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Call Iris Carrasquillo RN, CDE for Diabetes Issues 718 904-2883
The Conundrum of Diabetes In hospitalized patients Call Iris Carrasquillo RN, CDE for Diabetes Issues Joel Zonszein

The Conundrum of Diabetes In hospitalized patients
Joel Zonszein, MD, CDE, FACP, FACE Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York

CARDIOVASCULAR DISEASE
MICROVASCULOPATHY COMPLICATIONS CARDIOVASCULAR DISEASE INSULIN RESISTANCE INSULIN SECRETION HYPERGLYCEMIA IGT T y p e d I a b e t e s Zonszein J. in Hurst’s the Heart (Ch 78) 1998;

NG IGT T2DM METABOLIC SYNDROME BP (mmHg) >130/85
TG (mg/dl) > 150 HDL-C (mg/dl) Men < Women < 50 WAIST CIRCUMF (inches) Men > Women > 35 CARDIOVASCULAR RISK STRESS HYPERGLYCEMIA 2-hr PG mg/dl FG mg/dl mg/dl NG IGT T2DM DISEASE PROGRESSION Pantaleo A, Zonszein J. Heart Dis. 2003;5:323-33

Glycemic Control and Complications Older Studies -10 years latter
DCCT 9  7% 76% 54% 60% 57% p=.02* Kumamoto 9  7% 69% 70% - UKPDS 8  7% 17-21% 24-33% - 13% p=.007** HbA1c Retinopathy Nephropathy Neuropathy CVD Mortality 10 years letter This reduction in HbA1c was associated with significant reductions in microvascular disease. In the DCCT, when all major cardiovascular and peripheral vascular events were combined, intensive therapy reduced the risk of cardiovascular disease by 41%, although this reduction was not statistically significant. The relative youth of the patient cohort made the detection of a difference between treatments unlikely. The 16% reduced risk incidence of coronary heart disease in the UKPDS had a P value of 0.052, not quite statistically significant, but arguably clinically significant. ** N Eng J Med September 10, 2008 UKPDS Study Group: Lancet 352:837-53, 1998 *DCCT/EDIC Study Research Group, N Engl J Med December 353:2643-, 2005 Ohkubo Y: Diabetes Res Clin Prac 28:103-17, 1995 DCCT Study Group: N Engl J Med 329:977-86, 1993

Is Tighter Glycemic Control Better? Newer Studies
Characteristics ADVANCE VADT ACCORD No. participants Mean age (yr) Median study duration (yr) 11,140 66 5 1,791 60 5.6 10,251 62 3.4 Baseline A1c Outcome A1c (intensive /control) 7.2 6.3 vs. 7.0 9.4 6.9 vs. 8.5 8.1 6.4 vs. 7.5 Major Hypoglycemia (% yr) 2.7 vs. 1.5 21.2 vs. 9.9 16.2 vs. 5.1 Weight gain (Kg) 0.1 vs. 1.0 7.8 vs. 3.4 3.5 vs. 0.4 HR Primary outcomes (95% CI) HR Mortality (95% CI) 0.94 ( ) 0.93 ( ) 0.88 ( ) 1.07 ( ) 0.90 ( ) 1.22 ( ) HR for primary outcome (95% CI) 0.90 (0.78–1.04) 0.9 (0.82–0.98); macrovascular 0.94 (0.84–1.06) 0.88 (0.74–1.05) HR for mortality findings (95% CI) 1.22 (1.01–1.46) 0.93 (0.83–1.06) 1.07 (0.81–1.42) N Engl J Med 2009;360. The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P = 0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P = 0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group. ACCORD. N Engl J Med 2008;358 ADVANCE. N Engl J Med 2008;358 VADT N Engl J Med 2009;360

VADT in the context of the “natural history of Type 2 Diabetes
HbA1c (%) TIME (years since diagnosis) Del Prato S Diabetologia 2009;52:1259

VADT in the context of the “natural history of Type 2 Diabetes
Drive risk for complications Build up “bad” metabolic memory HbA1c (%) TIME (years since diagnosis) Del Prato S Diabetologia 2009;52:1259

Multiple Risk Interventions in Type 2 Diabetes (STENO-2 Trial)
160 patients with type 2 diabetes and microalbuminuria, randomized to conventional or intensive treatment for multiple risks for 8 years Conventional Intensive Blood Pressure <160/95 <140/85 HbA1c <7.5% <6.5% Total Chol <250 mg/dL <190 mg/dL ACE-Inhibitor No Yes Aspirin with known CAD Yes Yes with PVD No Yes No PVD or CAD No Yes Gaede P et al. N Engl J Med. 2003;348:

Multiple Risks Interventions in Type 2 Diabetes (STENO -2 Trial)
Relative Risk End Points Reduction Cardiovascular Composite 53% (P=0.007) Nephropathy 61% (P=0.003) Retinopathy 58% (P=0.02) Autonomic neuropathy 63% (P=0.002) Lower CVD mortality years) 43% (P=0.04) * Gaede P et al. N Engl J Med. 2003;348: *Gaede P et al. N Engl J Med. 2008;358:

Smoking cessation + Treatment of: Hypertension Dyslipidemia
Hyperglycemia 14

Mortality in People With Diabetes: Causes of Death
Diabetes and mortality closer to home… Mortality in People With Diabetes: Causes of Death During the last decade in NYC: All cause mortality: ▼by 12% Diabetes related mortality: ▲by 50% Diabetes related Hospitalizations: ▲by 44% Fang J, Alderman MH. Diabetes 2006;55:768 Worldwide increases in obesity and diabetes have aroused concern that increased morbidity and mortality will follow. The objective in this paper was to determine the trend of diabetes-related morbidity and mortality in New York, New York. Using New York death certificate data for 1989–1991 and 1999–2001 and hospital discharge data for 1988–2002, all-cause and cause-specific mortality in 1990 and 2000 was measured as well as annual hospitalization rates for diabetes and its complications among patients hospitalized with acute myocardial infarction and/or diabetes. During the past decade, all-cause and cause-specific mortality rates declined, with the striking exception of diabetes, which increased 61 and 52% for men and women, respectively, as did hospitalization rates for diabetes and its complications. The percentage of all acute myocardial infarctions occurring in patients with diabetes increased from 21 to 36%, and the absolute number doubled from 2,951 to 6,048. Although hospital days due to acute myocardial infarction fell overall, for those with diabetes, they increased 51% (from 34,188 to 51,566). These data document a marked upsurge in diabetes-related mortality and morbidity in New York City, including a sharp increase in diabetic patients hospitalized for myocardial infarction. If continued, this threatens the long-established nationwide trend to reduced coronary artery disease events.

