diabetes rx: a primer laura shane-mcwhorter, pharmd, bcps, fascp, cde, bc-adm professor (clinical)...

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)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%

www.diabetes.org/diabetes-statistics/prevalence.jsp

Prevalence of Diabetes in the USA

Diagnosed Diabetes

17.5 Million

Undiagnosed Diabetes

6.6 Million

Diabetes 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 USAhealthcare spending)

• Medical costs - $174.4 billion• $14.9 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

• < 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

TYPE 1 TYPE 2

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

Pathophysiology of Type 1 DM• 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

Glucose output Glucose uptake

Glucagon(alpha cells)

InsulinAmylin

(beta cells)

PancreasPancreas

Liver Muscle

Adipose tissue

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.

Blood glucose

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: 5.7-6.4%

ADAG Trial• Average glucose (mg/dL)

• 28.7 x A1C – 46.7• 28.7 x 6 – 46.7 = 126 mg/dL

A1C EAG5% 97 mg/dL (5.4 mmol/L)6% 126 mg/dL (7 mmol/L)7% 154 mg/dL (8.5 mmol/L)8% 183 mg/dL (10.1 mmol/L)9% 212 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

Seriously Elevated

Elevated

Slightly Elevated

Good Goal

Non-Diabetes

6-7 126-154 mg/dL

7-8 155-183 mg/dL

8-10 183-240 mg/dL

>10 >240 mg/dL

<6 <126 mg/dL

Estim

ated Average G

lucose (eAG

)%

A1C

Lev

el

ADAG Study. Diabetes Care 2008.

(Formula: 28.7 X A1C -46.7 = eAG)

Relationship Between A1C and Average Blood Glucose Over Past 2-3 Months

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• 70-130 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 0-6 < 8.5% (> 7.5%)

Higher goals due to hypoglycemia

vulnerabilityAge 6-12 < 8 % Adolescents/ young adults < 7.5%Elderly ?

Treatment of Type 1 DM

• Insulin• MNT• Exercise• Other?

• Pramlintide

Role of Insulin

• Suppresses• Hepatic glucose production• Lipolysis• Proteolyis• Gluconeogenesis

• Promotes• Transport of glucose into adipocytes/myocytes• Glycogen synthesis

Insulin Secretion

• In adults without DM, the pancreas secretes 25-50 units of insulin/day

• Basal insulin secretion 0.5-1 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:40-160 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

NORMAL PANCREASIn

sulin

Eff

ect

6-23

Insulin is released in response to varying blood glucose levels and hypoglycemia

does not occur

Basal Insulin (~0.5-1.0 U/hr)

‘Bolus’ Insulin (Meal Associated)

Human InsulinType Onset Peak DurationRapid 5-15 min 1-2 hr 4-6 hr Lispro/Aspart/Glulisine(Humalog/Novolog/Apidra)

Regular (Humulin/Novolin) 30-60 min 2-3 hr 6-8 hr

NPH (Humulin/Novolin) 2-4 hr 4-6 hr 14-18 hr

Detemir (Levemir) 2 hr 6-8 hr 12 hr (0.2 U/kg) 20 hr (0.4 U/kg)

Glargine (Lantus) 2-4 hr Flat 20-24 hr

Premix Rapid Humalog Mix 75/25 5-15 min Dual 7-12 hr 14-18 hr Humalog Mix 50/50 Novolog Mix 70/30

Premixed Regular Humulin 70/30 30-60 min Dual 7-12 hr 14-18 hr Novolin 70/30 30-60 min Dual 7-12 hr 14-18 hr

Islet Cell Dysfunction



InsulinAmylin

(beta cells)

PancreasPancreas

Liver Muscle

Adipose tissue


Blood glucose

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

PramlintideSide Effects• 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

• 140-180 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


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

HyperglycemiaBiguanides

(TZD)Insulin

TZD(Biguanides)

