Diabetes Rx: A Primer Laura Shane-McWhorter, PharmD,

Diabetes Rx: A Primer Laura Shane-McWhorter, PharmD,
BCPS, FASCP, CDE, BC-ADM Professor (Clinical) University of Utah College of Pharmacy Department of Pharmacotherapy

Objectives Describe presentation differences in persons with Type 1 and Type 2 diabetes Explain initial drug therapy choices for persons with Type 2 diabetes Differentiate between the available drug classes for treatment of Type 2 diabetes, based on dose, ADRs, pharmacokinetics, and efficacy Given a patient with Type 2 diabetes, develop a monitoring plan, including labs for disease outcomes and drug-related monitoring

Diabetes Mellitus (DM)
A chronic disorder: Characterized by hyperglycemia Abnormal CHO, fat, protein metabolism Acute complications (hypo/hyperglycemia, secondary infections) Marked propensity to develop chronic complications: Renal Ophthalmic Neurologic Cardiovascular disease - Macrovascular Microvascular

Diabetes: The Statistics
Persons with diabetes: 24 million persons 12.2 million in > 60 yrs 1.6 million new cases diagnosed in people aged 20 years or older in 2007 Pre-diabetes: 57 million people Lifetime risk Males: 32.8% Females: 38.5% Hispanic women: 52.5%

Prevalence of Diabetes in the USA
Diagnosed Diabetes 17.5 Million Undiagnosed Diabetes 6.6 Million

Diabetes Costs Total: $174 billion Medical costs
2007 Costs of diabetes in the US: Total: $174 billion Medical costs $116 billion Decreased productivity (absenteeism,  work productivity, inability to work due to disability, and premature mortality) $58 billion Diabetes Care 2008;31:1-20.

Diabetes Costs 2008 Costs of diabetes in the US:
Total: $218 billion (10% of USA healthcare spending) Medical costs - $174.4 billion $ billion for T1DM $159.5 billion for T2DM Cost for undiagnosed DM - $18 billion Cost for pre-DM - $25 billion Cost for GDM - $636 million Associated Press

Diabetes Statistics… Medications/supplies $3.7 billion for insulin
$1.8 for supplies $8.6 billion for oral agents $12.7 billion for retail Rxs Diabetes Care 2008;31:1-20.

BJ BJ is a 20 y/o junior in college. She is concerned about having a lot of UTIs in the last eight months. She is seen at Student Health for an upper respiratory infection and random glucose values in the last month have been > 200 mg/dL. She complains of polyuria and polydipsia. She has also been losing weight without trying. Her labs are the following: Glucose 340 mg/dL + Glutamic Acid Decarboxylase Antibodies C-peptide 0.5 ng/mL (0.5-5 ng/mL) + ketonuria 5’4” tall and 104 lbs (weight was 118 lbs 3 months ago)

RE RE is a 45 y/o male seen in clinic for balanitis and onychomycosis. The patient is 5’10” and weighs 240 lb. He complains of thirst and polyuria. His fasting glucose values have been in the low 120s (mg/dL). He has gained 40 lbs in the last 2 years. Today, random glucose is 359 mg/dL BP 148/98 mm Hg Fasting lipids total cholesterol 240 mg/dL, triglycerides 438 mg/dL, HDL of 32 mg/dL

Criteria for Diagnosis
Fasting plasma glucose (FPG) > 126mg/dL† Symptoms of diabetes plus casual plasma glucose concentration > 200 mg/dL* (3 Ps, wt loss) 2 hr PG during Oral Glucose Tolerance Test (75 g OGTT) is > 200 mg/dL A1C > 6.5% (NGSP) * Casual is defined as any time of day without regard to time since last meal. † Fasting is defined as no caloric intake for at least 8 hours. In absence of unequivocal hyperglycemia, confirm by testing on different day (same or different test) OGTT not for routine use

Classification TYPE 1 TYPE 2 < 30 y/o (75% < 18 y/o)
Abrupt onset (wt , 3 Ps) 5-10% FH – emerging genetic basis No insulin production Normal/underweight Ketosis common Whites: more common Etiology: Autoimmune Initially, no microvascular complications Initially, macrovascular complications rare Any age;  with age Gradual onset (+ Sx) 90-95% FH – strong Insulin resistance, impaired insulin secretion (may need insulin) 80% overweight Ketosis rare; HHS may occur Ethnic minorities: common Etiology: Obesity? Insulin resistance? Initially microvascular complications common Initially, macrovascular complications common

Pathophysiology of Type 1 DM
Primary defect is absolute insulin deficiency with almost total loss of functional beta cell mass in months before diagnosis Beta cell mass loss usually related to autoimmune destruction of pancreatic beta cells Fasting hyperglycemia when 80-90% of beta cell mass is destroyed e.g., no insulin secretion

Measurable antibodies due to autoimmune destruction of beta cells Glutamic acid decarboxylase autoantibodies (GAD) Insulin autoantibodies (against islet tyrosine phosphatase) Islet cell antibodies (not standardized in labs) Significant HLA association (DR3, DR4) on Chromosome 6 (40 known genes on Chromosome 6 contribute risk) Strong genetic linkage to DQA and B genes