Approved Antidiabetic Medications in the US
Medicaton Route Year (FDA approved) Insulin Inhaled Parenteral Pulmonary 1921 Sulfonylureas Oral 1946 Biguanides Phenphormin Metformin 1995 Alpha-glycosidase inhibitors Thiazolidinediones Troglitazone Rosiglitazone Pioglitazone 1999 Glinides 1997 GLP analogues Byetta® 2005 Amylin analogues Symlin® DPP-IV inhibitors Januvia® and Onglyza 2006 and 2009 Table of approved antidiabetic –or antihyperglycemic agents, and route of administration and approval date by the FDA Modified from Nathan D. N Eng J Med 2007;356: 16

Combination Therapy; Different Sites of Action
Injectables: INSULINS EXENATIDE and PRAMLINTIDE glucagon, insulin, gastric, orectins SITAGLIPTIN Liver: Glucose production BIGUANIDES Muscle and adipose tissue: Peripheral glucose uptake THIAZOLIDINEDIONES Pancreas: Insulin secretion SULFONYLUREAS MEGLITINIDES The major metabolic defects present in type 2 diabetes mellitus that lead to glucose elevation are: decreased glucose transport and utilization at the level of muscle and adipose tissue, increased glucose production by the liver, and relatively insufficient insulin secretion by the pancreas. Added to this abnormal flux is any dietary carbohydrate that is absorbed as glucose or converted to glucose during the absorptive or postabsorptive process. Sulfonylureas, the oldest oral agents used to treat type 2 diabetes, stimulate pancreatic insulin secretion. More recently, repaglinide, a meglitinide, has been added to the available agents that stimulate increased pancreatic insulin secretion. Insulin administration, the oldest pharmacologic therapy for diabetes is also a choice to increase circulating insulin levels in response to failing b-cell function and increased insulin resistance. Biguanides increase the sensitivity of the liver to circulating insulin, thereby reducing the level of glucose produced by the liver in type 2 diabetes. Thiazolidinediones, peroxisome proliferator-activated receptors act at a number of sites to lower blood glucose levels. They also improve insulin sensitivity at the level of the liver, thereby decreasing the excess glucose production by that organ. They are more commonly recognized for their action in increasing peripheral insulin sensitivity in muscle and adipose tissue. By improving this sensitivity, they allow for improvement in the utilization of glucose by the muscle and adipose tissue. It should be noted that biguanides, in high doses, also have some mild effect on increasing peripheral glucose utilization. -Glucosidase inhibitors decrease the rapid influx of carbohydrate from ingested food and slow the digestion of starches and the absorption of glucose and several other sugars. Sonnenberg GE, Kotchen TA. Curr Opin Nephrol Hypertens. 1998;7(5): In this cartoon insulin and EXENATIDE-Byetta, pramlintide-Symlin and sitagliptin-Januvia were added. Intestine: Digestion and absorption of carbohydrates a-GLUCOSIDASE INHIBITORS a

The 2006 ADA Treatment Algorithm
Yes* No A1C7% Diagnosis Lifestyle Intervention + Metformin Add Basal Insulin Most effective Add Sulfonylurea Least expensive Add Glitazone No hypoglycemia Intensify Insulin Add Basal or Intensify Insulin Intensive Insulin + Metformin  Glitazone *Check A1C every 3 months until <7% and then at least every 6 months thereafter. Nathan DM, et al. Diabetes Care. 2006;29:

FBG between 110 and 140 mg/dl A1c 8.1%
How are we managing hyperglycemia in 2008… What drug to use when combination of SUO and Metformin fails? Patient: Maria Age: 51 Height: 5' 3“, Weight: 224 lbs FBG between 110 and 140 mg/dl A1c 8.1% Treatment: maximum doses of MET (5 y) and an SFU (2 y) Patient goal: motivated; Choices: Add pioglitazone Add neutral protamine Hagedorn (NPH) h,s. Add exenatide twice daily DISCUSSION POINTS Doris is motivated to “take control” of her A1C level so she can “be around” for her grandchildren Doris is frustrated with all of the “planning and doing” associated with type 2 diabetes The physician wants to improve Doris’s A1C but knows that she has gained weight with current therapy SLIDE BACKGROUND Hypothetical patient profile See accompanying Prescribing Information and safety information included in this presentation N Engl J Med 2008;358: 19

53% add exenatide twice daily 32 % add NPH insulin before bedtime
How are we managing hyperglycemia in 2008… What drug to use when combination of SUO and Metformin fails? Patient: Maria USA Diabetologist: 53% add exenatide twice daily 32 % add NPH insulin before bedtime 15% add pioglitazone (15%) USA other specialties: 52% add NPH before bedtime 24% add exenatide twice daily 24% add pioglitazone DISCUSSION POINTS Doris is motivated to “take control” of her A1C level so she can “be around” for her grandchildren Doris is frustrated with all of the “planning and doing” associated with type 2 diabetes The physician wants to improve Doris’s A1C but knows that she has gained weight with current therapy SLIDE BACKGROUND Hypothetical patient profile See accompanying Prescribing Information and safety information included in this presentation N Engl J Med 2008;358: 20

