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Insulin Therapy in the Inpatient and Outpatient Setting

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Presentation on theme: "Insulin Therapy in the Inpatient and Outpatient Setting"— Presentation transcript:

1 Insulin Therapy in the Inpatient and Outpatient Setting
Agustin Busta, MD Assistant Professor Albert Einstein College of Medicine

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3 Association of DM with total life expectancy and life expectancy with and without cardiovascular disease Women with diabetes had more than double the risk of developing cardiovascular disease and, 2.2 times higher risk of dying among those with CVD, compared with non-diabetic women,“ Diabetic men, compared with non-diabetic men, had more than double the risk of developing CVD and a 1.7 times higher risk of dying once CVD was present. Among those age 50 and older, diabetic men lived an average of 7.5 years less than men without diabetes, and diabetes reduced women's life expectancy by an average of 8.2 years. Life expectancy free of cardiovascular disease was reduced by 7.8 years in men and 8.4 years in women with diabetes. Many years of research have shown that diabetes poses an increased risk of mortality and morbidity among those who have it. For instance,diabetic subjects have a greater than 2-fold–increased risk of developing cardiovasculardisease (CVD). However,there is limited information about the potential association of diabetes with total life expectancy (LE), LE with CVD, and LE without CVD. We aimed to calculate the association of diabetes mellitus at age 50 years (and older) with LE, with special attention to the number of years of life spent with and without CVD. Having diabetes significantly increased the risk of developing CVD (hazard ratio, 2.5 for women and 2.4 for men) and of dying when CVD was present (hazard ratio, 2.2 for women and 1.7 for men). Diabetic men and women 50 years and older lived on average 7.5 (95% confidence interval, ) and 8.2 (95% confidence interval, ) years less than their nondiabetic equivalents. The differences in life expectancy free of CVD were 7.8 and 8.4 years, respectively. OH Franco, et al. Arch Intern Med. 2007;167:

4 Associations of Diabetes Mellitus with Total Life Expectancy and Life Expectancy with and without Cardiovascular Disease Total LE and LE free of CVD were significantly decreased among men and women at age 50 years with diabetes compared with their nondiabetic equivalents (Figure). Differences in number of years lived with CVD between nondiabetic and diabetic subjects were minimal and not statistically significant (Table 3). Women and men with diabetes who were 50 years and older were expected to live on average 8.2 and 7.5 years less, respectively, than their nondiabetic equivalents. In women and men, diabetes led to 8.4 and 7.8 years less in LE free of CVD, respectively, and 0.2 and 0.3 (nonsignificant) years more in LE with CVD, respectively. Diabetic men and women 50y and older lived on average 7.5 & 8.2 years less than their nondiabetic equivalents OH Franco, et al. Arch Intern Med. 2007;167: 4

5 Background: Increasing evidence suggests a continuous relationship between blood glucose concentrations and cardiovascular risk, even below diagnostic threshold levels for diabetes. Objective: To examine the relationship between hemoglobin A1c, cardiovascular disease, and total mortality. Design: Prospective population study.Setting: Norfolk, United Kingdom. Participants: 4662 men and 5570 women who were 45 to 79 years of age and were residents of Norfolk. Measurements: Hemoglobin A1c and cardiovascular disease risk factors were assessed from 1995 to 1997, and cardiovascular disease events and mortality were assessed during the follow-up period to Results: In men and women, the relationship between hemoglobin A1c and cardiovascular disease (806 events) and between hemoglobin A1c and all-cause mortality (521 deaths) was continuous and significant throughout the whole distribution. The relationship was apparent in persons without known diabetes. Persons with hemoglobin A1c concentrations less than 5% had the lowest rates of cardiovascular disease and mortality. An increase in hemoglobin A1c of 1 percentage point was associated with a relative risk for death from any cause of 1.24 (95% CI, 1.14 to 1.34; P < 0.001) in men and with a relative risk of 1.28 (CI, 1.06 to 1.32; P < 0.001) in women. These relative risks were independent of age, body mass index, waist-to-hip ratio, systolic blood pressure, serum cholesterol concentration, cigarette smoking, and history of cardiovascular disease. When persons with known diabetes, hemoglobin A1c concentrations of 7% or greater, or a history of cardiovascular disease were excluded, the result was similar (adjusted relative risk, 1.26 [CI, 1.04 to 1.52]; P 0.02). Fifteen percent (68 of 521) of the deaths in the sample occurred in persons with diabetes (4% of the sample), but 72% (375 of 521) occurred in persons with HbA1c concentrations between 5% and 6.9%.

6 Glycemia & Macrovascular Disease in Non-Diabetic Subjects
Background: Increasing evidence suggests a continuous relationship between blood glucose concentrations and cardiovascular risk, even below diagnostic threshold levels for diabetes. Objective: To examine the relationship between hemoglobin A1c, cardiovascular disease, and total mortality. Design: Prospective population study. Setting: Norfolk, United Kingdom. Participants: 4662 men and 5570 women who were 45 to 79 years of age and were residents of Norfolk. Measurements: Hemoglobin A1c and cardiovascular disease risk factors were assessed from 1995 to 1997, and cardiovascular disease events and mortality were assessed during the follow-up period to 2003. Results: In men and women, the relationship between hemoglobin A1c and cardiovascular disease (806 events) and between hemoglobin A1c and all-cause mortality (521 deaths) was continuous and significant throughout the whole distribution. The relationship was apparent in persons without known diabetes. Persons with hemoglobin A1c concentrations less than 5% had the lowest rates of cardiovascular disease and mortality. An increase in hemoglobin A1c of 1 percentage point was associated with a relative risk for death from any cause of 1.24 (95% CI, 1.14 to 1.34; P < 0.001) in men and with a relative risk of 1.28 (CI, 1.06 to 1.32; P < 0.001) in women. These relative risks were independent of age, body mass index, waist-to-hip ratio, systolic blood pressure, serum cholesterol concentration, cigarette smoking, and history of cardiovascular disease. When persons with known diabetes, hemoglobin A1c concentrations of 7% or greater, or a history of cardiovascular disease were excluded, the result was similar (adjusted relative risk, 1.26 [CI, 1.04 to 1.52]; P 0.02). Fifteen percent (68 of 521) of the deaths in the sample occurred in persons with diabetes (4% of the sample), but 72% (375 of 521) occurred in persons with HbA1c concentrations between 5% and 6.9%. Conclusions: The risk for cardiovascular disease and total mortality associated with hemoglobin A1c concentrations increased continuously through the sample distribution. Most of the events in the sample occurred in persons with moderately elevated HbA1c concentrations. These findings support the need for randomized trials of interventions to reduce hemoglobin A1c concentrations in persons without diabetes. Khaw KT, et al Ann Intern Med. 2004; 141: 6

7 UKPDS Post-trial monitoring

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9 UKPDS 10 yr Follow-Up Study- insulin/sulfonylurea group
Differences in A1C between intensive & standard glycemic control treatment groups were lost after one year Relative risk reductions at 10 yr in intensive insulin/sulfonylurea group: 9% for any diabetes end point (P=0.04) 24% microvascular disease (P=0.001) 15% myocardial infarction (P=0.01) 13% death from any cause (P=0.007) Differences in the A1C values seen in the intensive & standard glycemic control treatment groups were lost one year after of the end of the original study. “Despite early loss of glycemic differences in the groups, a continued reduction in microvascular risk and emergent risk reductions for MI and death from any cause were observed during 10 years of post-trial follow up.” Relative risk reductions in intensive insulin/sulfonylurea group: 9% for any diabetes-related end point (P=0.04) 24% microvascular disease (P=0.001) 15% myocardial infarction (P=0.01) 13% death from any cause (P=0.007) Reference: 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes N Engl J Med 2008; 359 N Engl J Med /NEJMoa N Engl J Med 2008; 359

10 UKPDS 10 yr Follow-Up Study- Metformin group
Differences in A1C between intensive & standard glycemic control treatment groups were lost after one year Relative risk reductions at 10 yr in intensive metformin group: 21% for any diabetes end point (P=0.01) 33% myocardial infarction (P=0.005) 21% death from any cause (P=0.002) Differences in A1C between intensive & standard glycemic control treatment groups were lost one year after of the end of the original study. “Despite early loss of glycemic differences in the groups, a continued reduction in microvascular risk and emergent risk reductions for MI and death from any cause were observed during 10 years of post-trial follow up.” Relative risk reductions in the intensive metformin group: 21% for any diabetes-related end point (P=0.01) 33% myocardial infarction (P=0.005) 21% death from any cause (P=0.002) Reference: 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes N Engl J Med 2008; 359 N Engl J Med /NEJMoa N Engl J Med 2008; 359

11 DCCT- EDIC Post ad-hoc analysis shows a decreased of macrovascular complications on patients who received intensive insulin therapy in the DCCT trial.