Disturbances in lipid and amino acid metabolism in those that later declare with T1DM  succinic acid/phosphatidylcholine at birth  TGs/antioxidant ether phospholipids  lysophosphatidylcholines (pro-inflammatory) months before beta cell autoimmunity Absolute amylin deficiency (co-stored, co-secreted with insulin) Disrupted compensatory systems of glucose regulation (glucagon) that  risk for hypoglycemia and erratic glucose control

Presentation of Type 1 DM
20-40% of T1DM present with DKA after several days of polyuria, polydipsia, polyphagia, and weight loss Some T1DM pts may enter “honeymoon” phase Some residual beta cell function

Islet Cell Dysfunction
Glucagon (alpha cells) Pancreas Insulin Amylin (beta cells) Glucose output Glucose uptake Liver Muscle Adipose tissue Blood glucose 1. Del Prato S,Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. References: 1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 2. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544. 3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care ;26:2929–2940. 4. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830. 5. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441. 6. Holz GG, Chepurny OG. Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem. 2003;10:2471–2483. 7. Creutzfeldt WO, Kleine N, Willms B, Ørskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7–36) amide in type I diabetic patients. Diabetes Care. 1996;19:580–586. 8. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med ;18:247–254.

BJ BJ is a 20 y/o junior in college. She is concerned about having a lot of UTIs in the last eight months. She is seen at Student Health for an upper respiratory infection and random glucose values in the last month have been > 200 mg/dL. She complains of polyuria and polydipsia. She has also been losing weight without trying. Her labs are the following: Glucose 340 mg/dL + Glutamic Acid Decarboxylase Antibodies C-peptide 0.5 ng/mL (0.5-5 ng/mL) + ketonuria 5’4” tall and 104 lbs (weight was 118 lbs 3 months ago)

BJ How should we confirm the diagnosis of DM when a glucose is repeated? Fasting glucose? Postprandial glucose? OGTT? A1C?

BJ What tests suggest that BJ has Type 1 DM? Glucose 340 mg/dL?
+ Glutamic Acid Decarboxylase Antibodies? C-peptide 0.5 ng/mL (0.5-5 ng/mL)? + ketonuria? 5’4” tall and 104 lbs (weight was 118 lbs 3 months ago)?

What is A1C and Why is it Important ?
Glucose attaches to proteins throughout the body through a reaction called glycosylation HbA is the predominant form of Hb contained in RBCs This serves as a marker for the extent of protein glycosylation HbA has 3 fractions (1a, 1b, 1c) where 1c is the predominant form (95%) The higher the BG the greater the fraction of A1C that is glycosylated A1C represents average BG over previous 3 months Normal A1C is 4-6% (<126 mg/dL) Pre-DM: %

ADAG Trial Average glucose (mg/dL) 28.7 x A1C – 46.7
28.7 x 6 – 46.7 = 126 mg/dL A1C EAG 5% mg/dL (5.4 mmol/L) 6% mg/dL (7 mmol/L) 7% mg/dL (8.5 mmol/L) 8% mg/dL (10.1 mmol/L) 9% mg/dL (11.7 mmol/L) 10% 240 mg/dL (13.3 mmol/L) 11% 269 mg/dL (14.9 mmol/L) 12% 298 mg/dL (16.5 mmol/L) 13% 326 mg/dL (18.1 mmol/L) 14% 355 mg/dL (19.7 mmol/L) Diabetes Care 2008;31:1473-8

Relationship Between A1C and Average Blood Glucose Over Past 2-3 Months
Estimated Average Glucose (eAG) Seriously Elevated Slightly Elevated Good Goal Non-Diabetes 6-7 mg/dL 7-8 mg/dL 8-10 mg/dL >10 >240 mg/dL % A1C Level <6 <126 mg/dL (Formula: 28.7 X A1C = eAG) ADAG Study. Diabetes Care 2008.

Target A1C Values TN is a 42 y/o female with Type 2 diabetes. She has a 6 y/o child and a 14 y/o child – both have Type 1 diabetes. Her father is 75 y/o and also has diabetes. TN would like to know her goal A1C.

Target A1C Values TN is a 42 y/o female with Type 2 diabetes. She has a 6 y/o child and a 14 y/o child – both have Type 1 diabetes. Her father is 75 y/o and also has diabetes. TN would like to know her goal A1C. What is TN’s goal A1C (per ADA)? < 6% < 7% < 8%

Target A1C Values What is TN’s goal BG (per ADA)? Fasting/preprandial?
< 100 mg/dL < 110 mg/dL mg/dL Postprandial? < 130 mg/dL < 140 mg/dL < 180 mg/dL

Target A1C Values TN is a 42 y/o female with Type 2 diabetes. She has a 6 y/o child and a 14 y/o child – both have Type 1 diabetes. Her father is 75 y/o and also has diabetes. What is the goal A1C for her 6 y/o? Her 14 y/o? Her father?

Glycemic Control (2010 ADA Guidelines)
A1C Goal Adults < 7 % Children < 8.5% (> 7.5%) Higher goals due to hypoglycemia vulnerability Age < 8 % Adolescents/ young adults < 7.5% Elderly ?