The 2006 ADA Treatment Algorithm
Yes* No A1C7% Diagnosis Lifestyle Intervention + Metformin Add Basal Insulin Most effective Add Sulfonylurea Least expensive Add Glitazone No hypoglycemia Intensify Insulin Add Basal or Intensify Insulin Intensive Insulin + Metformin  Glitazone *Check A1C every 3 months until <7% and then at least every 6 months thereafter. Nathan DM, et al. Diabetes Care. 2006;29:

Another Day….. another new Consensus Algorithm the 2009…
Tier 1: Well-validated core therapies* At Diagnosis: Lifestyle + MET Lifestyle + MET + Basal Insulin Lifestyle + MET + Basal/Bolus Insulin A1c ≥7% Lifestyle + MET + SFU† STEP 1 STEP 2 STEP 3 Tier 2: Less well-validated therapies* Lifestyle + MET + Pio No hypoglycemia Edema/CHF Bone loss Lifestyle + MET + Pio + SFU† Lifestyle + MET + GLP-1 Agonist‡ No hypoglycemia Weight loss Nausea/vomiting Lifestyle + MET + Basal insulin *Validation based on clinical trials and clinical judgment †SFUs other than glybenclamide (glyburide) or chlorpropamide. ‡Insufficient clinical use to be confident regarding safety. Adapted from Diabetes Care. 2009;32: For Important Safety Information about exenatide (GLP-1 agonist), see slides 9-11 and the accompanying full Prescribing Information. F ©2007 AMYLIN PHARMACEUTICALS, INC. AND ELI LILLY AND COMPANY.

Management of Hyperglycemia
in Hospitalized patients

Intensive insulin therapy in critically ill patients.
NON-DIABETES Sodi-Pallares “polarizing GIK solution” Metabolic control in SICU patients Metabolic control in MICU patients Intensive insulin therapy in sepsis (German SepNet) NICE-SUGAR DIABETES DIGAMI DIGAMI 2 The German Competence Network Sepsis (SepNet) N Engl J Med 2008;358: Optimal glucose control and fluid resuscitation in patients with septic shock remain a challenge In this study involving more than 500 patients, the potential benefit of maintaining euglycemia through intensive insulin therapy and optimal fluid resuscitation with either pentastarch or Ringer's lactate was assessed There was no benefit in the intensive-therapy group with respect to either 28-day survival or organ function; there was more severe hypoglycemia in the intensive-therapy group and more acute renal failure in the pentastarch group Sodi-Pallares D, 1963 Dis Chest 43: 424 Diaz R, 1998 Circulation 24:2227–2234 Kjellman UW, 2000 Scand Cardiovasc J 34:321–330 Van Den Berghe G, 2001 N Engl J Med 345:1359 –1367 SepNet. Study. N Engl J Med 2008;358: NICE-SUGAR Study. N Engl J Med 2009;360:

Dr. Demetrio Sodi Pallares
Glucose Insulin and Potassium Infusion (GIK) Dr. Demetrio Sodi Pallares

Overview of GIK Therapy for AMI: A 30-Year Prospective
Overview of Glucose-Insulin-Potassium Therapy for AMI: A 40-Year Prospective OL (off-label) indicates that one or more drugs in the slide reflect nonFDA-approved use or are investigational in nature. Overview of Glucose-Insulin-Potassium Therapy for AMI: A 40-Year Prospective Glucose-insulin-potassium (GIK) therapy has been advocated for the treatment of acute myocardial infarction (AMI) as a polarizing agent to promote electrical stability and also as an agent for metabolic support. Fath-Ordoubadi and Beatt conducted a meta-analysis of the mortality data from 9 randomized placebo-controlled studies of GIK therapy in AMI. A total of 1,932 patients were included in the analysis (956 patients in the GIK group and 976 in the placebo group). As shown in this slide, the number of deaths in the GIK group was significantly lower than in the placebo group (16.1% [154/956] vs 21% [205/976]; P=0.004), with an odds ratio of 0.72 and 95% confidence interval (CI) of 0.57 to The proportional mortality reduction was 28% (95% CI, 10% to 43%). The number of lives saved per 1,000 patients treated with GIK therapy was 49 (95% CI, 14 to 83). These results suggest that GIK therapy may have an important role in reducing in-hospital mortality after AMI. Fath-Ordoubadi F, Beatt KJ. Circulation. 1997;96:

Glucose Insulin and Potassium Infusion (GIK)
in STEMI: Death at 30 Days by Predefined Subgroups CREATE-ECLA: Effect of GIK Therapy on Mortality in Patients With STEMI* OL (off-label) indicates that one or more drugs in the slide reflect nonFDA-approved use or are investigational in nature. CREATE-ECLA: Effect of GIK Therapy on Mortality in Patients With STEMI Glucose-insulin-potassium (GIK) therapy has been postulated to improve mortality in patients with acute myocardial infarction. The Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation-Estudios Cardiologicos Latin America (CREATE-ECLA) trial is a randomized, controlled study with the objective of determining the effect of high-dose GIK infusion on mortality in patients (N=20,201) with acute ST-segment elevation myocardial infarction (STEMI). The study infusion consisted of 25% glucose, 50 U/L of insulin, and 80 mEq/L of potassium and infused at a rate of 1.5 mL/kg per hour for 24 hours. Patients were randomly assigned to groups receiving either usual care (n=10,110) or usual care plus GIK infusions (n=10,091). The primary outcome measure was mortality from any cause at 30 days after randomization. Secondary outcome measures were nonfatal cardiac arrest, cardiogenic shock, and reinfarction. Overall this study demonstrated that GIK infusion did not significantly impact outcomes. The lack of apparent benefit may reflect the dominant effect of revascularization minimizing detection of any benefit of GIK that would have been seen in the absence of revascularization and in the presence of persistent ischemia. Within the study participant subgroups, individuals with diabetes were represented in both the control (n=1,802) and GIK treatment groups (n=1,780). As shown in this slide, GIK infusion did not provide benefit to either of these groups. The authors conclude that high-dose GIK infusion has a neutral effect on mortality, cardiac arrest, and cardiogenic shock in patients with acute STEMI. CREATE-ECLA Investigators. JAMA. 2005;293:

Intensive insulin therapy in SICU patients: Improves survival
100 Intensive treatment 96 92 Survival in ICU (%) Conventional treatment 88 84 RR 43% (95% CI ) 80 Intensive Insulin Therapy in Critically Ill Surgical Patients Improves Survival At 12 months, with a total of 1,548 patients enrolled, mortality during intensive care was reduced from 8.0% with conventional treatment to 4.6% with intensive insulin therapy (P < 0.04, with adjustment for sequential analyses). van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001;345:1359–1367. 20 40 60 80 100 120 140 160 Days After Admission Conventional: insulin when blood glucose > 215 mg/dL. Intensive: insulin when glucose > 110 mg/dL and maintained at 80–110 mg/dL van den Berghe G, et al. N Engl J Med. 2001;345:1359–1367.

Intensive insulin therapy in SICU patients baseline characteristics
Conventional n 783 Intensive n 785 Age 62.2 63.4 BMI 25.8 26.2 Cardiac surgery (%) 63 62 History of Diabetes 13 Glucose >110 (%) Glucose >200 (%) 76 73 11 Van den Berghe G. New Engl J Med 2001;345:

Intensive insulin therapy in SICU patients
Conventional n 783 Intensive n 785 p value Insulin therapy n (%) 307 (39.2) 755 (98.7) <0.001 Median Insulin does IU/D 33 71 Morning glucose 173 103 % BG < 40 mg/dL 6 39 Van den Berghe G. New Engl J Med 2001;345:

Glycemic Targets in Hospital Patients 2004
Glycemic Targets (ACE)1 ICU 110 mg/dL Medical/Surgical Units Preprandial: 110 mg/dL Maximal glucose: 180 mg/dL Glycemic Targets (ADA)2 <180 mg/dL (target, 110 mg/dL) Preprandial: mg/dL (target, 110 mg/dL) Postprandial <180 mg/dL Glycemic Targets in Hospital Patients  The American College of Endocrinology, working with the American Association of Clinical Endocrinologists, published the following recommendations for glycemic targets in hospitalized patients1: — In the intensive care unit, the target should be 110 mg/dL (6.1 mmol/L) — The target measurements on noncritical medical/surgical units include  Preprandial levels of 110 mg/dL (6.1 mmol/L)  Maximal glucose levels of 180 mg/dL (10.0 mmol/L) — Values above 180 mg/dL (10 mmol/L) are an indication to monitor glucose levels more frequently to determine the direction of any glucose trend and the need for more intensive intervention. Achieving these targets may require consultation with an endocrinologist or DM specialist  The American Diabetes Association gives the following recommendations for glycemic levels in hospitalized patients2: — In the intensive care unit, glucose levels should be <180 mg/dL, with an ideal target of 110 mg/dL — Targets for patients on noncritical medical/surgical units should include  Preprandial levels of 90 to 130 mg/dL, with a target of 110 mg/dL  Postprandial levels of <180 mg/dL _________________________________________________________________________________________________________ 1. Garber AJ, Moghissi ES. Position statement on inpatient diabetes and metabolic control. Endocr Pract. 2004;10(suppl 2):4-9. 2. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36. ACE indicates American College of Endocrinology; ADA, American Diabetes Association; ICU, intensive care unit. Garber AJ, Moghissi ES. Endocr Pract. 2004;10(suppl 2):4-9. American Diabetes Association. Diabetes Care. 2005;28(suppl 1):S4-S36.

Treating hyperglycemia aggressively “may be beneficial” and should be done in a sane and cost effective manner Counterpoint: Inpatient management. A premature call to arms Inzucchi and Rosenstock Diabetes Care April :976

NICE-SUGAR: Outcomes Conventional Conventional Intensive Intensive
180 1.0 Conventional 160 0.9 140 Conventional BG, mg/dL Probability of Survival 0.8 120 108 0.7 Intensive 100 Intensive P=.03 80 0.6 Base- line 1 2 3 4 5 6 7 8 9 10 11 12 13 14 10 20 30 40 50 60 70 80 90 Days After Randomization Days After Randomization The figure at the left shows mean BG levels. The dashed line indicates 108 mg/dL, the upper limit of the target range for intensive glucose control. The primary end point—death by 90 days after randomization—occurred significantly more often in the intensive-control group than in the conventional-control group (27.5% vs 24.9%; P=.02). The absolute difference in mortality was 2.6% (95% CI, ), and the odds ratio for death with intensive control was 1.14 (95% CI, ; P=.02). The figure at the right shows Kaplan-Meier estimates for the probability of survival, which at 90 days was greater in the conventional-control group than in the intensive control group (HR, 1.11; 95% CI, ; P=.03). Severe hypoglycemia (blood glucose level, ≤40 mg/dL) was significantly more common in the intensive-control group than in the conventional-control group (6.8% vs 0.5%; P<.001). The results of the NICE-SUGAR trial suggest that intensive glucose control harms critically ill patients in terms of mortality risk (number needed to harm, 38) and severe hypoglycemia. 90-day mortality: IIT: 829 patients (27.5%), CIT: 751 (24.9%) Absolute mortality difference: 2.6% (95% CI, ) Odds ratio for death with IIT: (95% CI, ; P=.02) 3054 received IIT goal: mg/dL (time weighted BG = 118 mg/dL) 3050 received CIT goal: <180 mg/dL (time-weighted BG = 145 mg/dL) Finfer S, et al. N Engl J Med. 2009;360::1283 NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, et al. Intensive versus conventional glucose control in critically ill patients. N Engl J Med. 2009;360(13): 34