12 Epidemiology of Diabetes Interventions and Complications Study (EDIC)
Observational study DCCT participants (type 1 diabetes) Looked at risk factors for long-term complications The Epidemiology of Diabetes Interventions and Complications Study (EDIC) Began in 1994 and studied participants previously enrolled in the Diabetes Control and Complications Trial (DCCT), to determined whether the use of intensive therapy, as compared to conventional therapy during the time period people were enrolled in the DCCT, affected the long-term incidence of cardiovascular disease. Reference The DCCT/EDIC Study Research Group. New England Journal of Medicine, 353: , December 22, 2005. DCCT/EDIC N Engl J Med 2005: 353: 12

13 DCCT-EDIC: Long-term Risk of Macrovascular Complications
Conventional Cumulative Incidence Any Cardiovascular Outcome 2 4 6 8 10 12 14 16 18 20 42% risk reduction P = 0.02 Intensive 0.12 0.10 0.08 0.06 0.04 0.02 0.00 DCCT End of Randomized Treatment EDIC Year 1 EDIC Year 7 12% 10% 8% 6% Hemoglobin A1C P < 0.001 P = 0.61 Conventional Intensive DCCT-EDIC: Long-term Risk of Macrovascular Complications At the end of the randomized treatment phase in the Diabetes Control and Complications Trial, the research group found a difference in the concentration of hemoglobin A1c between the patients with type 1 diabetes in the intensive treatment group and those in the conventional treatment group. At the end of the trial, there was a nonsignificant reduction in cardiovascular outcome in the intensively treated group. The trial ended at approximately 9 years; afterward, there was convergence of treatments and similar levels of glycemic control were achieved. There was persistent benefit, however, among the intensively treated group such that there was a statistically significant reduction in cardiovascular disease when compared to the conventionally treated group in the follow-up phase (up to 20 years) of the study. These data would indicate that 10 years of intensive treatment yielded a cardiovascular benefit during the first 10 years that was sustained and became greater in the follow-up phase. During the DCCT/EDIC follow-up period, intensive treatment reduced the risk of nonfatal myocardial infarction, stroke, or death from cardiovascular disease by 42 percent (95 percent confidence interval, 9 to 63 percent; P=0.02). References: Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287: Nathan DM, Cleary PA, Backlund JY, et al, for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353: Years Since Entry* *Diabetes Control and Complications Trial (DCCT) ended and Epidemiology of Diabetes Interventions and Complications (EDIC) began in year 10 (1993). Mean follow-up: 17 years. DCCT/EDIC Research Group. JAMA. 2002;287: Copyright © 2002 American Medical Association. All rights reserved. | Nathan DM, et al. N Engl J Med. 2005;353: Copyright © 2005 Massachusetts Medical Society. All rights reserved.

14 Key points of recent findings:
Intensive glucose control in newly diagnosed type 1 or type 2 diabetes has benefits during intensive therapy AND a legacy effect for later micro- and macrovascular benefits Optimal glucose management should start as early as possible & continue as long as possible While the A1C goal for the general population is <7%, treatment must be individualized. The key points regarding the recent research findings are: Intensive glucose control in newly diagnosed people with either type 1 or type 2 diabetes (A1C goal <7%) has benefits during the period of intensive therapy AND a “legacy effect” with micro- and macrovascular benefits realized years later. Starting optimal glucose management as early as possible and maintaining it as long as possible in people with either type 1 or type 2 diabetes is beneficial. While the A1C goal for the general population is <7%, treatment must be individualized and less stringent control may be appropriate in people with CVD or advanced diabetes complications and in those at risk of severe hypoglycemia. UKPDS follow up study results reinforce the need for early and optimal blood glucose control and underscore the importance of continual blood pressure management. Reference: 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes N Engl J Med 2008; 359 N Engl J Med /NEJMoa Long-Term Follow-up after Tight Control of Blood Pressure in Type 2 Diabetes N Engl J Med 2008; 359 N Engl J Med /NEJMoa N Engl J Med 2008; 359

15 Regression of atherosclerosis in patients with type 2 diabetes drug naive
Esposito K, On a study using OAD on 175 drug naïve patients with type 2 diabetes, resulted in a regression of carotid-intima media thickness after controlling postprandial glucose

16 Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. BACKGROUND: Postprandial hyperglycemia may be a risk factor for cardiovascular disease. We compared the effects of two insulin secretagogues, repaglinide and glyburide, known to have different efficacy on postprandial hyperglycemia, on carotid intima-media thickness (CIMT) and markers of systemic vascular inflammation in type 2 diabetic patients. METHODS AND RESULTS: We performed a randomized, single-blind trial on 175 drug-naive patients with type 2 diabetes mellitus (93 men and 82 women), 35 to 70 years of age, selected from a population of 401 patients who participated in an epidemiological analysis assessing the relation of postprandial hyperglycemia to surrogate measures of atherosclerosis. Eighty-eight patients were randomly assigned to receive repaglinide and 87 patients to glyburide, with a titration period of 6 to 8 weeks for optimization of drug dosage and a subsequent 12-month treatment period. The effects of repaglinide (1.5 to 12 mg/d) and glyburide (5 to 20 mg/d) on CIMT were compared by using blinded, serial assessments of the far wall. After 12 months, postprandial glucose peak was 148+/-28 mg/dL in the repaglinide group and 180+/-32 mg/dL in the glyburide group (P<0.01). HbA(1c) showed a similar decrease in both groups (-0.9%). CIMT regression, defined as a decrease of >0.020 mm, was observed in 52% of diabetics receiving repaglinide and in 18% of those receiving glyburide (P<0.01). Interleukin-6 (P=0.04) and C-reactive protein (P=0.02) decreased more in the repaglinide group than in the glyburide group. The reduction in CIMT was associated with changes in postprandial but not fasting hyperglycemia. CONCLUSIONS: Reduction of postprandial hyperglycemia in type 2 diabetic patients is associated with CIMT regression.

17 Natural History of Type 2 Diabetes
-10 -5 Years from diagnosis 5 10 15 Onset Diagnosis Insulin resistance Insulin secretion Postprandial glucose The natural history of type 2 diabetes is progressive and complex. Increasing insulin resistance characterizes the prediabetic state. When β- cells function well, insulin resistance results in compensatory hyperinsulinemia, which maintains relatively normal glucose metabolism. In this compensated, insulin-resistant state, individuals may have either normal glucose tolerance or IGT but not diabetes. Eventually, the β-cells begin to fail, and insulin secretion falls, resulting in postprandial hyperglycemia and further loss of insulin secretion. Fasting hyperglycemia and hepatic overproduction of glucose then occur, resulting in overt diabetes, which may or may not be diagnosed in a timely manner. This process typically begins 4 to 7 years prior to diabetes diagnosis.1 Importantly, although early type 2 diabetes may be asymptomatic, evidence suggests that the degree of associated hyperglycemia may be severe enough for microvascular complications of diabetes to begin to develop.1• β-cell function declines progressively in type 2 diabetes • The deterioration of β-cell function can precede the diagnosis of diabetes Analyses of the United Kingdom Prospective Diabetes Study (UKPDS), a randomized, controlled trial conducted with 5102 patients, demonstrated that type 2 diabetes is a progressive disease marked by declining β-cell function. Moreover, the rate of decline does not differ regardless of the therapy used to control hyperglycemia. An extrapolation of the observed rate of decline in β-cell function, as evaluated by homeostasis model assessment (HOMA), suggests that patients’ loss of function began approximately 10 to 12 years before type 2 diabetes was diagnosed. As the graph indicates, by the time of diagnosis, β-cell function was impaired to the point of <50% of normal functioning.1,2 Fasting glucose Microvascular complications Macrovascular complications Pre-diabetes Type 2 diabetes Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. NEJM. 2002;347:

18 UKPDS-DM Pancreas Is a continue state of beta cell function impairment that will lead to an state of complete pancreas exhaustation and lead to pancreatic insulin secretion unsuffiency. Pancreas exhaustion rapidly occurred at rate of 2-4 % year, and in 10 years majority of patient needs insulin Majority of T2dm will fail to maintain targets withA1c with OAD because pancreas run out of insulin

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20 Glycemic Control Declines Over Time With Traditional Monotherapy
Patients with A1C <7% (%) Patients with A1C <7% (%) COMMENT The increasing failure of monotherapy with sulfonylurea, metformin, or insulin to achieve tight glycemic control over the first 9 years following diagnosis of type 2 diabetes is consistent with the progressive decline of b-cell function.13 By 3 years after diagnosis of diabetes, approximately 50% of patients will need more than 1 pharmacological agent (ie, multiple therapies) because monotherapy does not achieve the target values of HbA1c, and by 9 years approximately 75% of patients will need multiple therapies to achieve FPG concentrations of less than 7.8 mmol/L (140 mg/ dL) or HbA1c levels below 7%. In an intent- to-treat analysis, the efficacy of early addition of metformin therapy to maximum sulfonylurea therapy has been shown after 3 years to increase the proportion of patients achieving HbA1c levels below 7% from 21% with sulfonylurea alone to 33% with additional metformin.15 It is apparent by 9 years after diagnosis that even with this combination of oral agents a substantial number, possibly the majority, of patients will need the addition of insulin therapy to obtain an HbA1c level below 7%. Since improved glucose control with insulin therapy is known to reduce the risk of diabetes complications, 4 the progressive decline in b-cell function with greater hyperglycemia13 will require considerably greater use of insulin therapy than that currently prescribed. While thiazolidinediones are an additional oral agent that can be used, in clinical practice they have similar efficacy to sulfonylurea or metformin in reducing glycemia, which usually remains supranormal,21,22 and these new agents are unlikely to prevent the increasing glycemia or to postpone the need for insulin therapy for more than a few years. Although insulin therapy was better than sulfonylurea or metformin at reducing FPG concentrations, it was not as effective in reducing HbA1c as might have been anticipated. This is partly because oral agents reduce the postprandial as well as fasting glucose level, whereas a basal insulin supply only reduced the basal glucose concentrations. 23 Adding soluble insulin to cover the meals can lead to hypoglycemic attacks that limit the degree to which near-normal glycemia can be attained. 20 According to published reports, HbA1c levels below 7% have only been achieved with high insulin doses, often well above 100 U/d, in small groups of obese patients receiving detailed attention over a short-term period In studies in fewer obese patients taking smaller insulin doses, mean HbA1c levels of 8% or above were achieved The UKPDS included patients who would not comply with a complex insulin regimen so it is thus a real-life study. While the American Diabetes Association guidelines suggest a glycemic goal of HbA1c below 7%, monotherapies can achieve this in only a minority of patients.30 This study shows that the initial severity of diabetes, assessed by the degree of hyperglycemia, is a major factor in determining the likelihood of achieving glucose target levels, and that it is also more difficult to achieve the target levels in more obese patients. Nevertheless, the allocation to therapy with sulfonylurea, basal insulin, or metformin compared with diet alone more than doubled the proportion of patients with type 2 diabetes who achieved the target levels. This degree of improved glucose control is clinically effective in preventing microvascular complications of diabetes.4 Adequately controlled and treated with metformin* Adequately controlled and treated with sulfonylureas† *Overweight drug-naïve patients. †Normal weight and overweight drug-naïve patients Turner RC, et al. JAMA. 1999;281:

21 NHANES III(1988-94) vs NHANES(1999-2000)
OBJECTIVE To describe the changes in demographics, antidiabetic treatment, and glycemic control among the prevalent U.S. adult diagnosed type 2 diab population between the National Health and Nutrition Examination Survey (NHANES) III (1988–1994) and the initial release of NHANES RESEARCH DESIGN AND METHODS— The study population was derived from NHANES III (n1,215) and NHANES 1999–2000 (n372) subjects who reported a diagnosis of type 2 diabetes with available data on diabetes medication and HbA1c. Four therapeutic regimens were defined: diet only, insulin only, oral antidiabetic drugs (OADs) only, or OADs plus insulin. Multiple logistic regression was used to examine changes in antidiabetic regimens and glycemic control rates over time, adjusted for demographic and clinical risk factors. The outcome measure for glycemic control was HbA1c. Glycemic control rates were defined as the proportion of type 2 diabetic patients with HbA1c level 7%. RESULTS— Dietary treatment in individuals with diabetes decreased as the sole therapy from 27.4 to 20.2% between the surveys. Insulin use also decreased from 24.2 to 16.4%, while those on OADs only increased from 45.4 to 52.5%. Combination of OADs and insulin increased from 3.1 to 11.0%. Glycemic control rates declined from 44.5% in NHANES III (1988–1994) to 35.8% in NHANES 1999–2000. CONCLUSIONS— Treatment regimens among U.S. adults diagnosed with type 2 diabetes have changed substantially over the past 10 years. However, a decrease in glycemic control rates was also observed during this time period. This trend may contribute to increased rates of macrovascular and microvascular diabetic complications, which may impact health care costs. Our data support the public health message of implementation of early, aggressive management

22 Insulin Use Remains Constant NHANES III(1988-94) vs NHANES(1999-2000)
Constant: 27% of patients treated with insulin 60 50 NHANES III NHANES 40 30 20 10 Diet/Ex Orals Orals + Ins Insulin Only CONCLUSIONS— Our findings show that the proportion of adults in the U.S. with adequately controlled, diagnosed type 2 diabetes decreased between 1988 and Diabetes is controlled in only 36% of the more recent survey participants, despite recommendations for early diagnosis and aggressive treatment in recent years. We also observed changes in the demographic distribution of the adults with diagnosed type 2 diabetes from NHANES III (1988 –1994) to NHANES 1999 –2000, such as an increased proportion of men and minority groups other than non-Hispanic blacks and Mexican Americans. In recent years, individuals with diagnosed diabetes tended to be younger, to weigh more, and to have a longer duration of diabetes. However, we found that these demographic differences did not fully explain the lower glycemic control rates seen in recent years. Other reasons might account for the observed declining rates over time, such as changes in patient compliance with treatment programs despite more aggressive management. Another possible explanation for this observation may be surveillance bias due to a preferential increased screening for diabetes in high-risk individuals in the late 1990s compared with the previous decade. In addition to changes in demographic features among patients over time, we also observed changes in the therapeutic regimen. The proportion of current individuals with diagnosed diabetes following diet-only or insulin-only treatment regimens has decreased since 1988–1994, but the proportion receiving OADs only or OADs in combination with insulin has increased. This change may be due to a larger selection of marketed oral agents. The increase in use of OADs from 1994 to 2000 is likely because only sulfonylureas were available in the earlier time period. By 2000, at least six new products in four new classes of OADs had become available. Another reason for the observed change may be a trend toward more aggressive and earlier treatment with OADs and OAD/insulin combinations. We have also demonstrated that glycemic control was better in older individuals with diagnosed diabetes, those with higher BMI, and those with a longer duration of diagnosed diabetes (Table 3). Diabetic control was worse in minority ethnic groups and those taking medications (as compared with those on diet only). It is not clear why glycemic control might be better in older individuals, but some studies have suggested that older patients may have better access to medical care, are more motivated to receive care, and are more compliant with medication use (15). This finding is somewhat in contrast to that of the U.K. Prospective Diabetes Study (UKPDS), which suggested that glycemic control rates among individuals with diabetes decrease with disease duration and, thus, with age (16). Also in contrast to the current study, Harris et al. (9) found that obesity was not related to glycemic control. They attributed their results to the cross-sectional design of the survey. There are several limitations to the current analysis. The sample size from the NHANES 1999–2000 survey is small relative to NHANES III (1988–1994). As the survey continues over the next few years, more subjects will accrue, and the analysis can be repeated. Another limitation is that medication use is self-reported, and this may cause some misclassification in measured treatment regimens. Additionally, because NHANES surveys are crosssectional in design, some of our findings may be related to survival bias in that individuals with diabetes having the poorest control may have died over time and could not participate in surveys. Also, in 1997, the American Diabetes Association changed the diagnostic criteria for diabetes, which may have influenced prevalence estimates of diagnosed diabetes between the two NHANES surveys (8). We conclude that the proportion of adults in the U.S. with diagnosed type 2 diabetes that is controlled is inadequate and less favorable than in previous years. The cardiovascular and other consequences of inadequate glycemic control warrant serious consideration by treating physicians and others who care for individuals with diabetes. These data lend support to public health initiatives advocating early and aggressive management of diabetes. Between NHANES III and NHANES , percentage of patients treated with drug therapy increased 7.2% Percentage of patients treated with insulin remained constant at ~27% Adapted from Koro et al, Diabetes Care. 2004; 27(1):17-20

23 Estimated Cost of Diabetes in U.S.
Total: $174 billion Direct Medical Cost: $116 billion Indirect Cost: $58 billion The total estimated cost of diabetes in the United States is $174 billion. The estimated direct medical cost of diabetes is $116 billion. This includes medical care and services. The estimated indirect cost of diabetes is $58 billion. This includes disability, work loss, and premature mortality. Medicines and supplies and outpatient services are responsible for a minority of these costs. Reference National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics, Bethesda, MD: U.S. Department of Health and Human Services, National Institutes of Health, 2008. NIDDK, National Diabetes Statistics 2007.

24 Recent Clinical Trial Findings:
Intensive glucose control in type 2 diabetes: lowers risk of new or worsening microvascular complications (ADVANCE) was associated with increased mortality in patients with longstanding DM and known CVD (ACCORD) increases risk of severe hypoglycemia (ADVANCE, ACCORD and VADT) A proven benefit of intensive glucose control: 1) Lowers risk of new or worsening microvascular complications (damage to small vessels that cause kidney and eye damage) (ADVANCE). However, results of three major clinical trials (ADVANCE, ACCORD and VA Diabetes Trial) confirmed that intensive glucose control in type 2 diabetes presents significant risks. These are: 1) Intensive glucose control was associated with increased mortality in patients with longstanding DM and known CVD (ACCORD). 2) Intensive control increases risk of severe hypoglycemia (ADVANCE, ACCORD and VADT). Reference: Action to Control Cardiovascular Risk in Diabetes (ACCORD) N Engl J Med 2008; 358(24): Action in Diabetes and Vascular Disease: PreterAx and DiamicroN MR Controlled Evaluation (ADVANCE) N Engl J Med 2008; 358 (24): Veterans Affairs Diabetes Trial (VDAT): J Diabetes Complications 2003; 17 (6): ACCORD: N Engl J Med 2008; 358(24): ADVANCE: N Engl J Med 2008; 358 (24): VADT: J Diabetes Complications 2003; 17 (6):