Treatment of Type 1 DM Insulin MNT Exercise Other? Pramlintide

Role of Insulin Suppresses Promotes Hepatic glucose production
Lipolysis Proteolyis Gluconeogenesis Promotes Transport of glucose into adipocytes/myocytes Glycogen synthesis

Insulin Secretion In adults without DM, the pancreas secretes units of insulin/day Basal insulin secretion units/hour Additional insulin is secreted when BG > 100 mg/dL Insulin is secreted in response to CHO intake at approximately 1 U/10-15 gram of CHO In humans without DM, BG: mg/dL BG> 40 mg/dL needed for normal brain function

The Basal/Bolus Insulin Concept
Basal Insulin (Background insulin) Suppresses glucose production between meals and overnight Nearly constant levels Supplies 50% of daily needs Bolus Insulin (Mealtime or Prandial) Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour 10% to 20% of total daily insulin requirement at each meal Slide 6-20 MIMICKING NATURE WITH INSULIN THERAPY The Basal/Bolus Insulin Concept Insulin is capable of restoring glycemia to nearly normal in most patients with type 2 diabetes. The basal/bolus insulin concept attempts to mimic, with insulin therapy, the patterns that normally control glucose in persons without diabetes. Basal insulin suppresses glucose production so that the levels remain nearly constant between meals and overnight. Basal insulin meets about half of the patient’s daily need for insulin and may be sufficient when considerable endogenous insulin remains. Bolus insulin (10% to 20% of the total daily insulin requirement given at each meal) limits hyperglycemia after meals. This tends to smooth the peaks of glucose that occur in response to these meals. Frequent glucose monitoring aids in determining the candidates for basal or mealtime regimens. Ideally, each component of insulin replacement therapy should come from a different type of insulin with a specific profile to fit the patient’s needs. Practical methods to accomplish this basal/bolus strategy will be illustrated later in this module. Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3: ; Kelley DB, ed. Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:56-72. 6-20

NORMAL PANCREAS ‘Bolus’ Insulin (Meal Associated)
Insulin Effect Slide 6-23 INSULIN TACTICS Twice-daily Split-mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split-mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times. Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews. 1995;3: Basal Insulin (~ U/hr) Insulin is released in response to varying blood glucose levels and hypoglycemia does not occur 6-23

Human Insulin Type Onset Peak Duration Rapid 5-15 min 1-2 hr 4-6 hr
Lispro/Aspart/Glulisine (Humalog/Novolog/Apidra) Regular (Humulin/Novolin) min hr hr NPH (Humulin/Novolin) hr hr hr Detemir (Levemir) hr hr hr (0.2 U/kg) 20 hr (0.4 U/kg) Glargine (Lantus) hr Flat hr Premix Rapid Humalog Mix 75/ min Dual 7-12 hr hr Humalog Mix 50/50 Novolog Mix 70/30 Premixed Regular Humulin 70/ min Dual 7-12 hr hr Novolin 70/ min Dual 7-12 hr hr

Islet Cell Dysfunction
Glucagon (alpha cells) Pancreas Insulin Amylin (beta cells) Glucose output Glucose uptake Liver Muscle Adipose tissue Blood glucose 1. Del Prato S,Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. References: 1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 2. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544. 3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care ;26:2929–2940. 4. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830. 5. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441. 6. Holz GG, Chepurny OG. Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem. 2003;10:2471–2483. 7. Creutzfeldt WO, Kleine N, Willms B, Ørskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7–36) amide in type I diabetic patients. Diabetes Care. 1996;19:580–586. 8. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med ;18:247–254.

What is Amylin? A 37-AA peptide hormone that is co-stored with insulin and co-secreted with insulin from the pancreatic ß cell in response to nutrient stimuli Secreted in a pulsatile manner similar to insulin Absent in Type 1 DM Deficient in Type 2 DM Pramlintide (Symlin®) is a synthetic analog of amylin

Pramlintide (Symlin®) - MOA
Complements insulin in PPG homeostasis Suppresses postprandial glucagon secretion from pancreatic  cells Neuroendocrine hormone – binds to CNS receptors Effects mediated through the vagus nerve Vagus nerve stimulates the gut Slows gastric emptying May enhance satiety through CNS activity High-affinity binding sites in the area postrema in the hindbrain

Pramlintide Side Effects Drug interactions Nausea, fullness
Abates with continued use ~ 4 weeks Hypoglycemia  prandial insulin dose by 50% Headache Drug interactions Drugs that alter GI motility Anticholinergics Drugs that alter nutrient intake AGIs May delay absorption of concomitant meds Give analgesics/OCPs 1 hr before/2 hrs after

Type 1 DM Type 2 DM

Pramlintide – Effects on A1C, BG, Weight, Insulin Dose
Overall,  A1C 0.5 to 1% BUT…PPG  to near normal levels mg/dL Possibly due to restoration of first-phase insulin secretion Weight  1 to 1.5 kg Allows  in insulin dose Variable effect for each person

SY SY is a 28 y/o patient with Type 1 DM and her insulin regimen consists of Lantus 18 Units at bedtime and Humalog 6 Units with meals. Her A1C is 7.8% and she carb counts but she still has high PPG values. She especially loves to have cinnamon rolls on Tuesdays and Thursdays and then again on the weekends. Is SY a candidate for pramlintide? What is the starting dose? If SY had Type 2 DM, what would be the starting dose of pramlintide?

