Diabetes Management in the Outpatient Setting

Diagnostic Criteria (before 2010) FPG≥126 mg/dl. Prediabetes (IFG)≥100 mg/dl. 75 gram OGTT 2 hour-value≥200 mg/dl. Prediabetes (IGT)≥140 mg/dl. Random blood glucose≥200 mg/dl + symptoms (polyuria, polydipsia, unexplained weight loss).

International Expert Committee Report on the Role of A1C in the Diagnosis of Diabetes 6.5% THE INTERNATIONAL EXPERT COMMITTEE. Diabetes Care 2009;32:1327

Random PG > 200 + symptoms 2010 Diagnosis of Diabetes and Categories of Increased Risk for Diabetes NORMAL IFG or IGT DIABETES FPG < 100 mg/dl IFG FPG > 100 - 125 mg/dl FPG > 126 mg/dl 2-h PG < 140 mg/dl IGT 2-h PG > 140 - 199 mg/dl 2-h PG > 200 mg Random PG > 200 + symptoms A1C 5.7% to 6.4% ≥ 6.5% ADA, Diabetes Care 33: Suppl. 1, S11-S61, 2010

Main factors in support of using HbA1C as a screening and diagnostic test A1c does not require patients to be fasting. HbA1c reflects longer-term glycemia than does plasma glucose. Relatively unaffected by acute (e.g., stress or illness related) perturbations in glucose levels. Currently used to guide management and adjust therapy. HbA1c laboratory methods are now well standardized and reliable. J Clin Endocrinol Metab 93: 2447–2453, 2008 Diabetes Care 32 (7):1327-1334, 2009

Limitations of the Use of A1C for the Diagnosis of Diabetes Greater cost Limited availability of A1C testing in certain regions of the developing world Incomplete correlation between A1C and average glucose Misleading in patients with anemia and hemoglobinopathies.

Factors influencing A1c

Recommendation of the International Expert Committee for the diagnosis of diabetes Diabetes should be diagnosed when A1C is ≥6.5% Diagnosis should be confirmed with a repeat A1C test Confirmation is not required in symptomatic subjects with plasma glucose levels >200 mg/dl If A1C testing is not possible, previously recommended diagnostic methods (e.g., FPG or2HPG, with confirmation) are acceptable. DIABETES CARE, VOLUME 32, NUMBER 7, JULY 2009

Who To Screen No major risk factors, FPG every 3 years beginning at 45 y.o. Any risk factors, screen earlier and more often: Overweight (BMI>25 kg/m2). First degree relative with T2DM. High risk ethnic group. Hypertension (≥140/90 mmHg). HDL≤35 mg/dl and/or triglycerides≥250 mg/dl. History of gestational diabetes or delivered baby ≥9lb. Polycystic ovary syndrome. History of vascular disease. Habitual physical inactivity.

Treatment Goals for Type 2 Diabetes

Guidelines for Glycemic, BP, & Lipid Control American Diabetes Assoc. Goals HbA1C < 7.0% (individualization) Preprandial glucose 70-130 mg/dL (3.9-7.2 mmol/l) Postprandial glucose < 180 mg/dL Blood pressure < 130/80 mmHg Lipids LDL: < 100 mg/dL (2.59 mmol/l) < 70 mg/dL (1.81 mmol/l) (with overt CVD) HDL: > 40 mg/dL (1.04 mmol/l) > 50 mg/dL (1.30 mmol/l) TG: < 150 mg/dL (1.69 mmol/l) Avoiding ‘glucocentricity’ is key in the comprehensive management of the patient with T2DM. Cardiovascular risk factor reduction must incorporate blood pressure and lipid control, in addition to, where indicated, anti-platelet therapy. HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides. ADA. Diabetes Care. 2012;35:S11-63

Standard of Care-Multifactorial Therapy DCCT (1993) and UKPDS (1998) established role for better glycemic control on prevention of microvascular complications. Studies that improved BP or lipids generally showed lower CAD in type 2 diabetes. Steno 2 trial (2003) showed a marked lowering of both micro and macrovascular events when all 3 utilized.

Standard of Care-Multifactorial Therapy DCCT (1993) and UKPDS (1998) established role for better glycemic control on prevention of microvascular complications. Studies that improved BP or lipids generally showed lower CAD in type 2 diabetes. Steno 2 trial (2003) showed a marked lowering of both micro and macrovascular events when all 3 utilized. Memory effect-longterm micro and macrovascular protection years after stopping the trial-in DCCT, UKPDS, and Steno 2 trials.

But…then the role of intensive glucose control management came under active debate.