25 AVAILABLE INSULIN PREPARATIONS
Product (Manufacturer) Form Rapid Acting (Onset min, duration hrs 3-4) Insulin Analog Aspart - Novolog (Novo Nordisk) Lispro - Humalog (Lilly) Glulisine – Apidra (Aventis) Analog** Short Acting (Onset hr, duration hrs 5-7)* Human Insulin Novolin R (Rugular) (Novo Nordisk) Humulin R (Regular) (Lilly) Human** Purified Insulin Regular Iletin II (Lilly) Pork Intermediate Acting (Onset 1-4 hrs, duration hrs 18-24)* Novolin N (NPH) (Lilly) Humulin N (NPH) (Lilly) Humulin L (Lente) (Lilly) Purified Insulin NPH Iletin III (Lilly) Long Acting (Onset 4-6 hrs, duration hrs 24-34)* Humulin Ultralente (Lilly) Basal Peakless Insulin Glargine-Lantus (Aventis) Detemir – Levemir (Novo Nordisk) Mixed Insulins 70/30 Insulin Novolin 70/30 (Novo Nordisk) Humulin 70/30 (Lilly) Humulin 50/50 (Lilly) Humalog 50/50 Product (Manufacturer) Form Analog Mix Humalog 75/25 Mix Novolog Mix 70/30 (combination of fast and intermediate acting insulin with action similar to that of Humalog 75/25 mix) Analog** Insulin for Special Use Buffered Insulin (for pumps) Humulin BR Refills for Novolin Pen Novolin R PenFill Novolin N PenFill Novolin 70/30 PenFill Novolog Mix 70/30 PenFill Prefilled Pens Novolin R Novolin N Novolin 70/30 Novolog Novolog Mix 70/30 Humalog Humalog Mix 75/25 Humalog Mix 50/50 Humulin N Apidra Human** * Onset and duration are rough estimates. They can vary greatly within the range listed and from person to person ** Human insulin is made by recombinant DNA technology

26 Schematic Time-Activity Curves for Selected Insulin Formulations
Figure 1. Schematic Time-Activity Curves for Selected Insulin Formulations. The graph depicts time-activity profiles for selected insulin formulations. For simplicity, the known dose-dependent variability in duration of action and the wide variability in hypoglycemic effect for the selected formulations among patients are not represented. Biphasic insulin preparations are not shown. (Updated October 17, 2007.) McMahon G and Dluhy R. N Engl J Med 2007;357:

27 Physiologic Insulin Secretion: Basal/Bolus Concept
Nutritional (Prandial) Insulin 50 Insulin (µU/mL) Suppresses Glucose Production Between Meals & Overnight 25 Basal Insulin Breakfast Lunch Supper 150 Nutritional Glucose The 50/50 Rule Glucose (mg/dL) 100 This slide shows a normal insulin profile and a normal glucose profile over the course of a day for a person without diabetes who is eating 3 meals (meal = red arrow). Notice that there is always a basal level of circulating insulin, which serves to suppress glucose and ketone production in periods of fasting. This component of insulin is referred to as “basal insulin,” and it is relatively constant. Next, notice that glucose levels rise, as expected, when the person eats a meal. When this occurs, the physiologic response is to rapidly increase insulin levels, and this figure shows how closely the curves for glucose levels and insulin levels match, after a meal. This rise in the insulin level above the “basal” level that occurs in response to nutritional intake is referred to as “nutritional insulin.” The goal of insulin therapy in patients with diabetes is to mimic normal physiologic insulin secretion as closely as possible. This slide illustrates the typical 24-hour insulin secretion pattern in response to three meals in individuals without diabetes. The insulin secretory response is pulsatile, with two to four pulses observed after each meal. Insulin concentrations rise rapidly during the first and second hours following the meal. Following breakfast, nearly 67% of the 4-hour secretory response occurs during the first 2 hours, compared with 33% during the third and fourth hours. A similar temporal distribution is seen after lunch and dinner. Between meals and overnight, a lower rate of insulin secretion maintains basal insulin concentrations. In type 2 diabetes, this pattern of insulin secretion is disrupted in three ways: Patients have an absent or blunted first-phase insulin response to glucose, as well as decreased overall insulin secretion, particularly when diabetes is severe. In addition, there is decreased sensitivity of the insulin response to glucose. Both basal and postprandial glucose levels fail to trigger normal insulin secretion; these defects result in postprandial and fasting hyperglycemia.2 To be fully successful, insulin therapy in patients with type 1 diabetes or long-duration type 2 diabetes must provide for both basal and meal-related insulin requirements. The following slides examine insulin regimens that have been developed to address these issues. A “normal” human (who does not have significant insulin resistance) secretes a total of about units of insulin per day. About ½ of this is secreted as basal insulin, and about ½ of this is secreted as nutritional insulin. Understanding this bit of physiology is very helpful for creating flexible insulin regimens in hospitalized patients. In acute illness, the total daily insulin requirement may actually increase, even if the patient’s caloric intake decreases. This increase in physiologic insulin requirement in illness reverts to baseline as recovery takes place. 50 Basal Glucose 7 8 9 10 11 12 1 2 3 4 5 6 7 8 9 A.M. P.M. Time of Day 12

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30 Insulin Glargine vs NPH Insulin Added to Oral Therapy
Treat to Target Study Insulin Glargine vs NPH Insulin Added to Oral Therapy Study Design 24-wk, multicenter, randomized, parallel, open- label trial. Compared insulin glargine vs NPH given at HS in type 2 diabetics patients inadequately controlled on 1 or 2 oral agents Insulin dosage adjusted weekly by forced-titration schedule seeking FPG 100 mg/dL Measure achievement of A1C 7% without clinically significant nocturnal hypoglycemia 756 insulin-naïve patients,on Glargine =367,on NPH = 389, mean age = 55yr, duration of diabetes = 8-9 yr, baseline A1c= 8.6%, BMI = 32 kg/m2. Slide 6 Insulin Glargine vs NPH Insulin Added to Oral Therapy The purpose of this study was to evaluate basal insulin glargine vs the currently used basal insulin, NPH insulin, in combination with oral therapy to determine if an insulin with smoother basal characteristics (no pronounced peak of activity) would provide better glycemic control and less frequency of nocturnal hypoglycemia The role of insulin glargine was also evaluated in restoring glycemic control in patients inadequately controlled on OHA Riddle MC, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P OBJECTIVE: To compare the abilities and associated hypoglycemia risks of insulin glargine and human NPH insulin added to oral therapy of type 2 diabetes to achieve 7% HbA(1c). RESEARCH DESIGN AND METHODS: In a randomized, open-label, parallel, 24-week multicenter trial, 756 overweight men and women with inadequate glycemic control (HbA(1c) >7.5%) on one or two oral agents continued prestudy oral agents and received bedtime glargine or NPH once daily, titrated using a simple algorithm seeking a target fasting plasma glucose (FPG) <or=100 mg/dl (5.5 mmol/l). Outcome measures were FPG, HbA(1c), hypoglycemia, and percentage of patients reaching HbA(1c) <or=7% without documented nocturnal hypoglycemia. RESULTS: Mean FPG at end point was similar with glargine and NPH (117 vs. 120 mg/dl [6.5 vs. 6.7 mmol/l]), as was HbA(1c) (6.96 vs. 6.97%). A majority of patients ( approximately 60%) attained HbA(1c) <or=7% with each insulin type. However, nearly 25% more patients attained this without documented nocturnal hypoglycemia (<or=72 mg/dl [4.0 mmol/l]) with glargine (33.2 vs. 26.7%, P < 0.05). Moreover, rates of other categories of symptomatic hypoglycemia were 21-48% lower with glargine. CONCLUSIONS: Systematically titrating bedtime basal insulin added to oral therapy can safely achieve 7% HbA(1c) in a majority of overweight patients with type 2 diabetes with HbA(1c) between 7.5 and 10.0% on oral agents alone. In doing this, glargine causes significantly less nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating insulin. This simple regimen may facilitate earlier and effective insulin use in routine medical practice, improving achievement of recommended standards of diabetes care. Riddle M, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P

31 Insulin Glargine vs NPH Insulin Added to Oral Therapy
Methods Forced-Titration Schedule Start with 10 IU/day bedtime basal insulin dose and adjust weekly Self-monitored FPG (mg/dL)*  in insulin dose (IU/day) 180 mg/dL 8 140 but <180 mg/dL 6 120 but <140 mg/dL 4 >100 but <120 mg/dL 2 Slide 8 Insulin Glargine vs NPH Insulin Added to Oral Therapy The forced-titration schedule with basal insulin (either NPH or glargine) is described here. Patients self-monitored their FPG for 2 consecutive days in which they suffered no episodes of hypoglycemia. Based on these results, insulin levels were titrated until patients reached a target FPG of 100 mg/dL Hypoglycemia was considered severe if measured by the patient to be 72 mg/dL. Patients with self-monitored glucose levels <56 mg/dL were allowed small decreases (2–4 IU/day) of insulin to adjust their FPG levels Riddle MC, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P Treat to target FPG 100 mg/dL *2 consecutive days with no episodes of severe hypoglycemia or PG ≤72 mg/dL Small  (2–4 IU/day/adjustment) in dose allowed when self-monitored PG <56 mg/dL or severe hypoglycemic episode occurs Riddle M, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P

32 Insulin Glargine vs NPH Insulin Added to Oral Therapy
Results 120 6.68 117 6.5 NPH Insulin Glargine ITT Analysis FPG, mg/dL mM 6.97 6.96 A1C, % Nocturnal hypoglycemia Patients,* % 40 49 Final A1C 7% (% patients) 57 Severe hypoglycemia 2.5 2.3 Patients, % Slide 12 Insulin Glargine vs NPH Insulin Added to Oral Therapy This study provided evidence that both insulin treatments improved glycemic control, reducing FPG and A1C 57% of patients in each group reached target A1C 7% Insulin glargine–treated patients showed a significantly lower risk for nocturnal hypoglycemia (fewer patients and fewer events) Severe hypoglycemia was uncommon in both study groups (P=NS), as measured by PG <56 mg/dL Riddle MC, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P *P<0.01; †P<0.002 Riddle M, Rosenstock J, HOE901/4002 Study Group. Diabetes. 2002;51(suppl 2):A113. Abstract 457-P