Trends in Type 2 Diabetes: 1988 - 2000 NHANES
Average BMI  from 30.4 to 32.3 kg/m2

Two main factors Insulin resistance Hepatic, skeletal muscle, adipose tissues Evident years before diagnosis Impaired insulin secretion Normal/  fasting plasma insulin At diagnosis, ~ 40% of beta cell mass is left (due to apoptosis)

Another main factor Patients have HTN Hyperlipidemia HIGH TGs Low HDL  PAI-1

RE RE is a 45 y/o male seen in clinic for balanitis and onychomycosis. The patient is 5’10” and weighs 240 lb. He complains of thirst and polyuria. His fasting glucose values have been in the low 120s (mg/dL). He has gained 40 lbs in the last 2 years. Today, random glucose is 359 mg/dL BP 148/98 mm Hg Fasting lipids total cholesterol 240 mg/dL, triglycerides 438 mg/dL, HDL of 32 mg/dL Does RE have Type 1 or Type 2 DM?

Pharmacology & Pathophysiology
Glucose Influx GLP-1 Analogs Insulin Secretion Sulfonylureas Glinides Insulin Pramlintide Alpha-glucosidase inhibitors Hepatic Glucose Output Hyperglycemia Biguanides (TZD) Insulin This slide illustrates the different modes of action of the various pharmacologic agents in the context of their potential use to improve hyperglycemia. (Review pathophysiology and associated therapies) Peripheral Glucose Uptake TZD (Biguanides) Insulin

Medications for Type 2 Diabetes
Biguanides – e.g., Metformin Sulfonylureas Thiazolidinediones (Glitazones) Exenatide DPP-IV Inhibitors Glinides (Meglitinides) Alpha glucosidase inhibitors Colesevelam Insulin AND… Bromocriptine (Cycloset®)

2009 ADA/EASD Consensus Algorithm Tier 1 (Well-validated therapies)
At Diagnosis: Lifestyle (LS) + Metformin Step 1 Lifestyle (LS) + Metformin + Basal Insulin Lifestyle (LS) + Metformin + Sulfonylurea Step 2 Lifestyle (LS) + Metformin + Intensive Insulin Step 3 Diabetes Care 2009;32:

ADA/EASD Tier 2 – Less Validated
At Diagnosis: Lifestyle (LS) + Metformin Step 1 Lifestyle (LS) + Metformin + Pioglitazone No hypoglycemia; Edema/HF; Bone  Lifestyle (LS) + Metformin + GLP-1 agonist No hypoglycemia; Wt ; N/V Step 2 Lifestyle (LS) + Metformin + Pioglitazone + Sulfonylurea Lifestyle (LS) + Metformin + Basal Insulin Lifestyle (LS) + Metformin + Intensive Insulin Step 3 Diabetes Care 2009;32:

RE RE is a 45 y/o male seen in clinic for balanitis and onychomycosis. The patient is 5’10” and weighs 240 lb. He complains of thirst and polyuria. His fasting glucose values have been in the low 120s (mg/dL). He has gained 40 lbs in the last 2 years. Today, random glucose is 359 mg/dL BP 148/98 mm Hg Fasting lipids total cholesterol 240 mg/dL, triglycerides 438 mg/dL, HDL of 32 mg/dL What medication should be started?

Biguanides - Metformin (Glucophage®)
MOA:  hepatic gluconeogenesis Other effects Advantages Possible weight loss Rapid effects CVD benefits No hypoglycemia Limitations GI side effects (titrate slowly) Renal dysfunction (Lactic acidosis risk) HF (but may use if HF is stable and Cr is normal) Females of childbearing age – RPh must counsel Effects  A1C – 1-2%

UKPDS, UKPDS 10-yr Follow-Up (RRR)
UKPDS1 10-yr UKPDS1 10-yr UKPDS1 10-yr Meta analysis3 36% 27% % 33% % 30% % Mortality MI Macrovascular DM-related C-V Mortality (all cause) (all endpoints) death P=0.01; p=0.01; p= p= % CI 1 Lancet 1998;352:854-65 2 N Engl J Med 2008;359: 3 Arch Intern Med 2008;168:

Sulfonylureas Glipizide, glimepiride, glyburide
MOA: Stimulate insulin secretion Monotherapy or combination Advantages Rapid effects Limitations Weight gain Hypoglycemia (Don’t delay/skip meals) Elderly/  renal function Benefit at half of max doses 5-15% yearly secondary failure Effects  A1C – 1-2%

UKPDS 10-yr Follow-Up (RRR)
9% % % % % DM related DM related Mortality MI Microvascular endpoints death (all cause) disease p= p= p= p= p=0.001 N Engl J Med 2008;359:

Thiazolidinediones Pioglitazone (Actos®), Rosiglitazone (Avandia®)
MOA: Bind PPAR ( insulin sensitivity in muscle, fat, liver) Monotherapy or combination Advantages Improves lipids  visceral fat/PAI-1 Limitations Fluid retention/weight gain HF/cardiac events  fracture risk Effect takes several weeks Effects  A1C – %

Alpha Glucosidase Inhibitors
Acarbose (Precose®), Miglitol (Glyset®) MOA: Inhibit intestinal brush border enzymes that break down saccharides (e.g.,  CHO absorption) Monotherapy or combination Advantages Weight neutral  PPG Limitations TID dosing Slow titration  GI side effects Effects  A1C – %

Glinides Repaglinide (Prandin®), Nateglinide (Starlix®)
MOA: Same as sulfonylurea (release insulin) Monotherapy or combination Advantages Less hypoglycemia than sulfonylureas  PPG May use in  renal function Limitations TID dosing  weight How to titrate repaglinide Effects  A1C – %