Conclusions Intensive treatment of glycemia in the ACCORD cohort did not reduce the risk of composite measures of advanced microvascular outcomes renal failure: initiation of dialysis or ESRD, or renal transplant, or a rise of serum creatinine above 3.3 mg/dL retinal photocoagulation or vitrectomy to treat diabetic retinopathy, or development of neuropathy Intensive therapy delayed the onset of albuminuria and some measures of eye complications and neuropathy Microvascular benefits of intensive therapy should be weighed against increase in total and CVD-related mortality, increased weight gain, and high risk for severe hypoglycemia

Depiction of the elements of decision-making used to determine appropriate efforts to achieve glycaemic targets. Greater concerns about a particular domain are represented by increasing height of the ramp. Thus, characteristics/predicaments towards the left justify more stringent efforts to lower HbA1c, whereas those towards the right are compatible with less stringent efforts. Where possible, such decisions should be made in conjunction with the patient, reflecting his or her preferences, needs and values. This ‘scale’ is not designed to be applied rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with permission from Ismail-Beigi et al [ref 20] Figure 1 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] (Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

Main Pathophysiological Defects in T2DM ? gut carbohydrate delivery & absorption incretin effect pancreatic insulin secretion + - pancreatic glucagon secretion HYPERGLYCEMIA peripheral glucose uptake hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Antihyperglycemic Agents Major Sites of Action Plasma glucose  Glucosidase Inhibitors (-) Glucose Production Glucose Uptake Carbohydrate Absorption Muscle/Fat GI tract (-) Injected Insulin Liver (+) Metformin Glitazones Antihyperglycemic agents act at several different sites to augment insulin availability and sensitivity1,2 The alpha-glucosidase inhibitors (acarbose and miglitol) reduce postprandial glucose by slowing carbodydrate absorption at the site of the GI tract The thiazolidinediones or glitazones (pioglitazone and rosiglitazone) sensitize muscle and fat cells to insulin and decrease hepatic glucose output (safe for patient) The biguanide (metformin) decreases hepatic glucose output and increases peripheral glucose uptake Injected insulins (lispro, aspart, regular, lente, Neutral Protamine Hagedorn (or NPH), glargine, and ultralente), increase peripheral glucose uptake and suppress the production of hepatic glucose The sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glycuride, tolazamide, and tolbutamide) stimulate beta cells in the pancreas to secrete insulin; relatively long-acting The meglitinides (repaglinide and nateglinide) promote insulin secretion from beta cells in the pancreas; relatively short acting Insulin Secretion Sulfonylureas Meglitinides (+) Pancreas Insulin Secretion 1. Hines SE. Intensive management of type 2 diabetes. Patient Care.April 30, 2000:91-107. 2. Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72.

Natural History of Type 2 DM Plasma Glucose Postmeal glucose Fasting glucose 126mg/dL Insulin resistance Relative -Cell Function Insulin secretion Type 2 diabetes is a progressive disease:1 Prior to diagnosis, postprandial and fasting plasma glucose levels begin to rise, due to an increase in insulin resistance The pancreas responds with an initial increase of insulin production When the elevated beta-cell response can not be maintained, insulin levels decline, fasting and postprandial plasma glucose levels continue to increase -30 -20 -10 10 20 30 Years of Diabetes DeFronzo RA. Pathogenesis of type 2 diabetes: Implications for metformin. Drugs. 1999;58 (suppl 1):29-30.

Management of Hyperglycemia in T2DM ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Lifestyle Weight optimization Healthy diet Increased activity level Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Oral agents & non-insulin injectables Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors GLP-1 receptor agonists Meglitinides a-glucosidase inhibitors Bile acid sequestrants Dopamine-2 agonists Amylin mimetics Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Class Mechanism Advantages Disadvantages Cost Biguanides Activates AMP-kinase  Hepatic glucose production Extensive experience No hypoglycemia Weight neutral ?  CVD Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Low SUs / Meglitinides Closes KATP channels  Insulin secretion  Microvasc. risk Hypoglycemia Weight gain Low durability ? Ischemic preconditioning TZDs PPAR-g activator  insulin sensitivity Durability  TGs,  HDL-C ?  CVD (pio) Edema / heart failure Bone fractures ?  MI (rosi) ? Bladder ca (pio) High a-GIs Inhibits a-glucosidase Slows carbohydrate absorption Nonsystemic  Post-prandial glucose ?  CVD events Dosing frequency Modest  A1c Mod. Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Class Mechanism Advantages Disadvantages Cost DPP-4 inhibitors Inhibits DPP-4 Increases GLP-1, GIP No hypoglycemia Well tolerated Modest  A1c ? Pancreatitis Urticaria High GLP-1 receptor agonists Activates GLP-1 R  Insulin,  glucagon  gastric emptying  satiety Weight loss ? Beta cell mass ? CV protection GI Medullary ca Injectable Amylin mimetics Activates amylin receptor  glucagon  PPG Hypo w/ insulin Dosing frequency Bile acid sequestrants Bind bile acids  Hepatic glucose production Nonsystemic  Post-prandial glucose  CVD events Dopamine-2 agonists Activates DA receptor Modulates hypothalamic control of metabolism  insulin sensitivity No hypoglyemia ?  CVD events Dizziness/syncope Nausea Fatigue Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Class Mechanism Advantages Disadvantages Cost Insulin Activates insulin receptor  peripheral glucose uptake Universally effective Unlimited efficacy  Microvascular risk Hypoglycemia Weight gain ? Mitogenicity Injectable Training requirements “Stigma” Variable Table 1. Properties of anti-hyperglycemic agents Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM ANTI-HYPERGLYCEMIC THERAPY Implementation strategies: Initial therapy Advancing to dual combination therapy Advancing to triple combination therapy Transitions to & titrations of insulin Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM ANTI-HYPERGLYCEMIC THERAPY Implementation strategies: If A1c >9% start with 2 meds. Consider insulin if BS>300 or A1c>10% Adding a second agent drops A1c on average 1%. A1c>8.5% and on 2 drugs=insulin.