33 Once-Daily Levemir Improved Glycemic Control
Results from a 20-week, multicenter, randomized, open-label clinical trial comparing the efficacy and safety of Levemir with NPH insulin administered once daily. Oral antidiabetic medication was administered to both treatment groups (N=336). Mean change in A1C from baseline was comparable for once-daily evening treatment with Levemir vs once-daily NPH (-1.48% vs -1.74%, respectively). Reference Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther. 2006;28:

34 INITIATE Trial 28-weeks, parallel group randomized study comparing the safety and efficacy of biphasic insulin Aspart mix 70/30 bid vs Glargine qd. Primary end point A1C reduction Secondary end points Proportion of patients achieving A1C <7.0% and ≤6.5% PPG control Safety, including number of hypoglycemic events (major, minor, nocturnal) and adverse events

35 Addition of glargine or biphasic aspart mix 70/30 to oral therapy
233 People with Type 2 Diabetes on 1 or 2 Oral Agents Glycaemic Control Hypoglycaemia Baseline HbA1c 9.7% 9.8% Events/Patient-year (PG  3.1 mmol/l) P<0.05  HbA1c INITIATE Study: 66% of Patients Got to Goal With NovoLog Mix 70/30 INITIATE was a 28-week, parallel-group, randomized study comparing the safety and efficacy of NovoLog Mix 70/30 BID to once-daily insulin glargine. Insulin-naïve patients with type 2 diabetes (N=233) and A1C values ≥8.0% who were taking >1000 mg daily of metformin with or without other OADs for at least 3 months before the trial (209 completed the study). During the 4-week run-in period, secretagogues and -glucosidase inhibitors were discontinued, pioglitazone was continued (up to 30 mg), and metformin was optimized to mg/day. Insulin was initiated with 5 to 6 U of NovoLog 70/30 BID or 10 to 12 U of insulin glargine once daily at bedtime and titrated to goal with algorithm-directed titration. At study end, the mean A1C value in the NovoLog Mix 70/30 group was 6.91% ± 1.17% and 7.41% ± 1.24%, in the basal analog group (P<.01). The A1C reduction in the NovoLog Mix 70/30 group was -2.79% ± 0.11% and ­2.36% ± 0.11% in the basal analog group (P<.01). 66% of subjects treated with NovoLog Mix 70/30 and 40% of patients in the basal analog group reached target A1C values of ≤7.0% (P<.001). Only one major hypoglycemic episode was reported by one patient in the insulin glargine group. Conclusion: In subjects with type 2 diabetes poorly controlled by OADs, initiating insulin therapy with twice-daily NovoLog Mix 70/30 enabled the majority of patients to achieve glycemic targets. P<0.01 Final HbA1c 6.9% 7.4% Biphasic aspart 70/30.( 66% A1c 7) Glargine. (40% A1C 7) Raskin P et al. Diabetes Care. 2005;28:

36 Background Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. Methods In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. Results 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. Conclusions A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain. (Current Controlled Trials number, ISRCTN )

37 Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes
Study Overview In an open-label trial, patients with type 2 diabetes with a suboptimal glycated hemoglobin level while receiving a maximally tolerated dose of metformin and sulfonylurea were randomly assigned to receive biphasic, prandial, or basal insulin The addition of a single analogue-insulin formulation resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. Regimens of biphasic or prandial insulin had greater efficacy than did the basal regimen but were associated with greater risks of hypoglycemia and weight gain Background Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. Methods In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. Results 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. Conclusions A single analogue-insulin formulation added to metformin and sulfonylurea resulted in a glycated hemoglobin level of 6.5% or less in a minority of patients at 1 year. The addition of biphasic or prandial insulin aspart reduced levels more than the addition of basal insulin detemir but was associated with greater risks of hypoglycemia and weight gain. (Current Controlled Trials number, ISRCTN )

38 Primary and Secondary Outcomes at 1 Year
Figure 2. Primary and Secondary Outcomes at 1 Year. Panel A shows mean levels of glycated hemoglobin in the three study groups. Panel B shows the proportion of patients in each group whose glycated hemoglobin values were below various levels, as compared with the distribution of values for all patients at baseline. Panel C shows mean body weight. Panel D shows eight-point self-measured capillary glucose values, with box-and-whisker plots representing medians and interquartile ranges and the 10th and 90th percentiles. Horizontal lines represent titration targets for fasting plasma glucose (99 mg per deciliter) and 2-hour postprandial levels (126 mg per deciliter). Panel E shows median insulin doses. Panel F shows the proportion of patients who reported grade 2 or grade 3 hypoglycemic events. I bars denote 90% confidence intervals. Holman RR et al. N Engl J Med 2007;357:

39 Mean (±SE) Percentage Change from Baseline to 1 Year in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, and Body Weight (Panel A) and Mean (+SD) Hypoglycemic-Event Rate (Panel B) Figure 3. Mean (±SE) Percentage Change from Baseline to 1 Year in Glycated Hemoglobin, Fasting Plasma Glucose, Postprandial Glucose, and Body Weight (Panel A) and Mean (+SD) Hypoglycemic-Event Rate (Panel B). For all measures, P<0.001, with values adjusted for baseline values (except hypoglycemia), center, baseline glycated hemoglobin level, and oral antidiabetic therapy where appropriate. Missing data were imputed with the use of a multiple-imputation technique.14 To convert the values for glucose to millimoles per liter, multiply by Holman RR et al. N Engl J Med 2007;357:

40 Glycated Hemoglobin Level, Hypoglycemia, and Increase in Body Weight at 1 Year and 3 Years
Figure 1. Glycated Hemoglobin Level, Hypoglycemia, and Increase in Body Weight at 1 Year and 3 Years. Shown are the proportions of patients who had a glycated hemoglobin level of 6.5% or less or who had grade 2 or 3 hypoglycemia and the relative increase from baseline in body weight after the first year5 and the third year8 of the Treat to Target in Type 2 Diabetes (4-T) study. Roden M. N Engl J Med 2009;361:

41 Evidence-based guideline-derived treatment algorithm
Diagnosis Lifestyle intervention then metformin HbA1c 6.5 % Add sulfonylurea HbA1c 6.5 % HbA1c 6.5 % *Alternatively, start thiazolidinedione before sulfonylurea, and sulfonylurea later. Add thiazolidinedione* Add insulin HbA1c 7.5 % HbA1c 7.0 % Start insulin intensify insulin Meal-time + basal insulin + metformin ± thiazolidinedione IDF. Global Guideline for Type 2 Diabetes. 2005

42 According to the IDF Global Guideline for Type 2 Diabetes:
How should I start insulin therapy for my patients with Type 2 diabetes? According to the IDF Global Guideline for Type 2 Diabetes: Insulin is the most effective way of reducing hyperglycaemia Insulin can be started as a basal insulin alone or with premix insulin Start insulin when glucose control on maximum tablets >7.5 % (HbA1c) Begin at low dose but titrate up rapidly in first month IDF. Global Guideline for Type 2 Diabetes. 2005

43 ADA/EASD Treatment Algorithm for Type 2 Diabetes
Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. The interventions should be changed if A1C is ≥7%. a)Sulfonylureas other than glybenclamide (glyburide) or chlorpropamide. b)Insufficient clinical use to be confident regarding safety. The new guidelines for tight glycemic control keep safety in mind when prescribing medications. The new algorithm is divided into two tiers. Tier 1 is well-validated core therapies, and tier 2 is less well-validated therapies. Both tiers suggest action every 3 months if the A1C is above 7%. From r n articleTier 1: Step 1, at diagnosis, start with lifestyle and metformin. Step 2, add basal insulin or sulfonylurea in three months. Step 3, if still above A1C goal 3 months later, add intensive insulin. Tier 2: If the lifestyle and metformin doesn’t bring the A1C to goal from step 1, move to step 2 and add Actos or a GLP-1 agonist (Byetta). If that doesn’t to the trick, then in step 3, add a sulfonylurea or Actos, or basal insulin. “” said it very well in her article “Translating ADA/EASD Guidelines and the ACE/AADE Road Maps into Primary Care with Patients with Type 2 Diabetes” (Journal for Nurse Practitioners, October 2008): we “agree that a patient-centered, team-care approach to achieving glycemic control, and ongoing self-management education to all patients, are essential to optimized diabetes care.” DIABETES CARE, VOLUME 31, NUMBER 12, DECEMBER 2008

44 Initiation and adjustment of insulin regimens
Start with bedtime intermediate-acting insulin or bedtime(HS) or morning long-acting insulin (can initiate with 10 U or 0.2 units per kg) Check FBG usually daily and increase dose, typically by 2U every 3 days until fasting levels are in target range( mg/dL). Can increase dose in larger increments,eg, by 4 U every 3 days, if FBS >180 mg/dL A1c ≥ 7% after 2-3 months ? If hypoglycemia occurs, or FBS< 70 mg/dL, reduce HS dose by ≥ 4U, or 10% if dose is > 60U Yes No If FBS in target range(70-130mg/dL),check bg before lunch,dinner, and at HS. Depending on bg results,add second injection as below. Can usually begin with ~ 4 U and ajust by 2 U every 3 days until bg is in range Continue regimen. Check A1c every 3 months Pre-lunch bg out of range. Add rapid-acting insulin at breakfast Pre-dinner bg out of range. Add NPH insulin at breakfast or rapid acting at lunch Pre-bed(HS) bg out of range. Add rapid-acting insulin at dinner No A1c ≥ 7% after 3 months Yes Recheck pre-meals bg levels and if out of range, may need to add another injection. If A1c continues to be out of range,check 2-h postprandial levels and adjust preprandial rapid-acting insulin ADA/EASD Consensus Algorithm 2009