Bile Acid Sequestrant Colesevelam (Welchol®)
MOA: Blocks glucose absorption Monotherapy or combination Advantages Not absorbed; not metabolized  lipids Limitations Constipation, nausea, dyspepsia  TGs May bind medications Effects  A1C – 0.5%

Dopamine Agonist Bromocriptine mesylate (Cycloset®)
MOA: DA boost may re-set biological clock to improve metabolic problems Monotherapy/Combination with SU, metformin/SU Advantages First “new” drug to follow FDA guidelines: Evaluated for potential CV adverse events (MI, stroke, other CV events) May help lower elevated PPG; may  weight Limitations Nausea/vomiting, HA, fatigue, orthostasis;  lactation “Psychosis;” May  effectiveness of DA antagonists May  ergot side effects; CYP3A4 substrate Effects  A1C ~ 0.5%

HC HC is a 56 y/o male with T2DM x 6 years
On glyburide/metformin 5/500 mg – 2 po BID H/O CAD, HTN, IBS, NASH (fatty liver) FBG: mg/dL PPG: mg/dL A1C = 9.6% Should we? Intensify lifestyle? Add TZD? Add exenatide? Start insulin?

Progressive Decline of -Cell Function-UKPDS
100 80 60 -Cell Function (% ) 40 20 10 9 8 7 6 5 4 3 2 1 1 2 3 4 5 6 Years Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:

Adding Insulin If patient on 2-4 oral agents and A1C still elevated, time to add insulin Typical delay when 2 oral meds fail?

Adding Insulin Add glargine 10 Units hs? Add NPH 10 Units hs?
Advantage – can titrate every few days or weekly; less weight gain/hypoglycemia but expensive Add NPH 10 Units hs? Advantage –  cost but must have good technique and patient may have hypoglycemia Add levemir 10 Units hs or 5 units bid? Advantage – can titrate; less weight gain/hypoglycemia BUT…half of all patients eventually need prandial insulin Bottom line: Must talk to patient and individualize treatment

Adding Insulin When to add prandial insulin in Type 2 DM?
One opinion: When basal insulin dose is > 40 to 50 Units and A1C > 7% When basal dose approaches 1 Unit/kg and A1C > 7% Add lispro 75/25 or aspart 70/30 twice/day? Advantage – starting bolus and basal insulin; but more weight gain/hypoglycemia Bottom line: Must talk to patient and individualize treatment

Islet Cell Dysfunction & Insulin Resistance
Glucagon (alpha cells) Gut Pancreas GLP-1 Insulin Amylin (beta cells) Glucose output Glucose uptake Liver Muscle Adipose tissue Blood glucose 1. Del Prato S,Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168. References: 1. Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep. 2003;3:365–372. 2. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology. 2002;122:531–544. 3. Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care ;26:2929–2940. 4. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830. 5. Holst JJ. Therapy of type 2 diabetes mellitus based on the actions of glucagon-like peptide-1. Diabetes Metab Res Rev. 2002;18:430–441. 6. Holz GG, Chepurny OG. Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem. 2003;10:2471–2483. 7. Creutzfeldt WO, Kleine N, Willms B, Ørskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7–36) amide in type I diabetic patients. Diabetes Care. 1996;19:580–586. 8. Porte D Jr, Kahn SE. The key role of islet dysfunction in type II diabetes mellitus. Clin Invest Med ;18:247–254.

The Incretin Effect

phase insulin secretion
GLP-1 restores first phase insulin secretion

What Are The Incretins? Gastrointestinal tract-derived hormones that are released in response to nutrient ingestion Approximately 60% of insulin secreted in response to a meal is due to the incretin effect 2 major incretins identified to date Glucagon-like peptide 1 (GLP-1) Released from L cells in ileum Glucose-dependent insulinotropic peptide (GIP) Released from K cells in jejunum

What Are The Incretins? Common actions of 2 major incretins
Exert effects on ß-cells to stimulate glucose- dependent insulin secretion Regulate ß-cell proliferation and cytoprotection GLP-1 and GIP produce similar insulin release effects up to BG of 108 mg/dL GIP has little effect at BG > 140 mg/dL

Exenatide (Byetta®) Synthetic GLP-1 analog
Synthetic version of exendin-4 (from Gila monster saliva) Injectable Side effects Nausea Hypoglycemia Pancreatitis Altered renal function

Exenatide – Drug Interactions
May see hypoglycemia if given with SU Consider  dose of SU before starting Dose reduction is a clinical judgment (~ ½) May slow rate of absorption of concomitant orally-administered drugs Take OCPs, antibiotics 1 hr before exenatide If a concomitant med must be given with food, consider administering with a snack other than when exenatide is injected Don’t use: Type 1 DM (or on insulin), ESRD, gastroparesis

Exenatide (Byetta®) Dose: Start out at 5 mcg bid (breakfast, supper) then increase to 10 mcg bid after at least one month if tolerated

Exenatide (Byetta®) Effects on A1C, BG, Weight A1C  0.5% to 1%
FBG  ~ 8 mg/dL PPG  mg/dL Weight  is variable In studies, up to 2.8 kg May be greater in individual patients