Management of Hyperglycemia in T2DM CONSIDERATIONS Age Weight Sex / racial / ethnic / genetic differences Comorbidities Coronary artery disease Heart Failure Chronic kidney disease Liver dysfunction Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM CONSIDERATIONS Age: Older adults Reduced life expectancy Higher CVD burden Reduced GFR At risk for adverse events from polypharmacy More likely to be compromised from hypoglycemia Less ambitious targets HbA1c <7.5–8.0% if tighter targets not easily achieved Focus on drug safety Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM CONSIDERATIONS Weight Majority of T2DM patients overweight / obese Intensive lifestyle program Metformin GLP-1 receptor agonists ? Bariatric surgery Consider LADA in lean patients Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM CONSIDERATIONS Sex/ethnic/racial/genetic differences Little is known MODY & other monogenic forms of diabetes Latinos: more insulin resistance East Asians: more beta cell dysfunction Gender may drive concerns about adverse effects (e.g., bone loss from TZDs) Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

T2DM Anti-hyperglycemic Therapy: General Recommendations Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] T2DM Anti-hyperglycemic Therapy: General Recommendations

Adapted Recommendations: When Goal is to Avoid Weight Gain Fig. 2A should be considered when the goal is to avoid hypoglycemia. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the risk of hypoglycemia when using the hidden agents will be, in part, dependent on the baseline degree of hyperglycemia, the treatment target, and the adequacy of patient education. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print] Adapted Recommendations: When Goal is to Avoid Weight Gain

Management of Hyperglycemia in T2DM CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: CVD benefit (UKPDS) Avoid hypoglycemia ? SUs & ischemic preconditioning ? Pioglitazone &  CVD events ? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Metformin: May use unless condition is unstable or severe Avoid TZDs ? Effects of incretin-based therapies Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Increased risk of hypoglycemia Metformin & lactic acidosis US: stop @SCr ≥ 1.5 (1.4 women) UK:  dose @GFR <45 & stop @GFR <30 Caution with SUs (esp. glyburide) DPP-4-i’s – dose adjust for most Avoid exenatide if GFR <30 Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Most drugs not tested in advanced liver disease Pioglitazone may help steatosis Insulin best option if disease severe Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM CONSIDERATIONS Comorbidities Coronary Disease Heart Failure Renal disease Liver dysfunction Hypoglycemia Emerging concerns regarding association with increased mortality Proper drug selection in the hypoglycemia prone Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

T2DM Anti-hyperglycemic Therapy: General Recommendations Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs. T2DM Anti-hyperglycemic Therapy: General Recommendations Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Avoid Hypoglycemia Fig. 2B should be considered when the goal is to avoid weight gain. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the chances of weight gain when using the hidden agents will be mitigated by more rigorous adherence to dietary recommendations and optimal dosing. Adapted Recommendations: When Goal is to Avoid Hypoglycemia Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Adapted Recommendations: When Goal is to Minimize Costs Fig. 2C should be considered when the goal is to minimize costs. This reflects prevailing costs in the North America and Europe in early 2012; costs of certain drugs may vary considerably from country to country and as generic formulations become available.   Adapted Recommendations: When Goal is to Minimize Costs Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Physiologic Insulin Secretion : Basal/Bolus Concept Prandial Insulin 50 Insulin (µU/mL) 25 Basal Insulin Breakfast Lunch Supper 150 Prandial Glucose Suppresses Glucose Production Between Meals & Overnight Basal  50% of Daily Needs When we consider glucose control, we need to focus on both postprandial and basal requirements. This slide illustrates the normal diurnal physiologic response, which highlights the need for both basal and meal insulin. Meal-insulin release occurs in response to nutrient ingestion. Basal insulin is continually secreted over a 24-hour period to maintain homeostasis in the body energy requirements and balance. The “normal” human adult secretes about 25-30 units of insulin a day. As you can see, about ½ of this is in “BASAL” insulin. You can also see that a “normal” patient would likely not exceed PG = 150 mg/dl, even after a meal. These ambient glucose levels (euglycemia) are reflected in a “normal” GHbA1c range of 4.5-6.5% in the USA. NOTE – if you take a random BG (about 15-20% less in value than PG) and it is >130mg/dl, it would be suspect. I will show you what I mean in later slides, but keep this in mind. - If the patient just ate, or it he/she ate 2-3 hours before, it would make a difference in how you may advise him/her concerning seeking medical advise. (Refer to OGTT – Oral Glucose Tolerance Test – data) In the past, we have had to make due with various insulin formulations that did not have adequate pharmacokinetics to duplicate these profiles. However, within the past few years, new insulin analogs have been developed, which provide more physiologic profiles. 100 Glucose (mg/dL) 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