45 How should I advance insulin therapy for people with Type 2 diabetes?
Algorithm driven dose titration – basal regimen* Once daily intermediate or long-acting insulin Begin 10 U or 0.2 U/kg, titrate by 2 U every 3 days using pre-breakfast plasma glucose (PG) until in target range ( mg/dL) HbA1c ≥7.0% after 3 months Check pre- breakfast, lunch, dinner, and bedtime PG Add rapid-acting insulin to the meal with the highest excursion Begin 4 U and adjust by 2 U every 3 days based on PG change† Add additional meal-time injections if HbA1c ≥7.0% after 3 months *Insulin regimens should be designed taking lifestyle and meal schedule into account; this algorithm provides a basic guideline for initiation and adjustment of insulin. Regimens with once- or twice-daily premixed insulins are also possible. †Inhaled insulin dosing in 1 mg (≈ 3 U) steps. Nathan DM et al. Diabetes Care. 2006;29:

46 Insulin in the Hospital Setting: Glycemic Control and Improved Outcomes

47 The Increasing Rate of Diabetes Among Hospitalized Patients
Hospitalizations for Diabetes as a Listed Diagnosis 5 4 Hospital Discharges (millions) 3 48% 2 The Increasing Rate of Diabetes Among Hospitalized Patients Data regarding the burden of diabetes among hospitalized patients is somewhat difficult to determine because diabetes is reflected in multiple codes in the International Classification of Diseases, Ninth Revision. In the 1990s the number of hospital discharges with diabetes as the first-listed diagnosis began increasing. Accessed June 15, 2004. 1 1991 92 93 94 95 96 97 98 99 2000 01 Available at: Accessed June 15, 2004.

48 Diabetes in Hospitalized Patients
At least 4 million patients with diagnosed diabetes are admitted to hospitals annually in the United States In 2000, 12.4% of hospital discharges in the United States listed diabetes as a diagnosis An accurate estimate of the number of patients admitted to hospitals with diabetes is difficult to attain, because type 2 diabetes is underdiagnosed.1,2 For example, of the projected 186 million hospital inpatient days in the U.S. in 2007, an estimated 40.7 million days (22%) are incurred by people with diabetes and 24.3 million (13%) are attributed to diabetes. References Centers for Disease Control and Prevention. National Diabetes Fact Sheet: General Information and National Estimates on Diabetes in the United States, Rev ed. Atlanta, Ga: US Dept of Health and Human Services, Centers for Disease Control and Prevention; 2004. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(suppl 1):S4-S36. Centers for Disease Control 2004.American Diabetes Association. Diabetes Care. 2005;28(suppl 1):S4-S36. 1- American Diabetes Association. Diabetes Care 2008;31:

49 Hyperglycemia Is Common in Hospitalized Patients
Non-critically ill medical / surgical: 38% Intensive care units (ICU): 29% – 100% Episodes of glucose >110 mg/dL: 100% Episodes of glucose >200 mg/dL: 31% Mean glucose >145 mg/dL: 39%(prevalence) [1/Umpierrez.JClin EnodcrinolMetab. Mar.2002/p980/c2/ line 21-22] [2/Levetan.Diabetes Care.Feb.1998/p246/Abstract/ line A10-A13] [3/Krinsley.Mayo ClinProc.Dec.2003/ p1475/Table 5] [4/Falciglia. [Hyperglycemia ICU Prevalence].2006 [ADA Abstract 19-LB]/p1/Table 1] Umpierrez G et al. J Clin Endocrinol Metabol. 2002, 87: Levetan CS et al. Diabetes Care. 1998;21: Krinsley JS. Mayo Clin Proc. 2003;78: Falciglia M et al. 66th ADA Scientific Meeting, 2006. 49

50 Hyperglycemia in Patients Predictor of Poor Outcome
Hyperglycemia occurred in 38% of patients admitted to a community hospital in Atlanta 26% had known history of diabetes 12% had no history of diabetes Newly discovered hyperglycemia was associated with: Higher in-hospital mortality rate (16%) compared with patients with a history of diabetes (3%) and patients with normoglycemia (1.7%; both P<.01) Longer hospital stays; higher admission rates to intensive care units (ICUs) Less chance to be discharged to home (required more transitional or nursing home care) Hyperglycemia in Patients With Undiagnosed Diabetes New hyperglycemia was defined as an admission or in-hospital fasting glucose level of 126 mg/dL (7 mmol/L) or more or a random blood glucose level of 200 mg/dL (11.1 mmol/L) or more on 2 or more determinations. Hyperglycemia was present in 38% of patients admitted to the hospital, of whom 26% had a known history of diabetes and 12% had no history of diabetes before admission. Newly discovered hyperglycemia was associated with a higher in-hospital mortality rate (16%) compared with patients with a history of diabetes (3%) and patients with normoglycemia (1.7%; both P<.01). In addition, new hyperglycemic patients had longer hospital stays and a higher admission rate to an intensive care unit (ICU), and were less likely to be discharged to home, frequently requiring transfer to a transitional care unit or nursing home facility. The results indicate that in-hospital hyperglycemia is a common finding and represents an important marker of poor clinical outcome and mortality in patients with and without a history of diabetes. Patients with newly diagnosed hyperglycemia had a significantly higher mortality rate and a lower functional outcome than patients with a known history of diabetes or normoglycemia. Reference Umpierrez GE, Isaacs SD, Bazargan N, et al. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87: Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87:978–982.

51 Effect of Hyperglycemia on Hospital Mortality
* * * The medical records of 2030 consecutive adult patients were analyzed for the presence of hyperglycemia and any association with poor hospital outcomes. New hyperglycemia was associated with a 16% mortality rate compared with 3% and 1.7% for patients with a prior history of diabetes or normoglycemia (P<.01). The mortality rate was significantly higher for patients with new hyperglycemia regardless of whether they were admitted to the ICU (P<.01 for both ICU and non-ICU patients compared with those with diabetes or normoglycemia). Mortality rates were 10% for non-ICU patients with new hyperglycemia and 31% for ICU patients. Reference Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87: *P<.01 compared with normoglycemia and known diabetes. Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87:978–982.

52 Hyperglycemia and Pneumonia Outcomes
[McAlister. Diabetes Care. Apr.2005/p811/ Table 1, c3/ line 27-29] * * * * N=2471 patients with CAP, Canada Others group have reproduce similar data This slide show results of group 2500 with cap from canada rate of mortality .RATE OF MORTALITY IN BLUE AND THE hospital complication IN YELLOW according to glucose concentration going from < 100 to >250 is associated with increase mortality and hospital complication. *P<0.05 vs BG<198 mg/dL (11 mmol/L) CAP, community acquired pneumonia McAlister et al. Diabetes Care. 2005;28: 52

53 Hyperglycemia and Mortality in the MICU
~4x N=1826 ICU patients. ~3x 45 [Krinsley.MayoClin Proc.Dec.2003/ p1471/Abstract/c1/ line A4-A8; p1476/ Table 7] 40 ~2x 35 30 25 Mortality Rate (%) 20 15 10 Effect of hyperglycemia seen in icu Mayo clinic, 1800 in mix icu,medical and surgical patients; date is clear hyperglycemia is a marker of por outcome 5 80-99 >300 Mean Glucose Value (mg/dL) Krinsley JS. Mayo Clin Proc. 2003;78: 53

54 Consequences of Poor Glycemic Control in Hospital Patients
Hyperglycemia, with or without a diagnosis of diabetes, can result in Increased Mortality Increased Morbidity Admission to the ICU Need for extended care Overall poor outcomes Hyperglycemia, regardless of the presence of diabetes, has been shown to be associated with poor outcomes in hospitalized patients.1 Numerous controlled, prospective, and observational studies provide evidence that hyperglycemia is associated with mortality, length of stay in the hospital, admission to the ICU, and the need for placement in an extended care facility after release from the hospital.1 Furthermore, for hospitalized patients with hyperglycemia, poor outcomes have been shown for acute myocardial infarction (MI), critically ill patients, and acute neurological disorders such as ischemic stroke.2-6 References 1. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. J Clin Endocrinol Metab. 2002;87: 2. Malmberg K, for 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: 3. Bolk J, van der Ploeg T, Cornel JH, Arnold AER, Sepers J, Umans VAWM. Impaired glucose metabolism predicts mortality after a myocardial infarction. Int J Cardiol. 2001;79: 4. Williams LS, Rotich J, Qi R, et al. Effects of admission hyperglycemia on mortality and costs in acute ischemic stroke. Neurology. 2002;59:67-71. 5. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345: 6. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients. A systematic overview. Stroke. 2001;32: Umpierrez GE et al. J Clin Endocrinol Metab. 2002;87: Bolk J et al. Int J Cardiol. 2001;79: Williams LS et al. Neurology. 2002;59: Malmberg K, et al. BMJ. 1997;314:1512. Van den Berghe G et al. N Engl J Med. 2001;345: Capes SE et al. Stroke. 2001;32:

55 Hyperglycemia is a Marker of Poor Outcome
Does control of hyperglycemia is important in improving outcomes?

56 DIGAMI Study Diabetes, Insulin Glucose Infusion in Acute Myocardial Infarction (1997)
Acute MI With BG > 200 mg/dl Intensive Insulin Treatment IV Insulin For > 24 Hours Four Insulin Injections/Day For > 3 Months Reduced Risk of Mortality By: 28% Over 3.4 Years 51% in Those Not Previous Diagnosed Malmberg BMJ 1997;314:1512

57 Mortality After MI Is Reduced by Insulin Therapy in DIGAMI
Standard treatment (314) IV insulin 48 hours, then 4 injections daily (306) All Subjects (N=620) Low-Risk & Not Previously on Insulin (N=272) 0.7 0.7 0.6 0.6 Risk reduction (28%) Risk reduction (51%) 0.5 0.5 P=.011 P=.0004 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 The Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction 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 MI. The subjects (n=620) were randomized to conventional therapy (n=314), according to the judgment of their physicians, or to an intravenous (IV) infusion of insulin and glucose for 48 hours followed by a multidose subcutaneous insulin regimen (n=306). After a mean follow-up of 3.4 years, mortality was 44% in the conventional therapy group compared with 33% in the intensive-treatment group. The absolute reduction in mortality in the intensive-treatment group was 11% (relative risk of 0.72, P=.011). This means one life saved for every nine patients. Benefits were even greater for patients who had not previously taken insulin and who were at low cardiovascular risk. The absolute reduction in morality was 15% (relative risk of 0.49, P=.004). Reference Malmberg K, for 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: 1 2 3 4 5 1 2 3 4 5 Follow-Up (y) Follow-Up (y) MI = myocardial infarction; DIGAMI = Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction. (Short and long term effect of intensive insulin therapy) 44vs33 Malmberg K et al. BMJ. 1997;314:

58 Intensive Insulin Therapy in Critically Ill Patients: The Leuven SICU Study
Randomized controlled trial: 1548 patients admitted to a surgical ICU, receiving mechanical ventilation. Patients were assigned to receive either: Conventional therapy: IV insulin only if BG >215 mg/dL Target BG levels: mg/dL Mean daily BG: 153 mg/dL Intensive therapy: IV insulin if BG >110 mg/dL Target BG levels : mg/dL Mean daily BG: 103 mg/dL [VandenBerghe. NEJM.Nov.2001/ p1359/Abstract/line A6-A15,p1360/c1/ line 23-43, p1361/ Table 2] Van den Berghe et al. N Engl J Med. 2001;345: 58

59 ICU Survival 1548 Patients (mostly OHS pts.) All with BG >200 mg/dl
Randomized into two groups Maintained on IV insulin Conventional group (BG ) Intensive group (BG ) Conventional Group had 1.74 X mortality Van den Berghe et al. N Engl J Med. 2001;345:

60 Intensive Glycemic Control and Survival in Critically Ill Patients
100 96 92 88 84 80 100 96 92 88 84 80 Intensive treatment, 4.6% mortality Intensive treatment Conventional treatment, 8% In-Hospital Survival (%) Survival in ICU (%) Conventional treatment 42.5% reduction in mortality with intensive treatment; P<.04 34% reduction in mortality with intensive treatment; P<.01 In a prospective, randomized, controlled study, 1548 patients received standard or intensive glycemic treatment after entry into the ICU. Intensive treatment Blood glucose levels were maintained between 80 and 110 mg/dL while in the ICU After discharge from the ICU, blood glucose levels were maintained between 180 and 200 mg/dL Conventional treatment Treatment initiated if blood glucose levels >215 mg/dL Blood glucose maintained between 180 and 200 mg/dL Patients discharged alive from the ICU (A) and from the hospital (B) were considered to have survived. For patients in intensive care, mortality was significantly reduced with intensive glycemic control (4.6%) compared with conventional treatment (8%). In-hospital mortality was also reduced by 34% for those in the glycemic control group. Survival analysis revealed a significant difference in mortality between the intensive glycemic control group and the conventional-treatment group. Those in the intensive-treatment group had significantly fewer deaths than the conventional-treatment group for both the ICU and total in-hospital patients (P<.04 and P=.01, respectively). Alternatively stated, for each 20 mg/dL increase in blood glucose, the risk of death was increased by 30%. Reference Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345: Days After Admission Days After Admission Van den Berghe et al. N Engl J Med. 2001;345:

61 Benefits of IV Insulin Treatment in Critically ill Hospitalized Patients
34% 41% 44% 46% The benefits of IV insulin infusion in the hospital have been shown in controlled and observational studies. These studies have demonstrated that IV insulin infusion decreases mortality and improves other outcomes for critically ill patients, patients who have had acute MI, and open-heart surgery, including coronary artery bypass grafting.1-4 Tight glycemic control in critically ill patients also improved other outcomes. There was a 46% reduction in blood infections, a 50% reduction in red-cell transfusions, a 41% reduction in acute renal failure that required dialysis or hemofiltration, and a 44% reduction in critical-illness polyneuropathy. References 1. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345: 2. Malmberg K, for 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: 3. Furnary AP, Wu Y, Bookin SO. Effect of hyperglycemia and continuous intravenous insulin infusions on outcomes of cardiac surgical procedures: the Portland Diabetic Project. Endocr Pract. 2004;10(suppl 2):21-33. 4. Furnary AP, Gao G, Grunkemeier GL, et al. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting J Thorac Cardiovasc Surg. 2003;125: 50% Intensive Glycemic Control BG = mg/dL in ICU BG = mg/dL after discharge from ICU Van den Berghe et al. N Engl J Med. 2001;345:

62 Improvement in Deep Sternal Wound Infection With Continuous IV Insulin
4 3 2 1 CII Patients with diabetes Nondiabetic patients DSWI (%) In a prospective study of patients with diabetes (N=2467) who underwent open heart surgery, patients were stratified into a control group who received sliding scale intermittent insulin treatment or continuous IV insulin infusions to maintain blood glucose levels <200 mg/dL. On postoperative day (POD) 1 and 2, DSWI was significantly greater in patients with higher POD glucose levels (P=.02 for POD 1 and P=.01 for POD 2). Implementation of tight glycemic control resulted in a 2.5-fold decrease in DSWI compared with those receiving sliding scale intermittent insulin (P=.011). After initiation of continuous IV insulin infusions in 1991, annual rates of DSWI at one medical center have been reduced and by 1997 were not significantly different for patients with diabetes compared with nondiabetic patients. Patients were treated according to the continuous IV insulin infusion protocol used in the Portland Diabetic Project. Reference Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Ann Thorac Surg. 1999;67: Year Target blood glucose <150 mg/dL. IV = intravenous; CII = continuous insulin infusion; DSWI = deep sternal wound infection. Furnary AP et al. Ann Thorac Surg. 1999;67: (prospective 2467)

63 AACE - Consensus Conference Suggested Blood Glucose Targets
Upper Limit Inpatient Glycemic Targets: ICU: 110 mg/dl (6.1 mmol/L) Non-critical care (limited data) Pre-prandial: 110 mg/dl (6.1 mM) Maximum: 180 mg/dL (10 mM) The current ADA guideline for pre-prandial plasma glucose levels is 90–130 mg/dl AACE- Endocrine Practice 10 (1): 77-82, 2004; AAE – Endocrine Practice February 2006; ADA- Diabetes Care 27: , 2004 63 63

64 Insulin: The Most Effective Treatment for Inpatient Glycemic Control
Adaptable to increased insulin requirement during acute illness Basal insulin administration can prevent excess gluconeogenesis and ketogenesis Dose can be adapted to various categories of patient nutrition status IV dextrose Total parenteral nutrition Enteral feeding Nutritional supplements Insulin is the most useful drug for controlling glucose levels in hospitalized patients. The dose can be rapidly adapted to changes in individual patient blood glucose levels and is also adaptable to various types of nutritional changes, such as the use of IV dextrose, total parenteral nutrition, enteral feeding, and the addition of nutritional supplements. Long-acting, short-acting, and IV insulin can be given to prevent uncontrolled gluconeogenesis and ketogenesis due to fluctuating illness-induced stress or glucocorticoid treatment. Reference Clement S, Braithwaite SS, Magee MF, et al, on behalf of the Diabetes in Hospitals Writing Committee. Management of diabetes and hyperglycemia in hospitals. Diabetes Care. 2004;27: Clement S et al. Diabetes Care. 2004;27:

65 Methods For Managing Hospitalized Patients with Diabetes
IV Insulin Drip Major Surgery, Cardiovascular procedures,NPO, MI, DKA, Steroids, Gastroparesis, MICU, etc Subcutaneous insulin injections: Basal / Bolus Therapy (MDI) when eating Basal / Correction Bolus when NPO

66 Initiate or continue IV insulin infusion as soon as patient comes out from the OR as follows:
Non-Diabetics Check Finger Stick (FS) and initiate or adjust insulin infusion as per TIER 1 (Green Wheel) if any BG > 200 mg/dL Diabetics Check FS and initiate or adjust insulin infusion as follows: If FS > 250 mg/dL bolus with 4 units of regular insulin IV and then follow IV Insulin rate as per weight (below) If FS < 250 mg/dL start as per weight (below) If patient < 70 Kg start as per TIER 1 (Green Wheel) If patient > 70 Kg start as per TIER 2 (Yellow Wheel)