On The Horizon? Exenatide Once Weekly Liraglutide (Victoza®)
Advantage – once/week 1.9%  in A1C for 2 mg vs 1.7%  for qd (10 mcg) Disadvantage – unknown long-term side effects Liraglutide (Victoza®) Advantage - Once/day dosing Disadvantage – a few patients developed small thyroid papillary carcinomas

Glucagon Like Peptide 1 pathophysiology
Mixed meal Long-term GLP-1 Actions: Increase insulin synthesis Promote ß-cell differentiation Intestinal GLP-1 release Active GLP-1 Acute GLP-1 Actions: Augment glucose-induced insulin secretion Inhibit glucagon secretion and hepatic glucose production Slow gastric emptying Increase glucose disposal DPP-4 DPP-4 inhibitor Inactive GLP-1 Adapted from Rothenberg P. Diabetes. 2000;49(suppl 1):A39 Drucker DJ. Diabetes Care 2003;26:

DPP-IV Inhibitors Sitagliptin (Januvia®) Saxagliptin (Onglyza®)
Mechanism of action Inhibit breakdown of GLP-1 and GIP Hence, levels of GLP-1 and GIP rise, especially in response to meals This inhibits glucagon Stimulates endogenous insulin secretion when glucose is highest Since these agents increase only glucose- stimulated insulin secretion, there is little risk of hypoglycemia

Gliptins Side effects Pancreatitis (within 30 days of start; metformin is protective) Headache Nasopharyngitis URIs (UTI with saxagliptin) Other concerns? Thus far, no problems but theoretical concerns regarding the immune system since other DPP-IV substrates include growth factors and cytokines DPP-IV may affect T-cell activity

Gliptins Sitagliptin dose adjustment in renal impairment
Cr Cl > 30 to < 50 mL/min is 50 mg daily Males: Cr > 1.7 to < 3 mg/dL Females: Cr > 1.5 to < 2.5 mg/dL Cr Cl < 30 mL/min is 25 mg daily Males: Cr > 3 mg/dL Females: Cr > 2.5 mg/dL On dialysis Not studied in hepatic impairment Saxagliptin 2.5 to 5 mg daily 2.5 mg daily for CrCl < 50 mL/min

DPP-IV Inhibitors Gliptins: Will help if close to A1C goals
If A1C is ~ 8-9% A1C  0.5 to 0.8% If A1C is 9-10% A1C  1.4% FBG  ~16 to 22 mg/dL (sitagliptin); mg/dL (saxagliptin) PPG  ~ mg/dL (sitagliptin); mg/dL (saxagliptin) Weight neutral Will help if close to A1C goals Will help with decreasing PPG Not evaluated in persons on insulin

Monitoring?

Drug Dose ADRs Cautions A1C
Metformin 2000 mg/day GI; lactic acidosis Cr < 1.4 mg/dL Cr < 1.5 mg/dL 1-2% Sulfonylureas ½ of max dose; glyburide,glipizide (10 mg) glimepiride (4 mg) Hypoglycemia, weight gain, photosensitivity Do not skip or delay meals; weight, sunscreen TZDs Pio – 45 mg/day Rosi – 8 mg/day Weight gain, fluid retention, HF, fractures LFTs, weight; baseline cardiac evaluation % Glinides Repaglinide – 16 mg/day Nateglinide – 120 mg/day Hypoglycemia, weight gain Weight, PPG % -glucosidase Inhibitors Acarbose/miglitol 50 mg tid GI; hypoglycemia Treat hypoglycemia with glucose % GLP-1 Agonists Exenatide 5 to 10 mcg bid GI;  BG; pancreatitis Cut dose of SU by 1/2 0.5-1% DPP-IV Inhibitors Sita: mg/d Saxa:2.5-5 mg/d Nausea, infections pancreatitis Renal function; infections Pramlintide 60 mcg/120 mcg Nausea,  BG  Dose of prandial insulin

Drug Class % A1C  Insulin Treat to target Biguanides 1-2
Sulfonylureas TZDs Glinides Alpha-glucosidase Inhibitors GLP-1 Agonists DPP-IV Inhibitors Pramlintide 0.5-1 Bile Acid Sequestrant Bromocriptine ~0.5

Monitoring Insulin Blood glucose (fasting/postprandial) A1C
Hypoglycemia Weight gain The dose that gets a person to target blood glucose/A1C (safely) is the right dose

DM Control: How Intensive?

Type 1 DM: Risk of Retinopathy
JAMA 2002;287:2563-9

A1C Distribution After DCCT And Each Year During EDIC
JAMA 2002;287:2563-9

Retinopathy:Cumulative Incidence
EDIC Trial (JAMA 2002;287;2563-9)

7-Yr Incidence of Fatal/Nonfatal MI in Finland
No diabetes Diabetes (n=1,373) (n=1,059) 50 45 45 P<0.001 P<0.001 40 35 7-Year incidence rate of MI (%) 30 25 20 19 20 15 10 4 5 No previous MI* Previous MI No previous MI* Previous MI *No previous myocardial infarction (MI) at baseline. Haffner SM et al. N Engl J Med. 1998;339:

Macrovascular Complications Treatment
Control of BG  macrovascular complications in post active-intervention: Type 1 DM: EDIC (at 17 years)1 42%  in CVD outcomes (p=0.02) 57%  in risk of nonfatal MI, stroke, or CVD death (p=0.02) Type 2 DM: UKPDS 10-year F/U2* SU + insulin: Metformin: 15% RRR in MI (p=0.01) 33% RRR in MI (p=0.005) 17% RRR in DM-related death (p=0.01) % RRR in DM-related death (p=0.01) 13% RRR in mortality (p=0.007) 27% RRR in mortality (p=0.002) *Criticized because of loss to F/U (selection bias?) 1 N Engl J Med 2005;353: 2 N Engl J Med 2008;359:

ACCORD ADVANCE VADT

ACCORD In T2DM pts with CVD or CVD risk, does intensive glucose control prevent CV events more than standard glucose control? Goal A1C < 6% in intensive control group vs % in standard control More CV mortality in intensive rather than standard control (trial stopped early) N Engl J Med 2008;358:

ACCORD N=10,251 Median BL A1C – 8.1% Achieved A1C – 6.4% vs 7.5%
Multiple drugs used to achieve goal (including 91% on rosiglitazone in intensive group) Median BL A1C – 8.1% Achieved A1C – 6.4% vs 7.5% N Engl J Med 2008;358:

ACCORD Primary outcome  Mortality 
Nonfatal MI or stroke, CVD death HR 0.9 (95% CI ) Significant? Mortality  HR 1.22 (95% CI ) (all-cause mortality) 257 vs 203 deaths Mortality higher if severe hypoglycemia, weight gain, on intensive insulin Reason – Fast glucose lowering? N Engl J Med 2008;358:

ADVANCE In T2DM pts does intensive glucose control prevent adverse events (microvascular + macrovascular) more than standard glucose control? Goal A1C < 6.5% vs “based on local guidelines” No difference in CV mortality between intensive and standard groups N Engl J Med 2008;358:

ADVANCE N=11,140 Median BL A1C – 7.2% Achieved A1C – 6.3% vs 7%
Compared gliclazide + multiple drugs (intensive) vs no gliclazide + multiple drugs (standard control) < 20% received a TZD Median BL A1C – 7.2% Achieved A1C – 6.3% vs 7% N Engl J Med 2008;358:

ADVANCE Primary outcome 
Microvascular (nephropathy, retinopathy) + macrovascular disease (nonfatal MI or stroke, CVD death) Decreased mostly because of  microvascular disease (specifically, nephropathy) HR 0.9 (95% CI ) (microvascular disease) HR 0.94 (95% CI ) (macrovascular disease) HR 0.93 (95% CI ) (mortality) N Engl J Med 2008;358:

ADVANCE vs ACCORD Comparison between the two studies
BL A1C lower than ACCORD (7.2% vs 8.1%) Duration of DM (2 yrs less) Less severe hypoglycemia in intensive gp (2.7% vs 16.2%) for ADVANCE BL BMI lower (28 vs 32) for ADVANCE Fewer on insulin in intensive gp (40% vs 77% at the end) for ADVANCE ADVANCE verified  risk with lower albuminuria if A1C  to 6.3%

VADT In pts with long-standing T2DM (not well- controlled with insulin or max dose oral agents): Does intensive glucose control prevent CV events more than standard glucose control? Goal A1C < 6% (action if A1C > 6.5%) vs standard (target of 1.5%  in intensive vs standard) Results: Intensive control had no effect on death, CV events, or microvascular complications N Engl J Med 2008;358:DOI: /NEJMoa

VADT N=1,791 Median BL A1C – 9.4% Achieved A1C – 6.9% vs 8.5%
Non-obese: rosiglitazone + glimepiride Obese: rosiglitazone + metformin Insulin if needed to reach goal 42% to 53% on TZD Median BL A1C – 9.4% Achieved A1C – 6.9% vs 8.5% N Engl J Med 2008;358:DOI: /NEJMoa

VADT Primary outcome  Nonfatal MI or stroke, CVD death, HF hospitalization, vascular disease surgery, inoperable CHD, ischemic gangrene amputation: HR 0.88 (95% CI ) Mortality HR 1.07 (95% CI ) N Engl J Med 2008;358:DOI: /NEJMoa

VADT vs ACCORD Comparison between the two studies
Mortality increase NS in VADT Endpoint A1C higher for VADT than ACCORD (6.9% vs 6.4%) In VADT more hypoglycemia, weight gain, insulin use than in ACCORD No difference in microvascular complications

ACCORD F/U Information
Hypoglycemia was not a cause of death Rate of glucose lowering not responsible for excess deaths 3 BL factors emerged as predictors of increased mortality risk: Higher BL A1C (> 8.5%) was associated with increased mortality Reason? Possibly a surrogate for greater DM severity H/O neuropathy Reason? Surrogate for significant microvascular disease ASA use Reason? Surrogate for known/suspected CVD Persons who got to goal did better in intensive group than those in standard group

ADVANCE F/U Information
Risks/benefits of glucose lowering was uniform across different sub-groups Intensive group had major reductions in microvascular disease without increased cardiovascular mortality Those with greatest benefit attained optimal glucose and BP measures

VADT F/U Information Risk factors for primary CV event or total mortality: Hypoglycemia Previous CV event Older age Impaired renal function

VADT Follow-Up Information
VADT – timing played a role If started on intensive treatment in first 15 yrs of diagnosis, lower cardiac risk including death from cardiac causes If started on intensive tx yrs after diagnosis, no benefit For those with DM > 21 yrs, cardiac risks more than doubled Take home message: treat early and treat carefully