Management of Hyperglycemia in T2DM ANTI-HYPERGLYCEMIC THERAPY Therapeutic options: Insulin Rapid (Lispro, Aspart, Glulisine) Short (Regular) Insulin level Intermediate (NPH) Diagrammatic representation of the approximate pharmacokinetic properties of various insulin formulations. Long (Detemir) Long (Glargine) Hours 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after injection

Establishing Basal Requirement for Glargine Initial calculation of basal dose BW in kilograms x sensitivity index (0.15 – 0.2 ) Or Body Weight in pounds x 0.1 From BID NPH Take total NPH dose and decrease by 20% for starting dose

Establishing Basal Requirement for Glargine Sequential increase Increase every 2-3 days by 4 U if FBG>140 mg/dL 2 U if FBG=120mg/dL to 140 mg/dL OR Mean of am BG after five days Add to initial Glargine by formula (Average BG-100)/10 Example: 200 pounds on 20 units glargine q hs, mean am BG is200 on 6th and 7th day Add (Av BG -100)10 to glargine, (200-100/10) i.e. increase from 20 to 30 units q hs 2nd week--average 130 ,increase glargine from 30 to 33

Establishing Basal Requirement for Glargine Sequential increase Increase every 2-3 days by 4 U if FBG>140 mg/dL 2 U if FBG=120mg/dL to 140 mg/dL OR Mean of am BG after five days Add to initial Glargine by formula (Average BG-100)/10 Example: 200 pounds on 20 units glargine q hs, mean am BG is200 on 6th and 7th day Add (Av BG -100)10 to glargine, (200-100/10) i.e. increase from 20 to 30 units q hs 2nd week--average 130 ,increase glargine from 30 to 33

Sequential Insulin Strategies in T2DM Basal insulin alone is usually the optimal initial regimen, beginning at 0.1-0.2 U/kg body weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 1-2 non-insulin agents. In patients willing to take >1 injection and who have higher A1c levels (≥9.0%), BID pre-mixed insulin or a more advanced basal plus mealtime insulin regimen could also be considered (curved dashed arrow lines). When basal insulin has been titrated to an acceptable FPG but A1c remains above target, consider proceeding to basal + meal-time insulin, consisting of 1-3 injections of rapid-acting analogues. A less studied alternative—progression from basal insulin to a twice daily pre-mixed insulin—could be also considered (straight dashed arrow line); if this is unsuccessful, move to basal + mealtime insulin. The figure describes the number of injections required at each stage, together with the relative complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is important, with dose adjustments made based on the prevailing BG levels as reported by the patient. Non-insulin agents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal insulin are utilized. Comprehensive education regarding self-monitoring of BG, diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient on insulin therapy. Sequential Insulin Strategies in T2DM Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM ANTI-HYPERGLYCEMIC THERAPY Glycemic targets HbA1c < 7.0% (mean PG 150-160 mg/dl [8.3-8.9 mmol/l]) Pre-prandial PG <130 mg/dl (7.2 mmol/l) Post-prandial PG <180 mg/dl (10.0 mmol/l) Individualization is key: Tighter targets (6.0 - 6.5%) - younger, healthier Looser targets (7.5 - 8.0%+) - older, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia PG = plasma glucose Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

Management of Hyperglycemia in T2DM KEY POINTS Glycemic targets & BG-lowering therapies must be individualized. Diet, exercise, & education: foundation of any T2DM therapy program Unless contraindicated, metformin = optimal 1st-line drug. After metformin, data are limited. Combination therapy with 1-2 other oral / injectable agents is reasonable; minimize side effects. Ultimately, many patients will require insulin therapy alone / in combination with other agents to maintain BG control. All treatment decisions should be made in conjunction with the patient (focus on preferences, needs & values.) Comprehensive CV risk reduction - a major focus of therapy.