67 Finger Stick (FS) Monitoring
FS Q 1 hour If no change in BG range for two (2) consecutive measurements move-up a tier within the same range If at goal for three (3) consecutive FS can change FS to Q2 hours, and if again at goal for three (3) consecutive measurements can change to FS Q 4 hours Resume monitoring FS Q 1 hour if: Significant change in clinical condition Initiation or cessation of corticosteroids and / or vasopressors Initiation or cessation of hemodialysis Initiation, cessation, or change in nutritional support No to be use

68 DIABETES / HYPERGLYCEMIA DISCHARGE SUMMARY
Date: Mr./ Ms □ Diabetes Mellitus Type 1 □ Diabetes Mellitus Type 2 □ Post-Operative Hyperglycemia Who underwent: □ Coronary Artery Bypass Grafting □ Cardiac Valve Surgery □ Other Post-operatively treatment : □ Novolog ( Aspart ) □ Lantus ( Glargine ) □ Oral antihyperglycemic medication(s) □ Diet-control only Important data: HgA1c _____ Ejection Fraction _____ % Serum creatinine _____ AST/ALT _____ Weight _____ LDL-c _____ Your patient’s Diabetes/Hyperglycemia discharge plan is as follows: □ Life style improvement- diet-control only Oral antihyperglycemic medication(s) Insulin(s) □ Glucophage (Metformin) □ Lantus _____ units at _____, daily □ Prandin (Repaglinide) □ Novolog/Humalog at meals □ Januvia (DPP-IV Inh ) □ Sulfonylureas: □ Other Diabetes follow up appointment : ▢ Dr. Gouller # □ Endo Clinic (212) □ Dr..Busta # □ Dr…… #420- Date : Location : Fierman Hall. 317East 17th street 7 Floor. Recommendations: 1) HgA1c goal of 7% or lower 2) You may also refer your patient to the Friedman Diabetes Institute for diabetes education.Friedman Diabetes Israel Medical Center317 East 17th Street, 8th Floor New York, NY

69 Comparison of Human Insulins and Analogues
Insulin Onset of Duration of Preparations Action Peak (h) Action (h) Lispro/Aspart/Glulisine min Regular human min Human NPH h Detemir h flat/ 6-8 * * Insulin Glargine h flat Time course of action of any insulin can vary in different people or at different times in the same person; thus, time periods indicated here should be considered general guidelines only. * Dose dependent Insulin lispro, aspart, glulisine, and regular human insulin show a rapid onset of action. The duration of action ranges from 4 to 6 hours for rapid-acting insulins to 10 hours for regular human insulins.1 The absorption of insulin glargine is prolonged without unwanted peaks and, thus, fulfills the basal insulin requirements.1 Both insulin glargine and human neutral protamine Hagedorn (NPH) insulin demonstrate an onset of action within 1 to 2 hours after subcutaneous administration. Although insulin glargine has a lower plasma concentration than that observed with NPH insulin, it has twice the duration of action.2 References 1. Mudaliar S, Edelman SV. Insulin therapy in type 2 diabetes. Endocrinol Metab Clin North Am. 2001;30: 2. 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: 1. Mudaliar S et al. Endocrinol Metab Clin North Am. 2001;30: ; 2. Endotext.com

70 Insulin Order There are 6 options (order sets) for the initial insulin orders: Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients eating Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients NPO Patients with type 2 diabetes previously on oral agents- insulin-naïve patients - eating Patients with type 2 diabetes previously on oral agents, insulin-naïve patients NPO Patients with newly diagnosed hyperglycemia - patient eating Patients with newly diagnosed hyperglycemia - patient NPO

71 Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients eating
Order HgbA1C Order hypoglycemia management nest Use Prior Total Daily Dose (TDD) of insulin, whenever possible, if patient was well controlled. If dose is not known or unable to assess control, TDD should be weight-based. TDD (0.4 u/kg)should be split as follows: Basal: 50% of TDD : Lantus dose should be calculated as 50% of 0.4units/kg (0.2 units/kg) and given immediately upon arrival to the floor. Prandial: Novolog should be calculated as 15% of 0.4units/Kg given before each meal (TID AC) Correction/Supplemental Insulin Scale: Standard (or Low, Medium or High Dose according to risk of hypo or hyperglycemia). Correction Scale is given before meals and is added to Prandial dose. HS Correction Scale may be ordered but separately. Reassess TDD in 24 hours.

72 Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients eating
Approximate dose for a 70 kg patient 0.4 u/kg x 70 kg= 28 units Lantus 15 units SC Q 24hr (Q HS) Novolog 5 units SC Q AC before Breakfast, before Lunch and Before Dinner Correction/Supplement Insulin (Novolog) Scale before meals TID AC (Pick Standard, Low Dose, Medium Dose or High Dose)

73 Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients NPO
Order HgbA1C Order hypoglycemia management nest Use Prior Total Daily Dose (TDD) of insulin, whenever possible, if patient was well controlled. If dose is not known or unable to assess control, TDD should be weight-based. TDD should be split as follows: Basal: 50% of TDD : Lantus dose should be calculated as 50% of 0.4 units/kg (0.2 units/kg) and given immediately upon arrival on the unit. Prandial: None Correction/Supplemental Insulin Scale: Standard Scale should be given q4-6 hours All Patients will need to be on D ml/hr. Reassess TDD in 24 hours.

74 Patients with type 1 diabetes or type 2 diabetes previously on insulin therapy- patients NPO
Approximate dose for a 70 kg patient : 0.4 u/kg x 70 kg = 28 units Lantus 15 units SC Q 24hr (Q HS) Correction/Supplement Insulin (Novolog) scale (Standard) Q 4h D5 1/2NS at 100 cc/hr

75 Patients with type 2 diabetes previously on oral agents, insulin-naïve - patients eating
Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) (0.3u/kg)of insulin should be weight-based; insulin should be dosed as follows: Basal: 50% of TDD: Lantus dose should be calculated as 50% of 0.3 units/kg (0.15 units/kg) and given immediately upon arrival on the unit. Prandial: Novolog should be calculated as 15% of 0.3 units/kg and given before each meal (TID AC). Correction/Supplemental Insulin Scale: Standard (or Low, Medium or High Dose according to risk of hypo or hyperglycemia). Correction Scale is given before meals and is added to Prandial dose. HS Correction Scale may be ordered but separately. Reassess TDD in 24 hours.

76 Patients with type 2 diabetes previously on oral agents- insulin-naïve patients - eating
Approximate dose for a 70 kg patient: 0.3 u/kg x 70 kg = 21 units Lantus 10 units SC Q 24hr (Q HS) Novolog 3 units SC Q AC before Breakfast, before Lunch and Before Dinner Correction/Supplement Insulin (Novolog) Scale before meals TID AC (Pick Standard, Low Dose, Medium Dose or High Dose)

77 Patients with type 2 diabetes previously on oral agents, insulin-naïve - patients NPO
Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) of insulin should be weight-based; insulin should be dosed as follows: Basal: Lantus dose should be calculated as 0.1 U/kg and given immediately upon arrival to the floor. Prandial: None Correction/Supplemental Insulin Scale: Standard Scale should be given q4-6hours. Reassess TDD in 24 hours.

78 Patients with type 2 diabetes previously on oral agents, insulin-naïve - patients NPO
Approximate: 0.1 u/kg x70 kg = 7 units Lantus 7 units SC Q 24hr (Q HS) Correction/Supplement Insulin (Novolog) scale (Standard) Q 4h D5 1/2NS at 100 cc/hr

79 Patients with newly diagnosed hyperglycemia - patient eating
Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) of insulin should be weight-based; insulin should be dosed as follows: Basal: 50% of TDD: Lantus dose should be calculated as 50% of 0.3 units/kg and given immediately upon arrival to the floor. Prandial: Novolog should be calculated as 15% of 0.3 units/kg and given before each meal (TID AC). Correction/Supplemental Insulin Scale: Standard (or Low, Medium or High Dose according to risk of hypo or hyperglycemia). Correction Scale is given before meals and is added to Prandial dose. HS Correction Scale may be ordered but separately. Reassess TDD in 24 hours.

80 Patients with newly diagnosed hyperglycemia - patient eating
Approximate: 0.3u/kg x 70 kg = 21 units Lantus 10 units SC Q 24hr (Q HS) Novolog 3 units SC Q AC before Breakfast, before Lunch and Before Dinner Correction/Supplement Insulin (Novolog) Scale before meals TID AC (Pick Standard, Low Dose, Medium Dose or High Dose)

81 Patients with newly diagnosed hyperglycemia - patient NPO
Order HgbA1C Order hypoglycemia management nest Total Daily Dose (TDD) of insulin should be weight-based; insulin should be dosed as follows: Basal: None Prandial: None Correction/Supplemental Insulin Scale: Standard Scale should be given q4-6hours. Reassess TDD in 24 hours.

82 Patients with newly diagnosed hyperglycemia - patient NPO
Approximate: Correction/Supplement Insulin (Novolog) scale (Standard) Q 4h

83 Hypoglycemia Treatment of Hypoglycemia
Patient alert : gm of carbs ( 8 onz of juice, 2 crackers=10 carbs , glucose tablets) Non alert patient : 1 amp D50 or 1 mg glucagon IM (repeat q 15 min ) RULE OF THUMB : 15 gm of carbs will increased glucose levels mg/dL Do Not Hold Insulin When BG Normal


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