ACCORD, ADVANCE, VADT Take home messages CVD Risk Management Critical
Manage BP, lipids, risk reduction (ASA, smoking cessation) Less stringent goals for glucose (A1C <7% not <6%) if: H/O severe hypoglycemia Limited life expectancy Have micro or macrovascular complications Long-standing DM where goals haven’t been achieved

BP Management (per ADA) Goal is < 130/80 mm Hg Lifestyle (3 mo): SBP mm Hg DBP is mm Hg Meds if BP > 140/90 mm Hg ACE Is, ARBs, non dihydropyridine CCBs (if fail or can’t tolerate ACE Is or ARBs) Diabetes Care (Suppl 1):S13-61

CARDS: Major CVD Events
20 Placebo (n=1,410) Atorvastatin 10 mg/d (n=1,428) Primary prevention study in persons With DM and at least 1 risk factor 37% reduction P=0.001 15 Cumulative hazard (%) 10 5 1 2 3 4 4.7 5 Years CARDS=Collaborative Atorvastatin Diabetes Study Lancet. 2004;364:

Hyperlipidemia Treatment (per ADA) If person doesn’t reach goal on max statin dose, lowering LDL by 30-40% from BL is alternative goal May need concomitant meds to  TGs or  HDL TGs do decrease if elevated A1C is decreased to goal Diabetes Care (Suppl 1):S13-61

Hyperlipidemia Treatment (per ADA) IF TGs are > 200 mg/dL: Non HDL goal (TC – HDL) is 30 mg/dL higher than goal LDL 2008 ACC/ADA guidelines: Measure Apo B Represents most atherogenic lipoprotein particles In children screen lipids at age 2 if FH positive or unknown; otherwise screen at puberty (> 10 years) Diabetes Care (Suppl 1):S13-61

Risk Reduction ASA or other antiplatelets Smoking cessation (Immunizations) Lifestyle Medical Nutrition Therapy Physical activity Diabetes Care (Suppl 1):S13-61

Multifactorial Intervention
in Type 2 DM P = 0.007 Conventional Therapy Intensive Therapy Months of Follow-up Primary Composite End Point (%)  cardiovascular and microvascular events by 50% N Engl J Med 2003;348:

HC HC is a 56 y/o male with T2DM x 6 years
On glyburide/metformin 5/500 mg – 2 po BID H/O CAD, HTN, IBS, NASH (fatty liver) FBG: mg/dL;PPG: mg/dL Wt 220 lb; BMI – 30kg/m2; A1C = 9.6% BP 142/85 mm Hg on lisinopril/HCTZ (40/25); HR - 90 Lipids: LDL only abnormal value (80 mg/dL) on Lipitor 20 mg Should we? Intensify lifestyle? Add TZD? Add exenatide? Start insulin?

HC - Plan Should we? Intensify lifestyle Add TZD Add exenatide?
Yes; send to a dietitian Add TZD No; h/o of CAD Add exenatide? Possibly; but pt has IBS and this is Tier 2 per ADA algorithm Start insulin? Yes; start with basal; titrate/treat to target (A1C: 3 mo) Stop glyburide? Prandial insulin when basal dose is ~ 50 Units/day (A1C: 3 mo) Treat intensively to A1C < 6.5%? No; goal is < 7%; monitor for hypoglycemia/weight gain Intensify treatment of co-morbidities? Yes; LDL goal is < 70 mg/dL;  dose of Lipitor to 40 mg/day (re- check LDL and Apo-B in 4-6 weeks); monitor for ADRs Yes; lifestyle for BP; add diltiazem 120 mg/day (re-check in 2 weeks); monitor BP and HR

Role of the Clinician Provide education What is DM?
Target BG, A1C, BP, LDL Information during pregnancy Assess patient needs and provide MI Provide information on how to recognize both hyperglycemia and hypoglycemia Provide information on possible complications and how to avoid them (checklist)

Role of the Clinician Diabetes care checklist
How to use a BG monitor; check pt’s technique Review BG log regularly, A1C goals Information on optimal medication use Remind pt of risk reduction (immunizations, smoking cessation, ASA use) How to recognize hyperglycemia and a management plan Sick day management instructions

Management of Diabetes
Goals A1C < 7% Plasma glucose (mg/dL) Preprandial mg/dL Peak PPG < 180 mg/dL BP < 130/80 mm Hg Lipids TC <200 mg/dL LDL <100 mg/dL (<70 mg/dL) TG <150 mg/dL HDL >40 mg/dL Males >40 mg/dL Females >50 mg/dL

Pre-Diabetes And Risk for DM?
My wt is > 20% of my IBW for ht (5 pts) I am < 65 y/o and do little/no exercise (5 pts) I am between y/o (5 pts) I am > 65 y/o (9 pts) I am a woman who has had a baby weighing > 9 lb (1 pt) I have a sister/brother with DM (1 pt) I have a parent with DM (1 pt) Total # of pts scored: 3-9 pts: low risk, but note if in high-risk gp (wt, BP, ethnicity, etc.) > 10 pts: high risk; see HCP for further eval Pre-DM: Target values for BP and LDL same as DM

Diabetes Rx: A Primer Laura Shane-McWhorter, PharmD,

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Diabetes Rx: A Primer Laura Shane-McWhorter, PharmD,

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