (Glargine/NPH) & (Detemir BID/NPH) Patient- led titration (usually every 2-3 days according to BG goal) AT.LANTUS trial PREDICTIVE trial

Titration For titrating prandial insulin pre-meal BG and 2 hour post meal BG is needed and doses are adjusted according to the goals

Glycemic Control

LANTUS Vs NPH + Oral agents (Treat to Target Trial) Large multicenter trial, patients had A1c Between 8-10%, 24 weeks duration with either Lantus/NPH + 2 oral agents to bring FBG to <100mg/dL Treat to Target Trial was done to test two hypothesis 1.Whether adding a basal insulin to failing combination therapy would bring HbA1c to < or = 7% 2.whether a long acting insulin such as glargine has different side effects than insulin when used in the same way.Therefore when insulin is added it can frequently improve goals Large multicenter trial where pateints had HbA1c between 8-10% and were treated for 24 weeks with either NPH or glargine and titrated weekly to bring down the FBG to <100.More than 80% were taking 2 oral agents Riddle et al.Diabetes Care;2003:3080-3086

Adverse effects

4T Study (Three year efficacy of complex insulin regimens ) 3 year open label, multicenter trial 708 patients with A1c levels between 7-10% On Metformin and a SFU Outcomes – A1c , hypoglycemia & weight gain Randomly assigned to 3 groups Biphasic aspart Aspart pre-meals TID Basal Detemir once daily (twice if needed) Holman et al.NEJM.2009,361,18

Results Median A1c was similar in biphasic (7.1%) prandial (6.8%) and basal (6.95) Median rates of hypoglycemia per patient per year were lowest in the basal (1.7), biphasic (3.0), and prandial (5.7), p<0.001 for overall comparison Mean weight gain was higher in the prandial group(5.7kg±0.5) than either biphasic (6.4±0.5) or basal (3.6 ±0.5)

Adverse effects Detemir has been associated with less weight gain when compared with NPH at equivalent glycemic control Detemir also had significantly less weight gain when compared with glargine (Detemir 3kg; glargine 3.9kg,P<0.012) Raslova et al, 2004.Diabetes.Res.Clin.Pract 66:193-20 Haak T et al.2005.Diabetes Obes metab.7:56-64 Hermansen K et al 2006.Diabetes Care 29;1269-1274

Conclusions The insulin analogues offer improved pharmacokinetic and pharmacodynamic profiles compared to NPH and RI and therefore offer advantages with respect to safety,efficacy and variability These advantages may help Type 2 Diabetics overcome some of the barriers associated with insulin initiation, hypoglycemia and weight gain

Conclusions Lantus offers a consistent 24 hour profile and predictability and a lower risk of hypoglycemia when compared with NPH and therefore facilitates more aggressive titration Detemir is associated with equivalent glycemic control, less risk of hypoglycemia lower within-subject day-to-day control and less weight gain

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