Glycemic Targets in Hospital Patients 2009
Glycemic Targets (ACE)1 ICU 110 mg/dL Medical/Surgical Units Preprandial: 110 mg/dL Maximal glucose: 180 mg/dL Glycemic Targets (ADA)2 <180 mg/dL (target, 110 mg/dL) Preprandial: mg/dL (target, 110 mg/dL) Postprandial <180 mg/dL Glycemic Targets (ADA) and (ACE) (target, 140 to 180 mg/dL) Preprandial: target < 140 mg/dL Postprandial or random <180 mg/dL Glycemic Targets in Hospital Patients  The American College of Endocrinology, working with the American Association of Clinical Endocrinologists, published the following recommendations for glycemic targets in hospitalized patients1: — In the intensive care unit, the target should be 110 mg/dL (6.1 mmol/L) — The target measurements on noncritical medical/surgical units include  Preprandial levels of 110 mg/dL (6.1 mmol/L)  Maximal glucose levels of 180 mg/dL (10.0 mmol/L) — Values above 180 mg/dL (10 mmol/L) are an indication to monitor glucose levels more frequently to determine the direction of any glucose trend and the need for more intensive intervention. Achieving these targets may require consultation with an endocrinologist or DM specialist  The American Diabetes Association gives the following recommendations for glycemic levels in hospitalized patients2: — In the intensive care unit, glucose levels should be <180 mg/dL, with an ideal target of 110 mg/dL — Targets for patients on noncritical medical/surgical units should include  Preprandial levels of 90 to 130 mg/dL, with a target of 110 mg/dL  Postprandial levels of <180 mg/dL _________________________________________________________________________________________________________ 1. Garber AJ, Moghissi ES. Position statement on inpatient diabetes and metabolic control. Endocr Pract. 2004;10(suppl 2):4-9. 2. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36. ACE indicates American College of Endocrinology; ADA, American Diabetes Association; ICU, intensive care unit. Garber AJ, Moghissi ES. Endocr Pract. 2004;10(suppl 2):4-9. American Diabetes Association. Diabetes Care. 2005;28(suppl 1):S4-S36. Consensus: Inpatient Hyperglycemia. Endocr Practice 2009;15 (No.4)

DIGAMI: Intensive insulin therapy improves mortality: AMI in patients with Diabetes
Standard treatment IV insulin 48 hours, then 4 injections daily All subjects Low-risk and not previously on insulin 70 70 (N = 620) (N = 272) 60 60 Risk reduction (28%) Risk reduction (51%) 50 50 P = 0.011 P = Mortality (%) 40 40 30 30 20 20 DIGAMI: Insulin Therapy Improves Outcomes in Patients With MI 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 4-injection regimen subsequently for as long as 5 years. The figure shows the cumulative total mortality rates in the whole population of 620 subjects randomized to the 2 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 due partly to immediate intravenous infusion of insulin; however, the survival curves tended to separate further over time, suggesting an ongoing benefit from intensive treatment or the benefit of long-term subcutaneous insulin therapy. Malmberg K, Rydén L, Hamsten A, et al., 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. 10 10 1 2 3 4 5 1 2 3 4 5 Follow-up (years) Follow-up (years) DIGAMI = Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction. Malmberg K, et al. BMJ. 1997;314:1512–1515. (Reproduced with permission from the BMJ Publishing Group.)

DIGAMI 2: Intensive insulin therapy during AMI n1253
Grup 1 n=474 Intensive Insulin Control IV insulin + glucose Grup 2 n=473 Standard Control IV insulin + glucose Grup 3 n=306 Routine use of insulin HbA1c 7.2% 7.3% FG mg/dl Admision hrs Final ~6.8% European Heart Journal 2005;26:

DIGAMI 2: Time to first major event Death, Reinfarction, or Stroke
same outcomes European Heart Journal 2005;26:

(Reference: Mean BG 100-110 mg/dl)
Mean Glucose & In-Hospital Mortality in Patients with AMI (Reference: Mean BG mg/dl) N= 16,871 Kosiborod M et al. Circulation 2008:117:1018 40

Is hypoglycemia simply a ‘marker’ of the sickest patients?
Hypoglycemia & Mortality in Hyperglycemic AMI Patients: Influence of Insulin Therapy N=7338 no hypo N=482 hypo (BG <60) 20 18.4 Hypoglycemia P<.001 P=.92 No hypoglycemia 10.4 10.2 Mortality, % 9.2 10 Is hypoglycemia simply a ‘marker’ of the sickest patients? In the unadjusted analyses, hypoglycemia was associated with worse survival (mortality for patients with hypoglycemia versus without hypoglycemia was 12.7% [61/482] vs 9.6% [701/7338], respectively; P=.03). However, the relationship between hypoglycemia and mortality was markedly different within subgroups of patients who developed it following insulin therapy. Among patients who were not treated with insulin, those with hypoglycemia had much higher mortality compared with those who did not develop hypoglycemia (18.4% [25/136] vs 9.2% [425/4639], respectively; P<.001). In contrast, among patients who were treated with insulin, mortality rates were similar between those who did and did not develop hypoglycemia (10.4% [36/346] vs 10.2% [276/2699], respectively; P=.92 [P=.008 for hypoglycemia x insulin interaction]. Hypoglycemia was a predictor of higher mortality in patients not treated with insulin (odds ratio, 2.32 [95% CI, ] vs patients without hypoglycemia), but not in patients treated with insulin (odds ratio, 0.92 [95% CI, ] vs patients without hypoglycemia). These data suggest that hypoglycemia during hospitalization for AMI is a marker of severe illness, rather than a direct cause of adverse outcomes and should provide some reassurance to clinicians in their efforts to manage glucose level after AMI. No Insulin Treatment Insulin Treatment Kosiborod M, et al. JAMA. 2009;301:1556 Kosiborod M, Inzucchi SE, Goyal A, et al. Relationship between spontaneous and iatrogenic hypoglycemia and mortality in patients hospitalized with acute myocardial infarction. JAMA. 2009;301(15): 41