Insulin

SulfonylureasGlinidesInsulin

PramlintideHepaticGlucose Output

PeripheralGlucose Uptake

Glucose Influx

InsulinSecretion

Alpha-glucosidase inhibitors

GLP-1Analogs

Medications for Type 2 Diabetes

• Biguanides – e.g., Metformin• Sulfonylureas• Thiazolidinediones (Glitazones)• Exenatide• DPP-IV Inhibitors• Glinides (Meglitinides)• Alpha glucosidase inhibitors• Colesevelam• InsulinAND…• Bromocriptine (Cycloset®)

Lifestyle (LS) + Metformin+

Sulfonylurea


Intensive Insulin

Step 1

Step 2

Step 3

At Diagnosis:Lifestyle (LS) + Metformin


Basal Insulin

2009 ADA/EASD Consensus AlgorithmTier 1 (Well-validated therapies)

Diabetes Care 2009;32:193-203


GLP-1 agonist

No hypoglycemia; Wt ; N/V

Lifestyle (LS) + Metformin+ Pioglitazone+ Sulfonylurea

Step 1

Step 2

Step 3

At Diagnosis:Lifestyle (LS) + Metformin


Pioglitazone

No hypoglycemia; Edema/HF; Bone


Basal Insulin


Intensive InsulinDiabetes Care 2009;32:193-203

ADA/EASD Tier 2 – Less Validated


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)

-40

-35

-30

-25

-20

-15

-10

-5

0

Mortality MI Macrovascular DM-related C-V Mortality(all cause) (all endpoints) death P=0.01;0.002 p=0.01;0.005 p=0.02 p=0.01 95% CI 0.62-0.89

UKPDS1 10-yr2 UKPDS1 10-yr2 UKPDS1 10-yr2 Meta analysis3

36% 27% 39% 33% 30% 30% 26%

1 Lancet 1998;352:854-652 N Engl J Med 2008;359:1577-893 Arch Intern Med 2008;168:2070-80

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)

-25

-20

-15

-10

-5

0

DM related DM related Mortality MI Microvascular endpoints death (all cause) disease p=0.04 p=0.01 p=0.007 p=0.01 p=0.001

9% 17% 13% 15% 24%

N Engl J Med 2008;359:1577-89

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 – 0.5-1.4%

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 – 0.5-0.8%

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 – 0.5-1.5%

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: 180-220 mg/dL• PPG: 250-320 mg/dL• A1C = 9.6%• Should we?

• Intensify lifestyle?• Add TZD?• Add exenatide? • Start insulin?

Progressive Decline of -Cell Function-UKPDS

0

20

40

60

80

100

10 9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6Years

-C

ell F

un

ctio

n (

%

)

Adapted from UK Prospective Diabetes Study (UKPDS) Group. Diabetes. 1995; 44:1249-1258.

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?

• 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



InsulinAmylin

(beta cells)

PancreasPancreas

Liver Muscle

Adipose tissue


GLP-1Gut

Blood glucose

The Incretin Effect

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 60-70 mg/dL• Weight is variable

• In studies, up to 2.8 kg• May be greater in individual patients

On The Horizon?

• Exenatide Once Weekly• 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

Inactive GLP-1

IntestinalGLP-1

release

Mixed meal

ActiveGLP-1

DPP-4

Adapted from Rothenberg P. Diabetes. 2000;49(suppl 1):A39Drucker DJ. Diabetes Care 2003;26:2929-2940.

DPP-4inhibitor

Acute GLP-1 Actions:•Augment glucose-induced insulin secretion•Inhibit glucagon secretion and hepatic glucose production•Slow gastric emptying•Increase glucose disposal

Long-term GLP-1 Actions:•Increase insulin synthesis•Promote ß-cell differentiation

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:• 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); 10-15 mg/dL (saxagliptin)• PPG ~ 50-60 mg/dL (sitagliptin); 43-45 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