TREATING THE PATIENT, NOT THE BLOOD SUGARS
Insulin replacement therapy in type 1 diabetes Insulin supplementation in type 2 diabetes INSULIN DOSE IS RELATED TO THE DEGREE OF ISENSITIVITY NOT GLYCEMIC LEVEL

Case 1: 52-year-old male • Hospitalized with atypical chest pain ROMI
Reports previous good health, on no meds, no prior Hx of DM, his 57-year-old brother has T2DM Ht: 5’9”; Wt: 221 lb Abdominal obesity, Acanthosis • BP: 130/92 mm Hg • Random plasma glucose: 219 mg/dL • Lipids: – TG: 380 mg/dL – HDL-C: 28 mg/dL – LDL-C: 170 mg/dL

Case 1: 52-year-old male What tests will your order? What diet will your order? How will you treat his hyperglycemia? Continuity of care…..

Programmed Insulin Therapy
Insulin replacement therapy in type 1 diabetes Basal Bolus Insulin supplementation in type 2 diabetes Change RISSC for PIT Avoid oral antidiabetic agents Use basal insulin for supplementation Avoid insulin meal coverage in T2DM Intensive Intravenous Insulin Therapy

Programmed Insulin Therapy (PIT): Insulin therapy
Insulin replacement in T1DM Intravenous insulin in acute care Avoid continuation or initiation of oral agents Avoid combination (cocktail) therapies Replace RISSC for PIT Use of intermediate or long acting insulin vs. rapid or short acting insulins

Programmed Insulin Therapy (PIT): Goals
Provide education and improve patient care Better but less intensive and cost effective glycemic control Optimize Point of care CBG Avoid HYPOGLYCEMIA Avoid HYPERGLYCEMIA Avoid “glucose toxicity” Continuity of care Improve LOS

Programmed Insulin Therapy (PIT): Insulin dose
Use intermediate or long-acting insulins: Lantus (glargine) can be given at AM, bed time, or at any time, but should be “synchronized to the same hour every day NPH, 7AM (50% of daily dose) and bed-time (50% of daily dose) Starting dose by weight and other factors 0.3 units/Kg/day in end-organ failure 0.5 units/Kg/day in stable medical patients 0.7 units/Kg/day in surgical interventions or acute illnesses Constant dose adjustments

Insulins Peak (duration) hrs
RAPID-ACTING Humalog lispro (2-6) Novolog aspart (2-6) Apidra glulisine (2-6) SHORT-ACTING Regular (3-6) INTERMEDIATE-ACTING NPH (10-24) LONG ACTING Lantus glargine none (24) Levemir detemir none (20-24) BASAL BOLUS Insulin analogues Modified from: Ragucci E, Zonszein J, Frishman WH. Heart Dis. 2003;5:18-33

Insulins Peak (duration) hrs
RAPID-ACTING Humalog lispro (2-6) Novolog aspart (2-6) Apidra glulisine (2-6) SHORT-ACTING Regular (3-6) INTERMEDIATE-ACTING NPH (10-24) LONG ACTING) Lantus glargine none (24) Levemir detemir none (20-24) BASAL BOLUS Insulin analogues Modified from: Ragucci E, Zonszein J, Frishman WH. Heart Dis. 2003;5:18-33

Fixed-Mixed Insulins HUMULIN (NPH/REG) 70/30 50/50
HUMALOG (Prot-lispro/free lispro) 75/25 NOVOLIN (NPH/REG) NOVOMIX (Prot-aspart/aspart) Insulin analogues

Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy; Primary and Secondary Outcomes at 1 Year Biphasic Prandial Basal A1c (%) <6.5(%) Hypo pt/yr Wt gain (Kg) At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P = 0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups. In Figure 3 of the same article: Mean (±SE) Percentage Change from Baseline to 1 Year in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, Body Weight and Hpoglycemic-Event Rate. Holman R et al. N Engl J Med 2007;357:

Mean A1C Levels During a 24-Week Study (N=756)
Lantus® (insulin glargine [rDNA origin] injection) vs NPH in Insulin-naïve Patients: Mean Reduction in A1C1,2 Mean A1C Levels During a 24-Week Study (N=756) 9.0 8.5 8.0 7.5 7.0 6.5 8.61 Lantus® (n=367) NPH (n=389) P=NS vs NPH A1C 1.7% 8.56 7.5 Mean A1C (%) 7.1 7.5 6.96 6.96 7.1 6.91 6.97 Lantus® (insulin glargine [rDNA origin] injection) vs NPH in Insulin-naïve Patients: Mean Reduction in A1C  Over the 24 weeks of the study, the mean A1C level fell in both the insulin glargine and NPH groups, with the majority of patients achieving the A1C goal of 7.0% or less  In the group receiving insulin glargine, the change from baseline was 1.7, and in the NPH group, the change from baseline was 1.6% — The difference between the groups was not significant ________________________________________________________________________________________________________ 1. Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003;26: 2. Data on file. Aventis Pharmaceuticals Inc. Study End Week of Treatment Please see Important Safety Information for Lantus (insulin glargine [rDNA origin] injection) at the end of the presentation. Please see accompanying Full Prescribing Information for Lantus. 1. Adapted from Riddle M et al. Diabetes Care. 2003;26: 2. Data on file. Aventis Pharmaceuticals Inc. 53

Comparison of Insulin Regimens Among Oral Treatment Failures
2.9* 2.2* 1.8* 1.2*† -0.5 -0.9 -1.7* -1.8* -1.6* -1.9* The same findings as Treat to Target and 4-T were shown in 1992 with the use of NPH and Regular insulin. These studies showed that basal insulin only –NPH at bed time in this case was effective and reducing weight gain and hypoglycemic events. Change in HbA1c (%) Weight Change (kg) *P  0,001 vs. control group †P < 0.05 vs. other insulin treatment groups Yki-Jarvinen H et al. N Engl J Med. 1992;327:

Pathophysiology of Type 1 Diabetes
Loss of -cell mass Insufficient insulin Absolute insulin deficiency Type 1 diabetes is an autoimmune disease, which leads to progressive destruction of the insulin-secreting -cells of the pancreas. The resulting insulin deficiency is responsible for hyperglycemia In addition, patients may experience insulin resistance, a decreased ability to use the circulating insulin, which results in ineffective glucose metabolism Administration of exogenous insulin reduces insulin deficiency and glucotoxicity leading to secondary improvement in insulin sensitivity at the peripheral insulin receptors Administration of insulin early in the disease and aggressive approaches to reduction of blood glucose levels are important to reduce the risk of complications such as CV disease ADA. Clinical Practice Recommendations Diabetes Care. 2002;25(suppl 1):S1 ADA. Diabetes Care. 2002;25(suppl 1):S1

Insulin Therapy “Basal – Bolus” Concept
Some insulin is secreted at all times – the basal insulin Incremental amounts of insulin are secreted in response to rising postprandial glucose levels –the bolus insulin

Insulin Dosage Schedules
T1DM Insulin replacement U/Kg/D 2/3 given in the AM, 1/3 in the PM 2/3 long acting, 1/3 short acting T2DM Insulin supplementation U/K/D Bedtime only (h.s.) AM + h.s. If elevated postprandials: change to “insulin replacement”

Difficult to replicate
Normal insulin secretion prandial 100 GLUCOSE mg % or U/ml INSULIN 12 6 12 6 12 Breakfast Lunch Tea Dinner basal Difficult to replicate

23 T1DM a state of insulin deficiency Insulin as replacement basal/bolus pattern 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.

Insulin Dosage Schedules
T1DM Insulin replacement U/Kg/D 2/3 given in the AM, 1/3 in the PM 2/3 long acting, 1/3 short acting T2DM Insulin supplementation U/K/D Bedtime only (h.s.) AM + h.s. If elevated postprandials: change to “insulin replacement”

Hyperbolic Relationship Between Insulin Secretion and Insulin Sensitivity
High Obese Insulin Secretion Lean Type 2 Diabetes Low Low High Insulin Sensitivity Adapted from Kahn SE et al. Diabetes. 1993;42: 61

Treating according to degree of insulin resistance
SENSITIZERS + PROVIDERS + INCRETINOMIMETICS High sensitizers Insulin Secretion Incretinomimetics Insulin-providers Insulin or Potential mechanism of action and place for oral antidiabetic agents and preservation –durability of glycemic control. SE Kahn, SM Haffner, MA Heise, WH Herman, RR … Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy New England Journal of Medicine, 2006 Low High Insulin Sensitivity 62

Glucose and insulin in T2DM and acute illness
300 mg/dl mcu/L 100 mg/dl 5-20 mcu/L Breakfast Lunch Dinner

Insulin therapy in T2DM and acute illness
BG mg/dl Insulin units <250 0 >400 10 GLUCOSE 300 mg/dl Regular Insulin 30 units/D in 100 K 100 mg/dl Breakfast Lunch Dinner

GLYCEMIC CONTROL “REGULAR INSULIN SLIDING SCALE” (RISSC)
HYPERGLYCEMIA ……………...40% severity of illness high admission glucose level infection disorders corticosteroids HYPOGLYCEMIC EPISODES……23% African-American low serum albumin Queale WS. Arch Intern Med 1997;157:

Mean Blood Glucose Levels During Insulin Therapy
* * * 229 mg/dl was the average  How many patients left after 5 days 26 left on day 5; 20 left on day 6; 18 left on day 7; 12 left on day 8; 11 left on day 9; 9 left on day 10 * p<0.01 ¶ p<0.05 Day 3: P=0.06 66

Insulin therapy in T2DM Long-acting insulin
Fewer POC glucose monitoring 300 mg/dl Insulin Glargine 50-70 units/D in 100 K CBG CBG GLUCOSE 100 mg/dl Breakfast Lunch Dinner

Insulin therapy in T2DM Intermediate-acting insulin
Fewer POC glucose monitoring 300 mg/dl GLUCOSE CBG NPH 50-70 units/D in 100 K CBG 100 mg/dl Breakfast Lunch Dinner

Montefiore Programmed Insulin Therapy: Continuous Intravenous Intensive Insulin Therapy Insulin replacement in T1DM Insulin supplementation in T2DM

Montefiore: Intravenous Insulin Protocol
Indications* AMI Revascularization Selective surgical cases Labor intensive and expensive More feasible in acute care units Changed early to aggressive subcutaneous insulin regimens * Not for DKA and or HHC

Insulin in acute illness: Continuous Intravenous Insulin Protocol (CIIP)
DATE TIME HOURS GLUCOSE ACTION Infusion rate (ml/hr) = (Glucose – 80) x 0.03 (round to the nearest cc.) UNITS /HR X -80 X 0.03= 1 2 3 *4* 5 6 7 8

Insulin therapy in T2DM and acute illness Intravenous Insulin Therapy
300 mg/dl GLUCOSE mcu/L 100 mg/dl 5-20 mcu/L Breakfast Lunch Dinner

Glucose and insulin in T2DM and acute illness
Transition to Regular 300 mg/dl IV Insulin mcu/L GLUCOSE 100 mg/dl Regular Insulin 5-20 mcu/L Breakfast Lunch Dinner

Glucose and insulin in T2DM and acute illness Transition to Glargine
IV Insulin 300 mg/dl Insulin Glargine mcu/L GLUCOSE 100 mg/dl 5-20 mcu/L Breakfast Lunch Dinner

39-year-old Hispanic female
Hospitalized with abdominal pain and vomiting for 2 days 10-year history of hypertension, told to have T1DM • No significant cardiac, vascular, or neurologic symptoms Readily admits to ‘difficulty’ with diet and lifestyle. Current management: HCTZ (25 mg/d), NPH Insulin 20 units in AM 15 units h.s. Weight: 158 lbs; height: 5’5” (BMI 26 kg/m2) BP: 140/100 mm Hg without orthostatic changes • EKG: T-wave flattening in V4-6, more pronounced since last EKG two years ago. No R-wave criteria for LVH. Random glucose 444 mg/dL; K: 3.6 mEq/L; BUN/CR: 38/1.6 mg/dL; urinalysis = trace protein

39-year-old Hispanic female
What tests will your order? What diet will your order? How will you treat his hyperglycemia? Continuity of care…..

Examples of “Pen” Insulin Delivery Devices

Case 2: 72-year-old African-American
• Hospitalized with pneumonia 18-year history of poorly controlled diabetes; obese • Failed sulfonylureas; on increasing insulin for 10 years • Current dose: 107 U/three divided doses • Blood glucose (2-h pp): 265 mg/dL • HbA1c: 13.4% • Urine albumin excretion: 492 mg protein/g creatinine • Serum creatinine: 1.4 mg/dL • BP: 148/94 mm Hg

Case 2: 72-year-old African-American
What tests will your order? What diet will your order? How will you treat his hyperglycemia? Continuity of care…..

Montefiore Length of Stay –LOS
MOSES WEILER NORTH NON DIABETES 2002 5.9 5.3 5.7 2007 4.3 4.8 5.4 4.6 2008 5.2 4.2 6.9 6.3

70 THANKS QUESTIONS ?

Fuel dysregulation during acute illness and starvation
Fuel dysregulation during acute illness and starvation. A state of further “insulin resistance” Glycogenolysis Hyperglycemia Gluconeogenesis Ketone bodies Glucose Pyruvate Lactate 50 g per hour in our 100 kg subjects would be 8.3 mg/kg/min, and the highest we have ever seen is 4 mg/kg/min, the time we gave 10 times too much glucagon by mistake (!). under our usual fasting conditions, the normal rate is 2 mg/kg/min.. During stress + acute illness HGP is > 50 g/hour but peripheral glucose uptake decreases from 40g/hour to < 1g/hour FFA’s further increase insulin resistance and gluconeogenesis Lactate is the main substrate Ketone bodies replace glucose as the major fuel From Unger H N Engl J Med 1981;301: Glucagon and the A cell: physiology and pathophysiology (first two parts) R. H. Unger and L. Orci N Engl J Med 1981;304 Glucagon and the A cell: physiology and pathophysiology (second of two parts) R. H. Unger and L. Orci Volume 304 June 25, 1981 Number 26 Hyperglycemia develops due to stress and insulin resistance Gluconeogenesis becomes the main source of glucose, and alternative substrates replace glucose as a metabolic fuel Lipolysis with increase FFA’s (become the main fuel for skeletal muscle and kidney) Increase glucagon/insulin ratio = increase ketone bodies by the liver (become an alternative fuel for muscle, kidney, and brain) Proteolysis reflects the requirements by the liver and kidney substrates (glyconeogenesis + ammoniagenesis) Increased generated anions (ketone bodies) induces Na excretion and ammonium derived from glutamine replaces Na as a urinary cation In spite of hyperinsulinemia, effects are blunted Catecholamines rise early Glucocorticoids (necessary for pyruvate carboxylase activity rate limited for gluconeogenesis Glucagon hGH increases without physiologic feedback from IGF-1. IGF-1 decrease in spite of high hGH, decrease IGF-1 mRNA synthesis Decrease IGFBP-3 (prolonged starvation). Increased IGFBP-1 and IGBP-2 (due to decrease insulin) IGFP-1 sensitive indicator of nutritional rehabilitation Thyroid hormone decrease T3 increase rT3 Increase cytokines FFA Lactate AA

High Normal Fasting Rate
Fuel dysregulation during acute illness Endogenous glucose production in a 100 Kg man Endogenous Glucose Production High Normal Fasting Rate Euglycemia Stress Rate Hyperglycemia Rate mg/kg/min Total grams/day 2 288 4 576 D5W equivalent Coke equivalent 6 Liters 7 cans 12 Liters 14 cans I recommend a 3L of D5W (total 150g of dextrose) daily to provide 600 cal/D and prevent ketosis in sick hospitalized patients. Assuming a non-ill normal 100 kilo patient has: 2mg/k/min or an output of 288g/D (this is equivalent to 5.76 Liters of D5W). This results in euglycemia when glucose utilization equals glucose production in healthy individuals, but may create hyperglycemia when D5W is given to insulin resistant individuals with inappropriate increased HGP and decreased peripheral glucose utilization. Assuming a high normal rate (4mg/k/min) patient 100 kilo patient has: 100 kilo = 576g/D, this is equivalent to Liters of D5W If Unger is correct, a high Stress Rate of 8mg/k/min in a 100 kilo patient is: 8mg/k/min = 1,152g/D, or the equivalent of 23.4 Liters of D5W where 90% will be accumulated in blood since there is only a 10% peripheral glucose utilization. Van den Bergh showed that improvement in glycemia in ill patients is mainly by improving peripheral glucose uptake but not by decreasing the inappropriately high glucose output (mostly liver while in these patients renal output may also have an important role). I Liter of D5W = 50 g glucose 12 oz can of Coke = 39 g glucose

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