1-2%

TZDs Pio – 45 mg/day

Rosi – 8 mg/day

Weight gain, fluid retention, HF, fractures

LFTs, weight; baseline cardiac evaluation

0.5-1.4%

Glinides Repaglinide – 16 mg/day

Nateglinide – 120 mg/day

Hypoglycemia, weight gain

Weight, PPG 0.5-1.5%

-glucosidase Inhibitors

Acarbose/miglitol 50 mg tid

GI; hypoglycemia

Treat hypoglycemia with glucose

0.5-0.8%

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:50-100 mg/d

Saxa:2.5-5 mg/d

Nausea, infections

pancreatitis

Renal function; infections

0.5-0.8%

Pramlintide 60 mcg/120 mcg Nausea, BG Dose of prandial insulin

0.5-1%

Insulin Treat to target

Biguanides 1-2

Sulfonylureas 1-2

TZDs 0.5-1.4

Glinides 0.5-1.5

Alpha-glucosidase Inhibitors 0.5-0.8

GLP-1 Agonists 0.5-1.0

DPP-IV Inhibitors 0.5-0.8

Pramlintide 0.5-1

Bile Acid SequestrantBromocriptine

~0.5

Drug Class % A1C

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 IncidenceEDIC Trial (JAMA 2002;287;2563-9)

*No previous myocardial infarction (MI) at baseline.

05

101520253035404550

7-Y

ear

inci

den

ce

ra

te o

f M

I (%

)

No previous MI* Previous MI No previous MI* Previous MI

No diabetes Diabetes(n=1,373) (n=1,059)

P<0.001 P<0.001

4

19 20

45

7-Yr Incidence of Fatal/Nonfatal MI in Finland

Haffner SM et al. N Engl J Med. 1998;339:229-234.

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) 30% 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;353:2643-532 N Engl J Med 2008;359:1577-89

ACCORDADVANCE

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 7-7.9% in standard control

•More CV mortality in intensive rather than standard control (trial stopped early)

N Engl J Med 2008;358:2545-59

ACCORD

• N=10,251• 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;358:2545-59

ACCORD• Primary outcome

• Nonfatal MI or stroke, CVD death• HR 0.9 (95% CI 0.78-1.04)• Significant?

• Mortality • HR 1.22 (95% CI 1.01-1.46) (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;358:2545-59

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;358:2560-72

ADVANCE

• N=11,140• 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;358:2560-72

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 0.82-0.98) (microvascular disease)• HR 0.94 (95% CI 0.84-1.06) (macrovascular

disease)• HR 0.93 (95% CI 0.83-1.06) (mortality)

N Engl J Med 2008;358:2560-72

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:10.1056/NEJMoa0808431

VADT• N=1,791

• 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%


VADT

• Primary outcome • Nonfatal MI or stroke, CVD death, HF hospitalization,

vascular disease surgery, inoperable CHD, ischemic gangrene amputation:• HR 0.88 (95% CI 0.74-1.05)

• Mortality• HR 1.07 (95% CI 0.81-1.42)


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

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

Macrovascular Complications Treatment• BP Management (per ADA)

• Goal is < 130/80 mm Hg• Lifestyle (3 mo):

• SBP 130-139 mm Hg • DBP is 80-89 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 2009 32(Suppl 1):S13-61

CARDS: Major CVD Events

Lancet. 2004;364:685-696.

Cu

mu

lati

ve h

azar

d (

%)

37% reduction

P=0.001

Placebo (n=1,410)Atorvastatin 10 mg/d (n=1,428)Primary prevention study in personsWith DM and at least 1 risk factor

Years0 1 2 3 4 4.7

20

15

10

5

05

CARDS=Collaborative Atorvastatin Diabetes Study

Macrovascular Complications Treatment• 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


Macrovascular Complications Treatment• 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)


Macrovascular Complications Treatment• Risk Reduction

• ASA or other antiplatelets• Smoking cessation• (Immunizations)• Lifestyle

• Medical Nutrition Therapy • Physical activity


0 12 24 36 48 60 72 84 96

0

10

2

0

30

4

0

50

60

P = 0.007

Conventional Therapy

Intensive Therapy

Months of Follow-up

Pri

mar

y C

om

po

site

En

d P

oin

t (%

)

Multifactorial Intervention in Type 2 DM

N Engl J Med 2003;348:383-93.

cardiovascular and microvascular events by 50%

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: 180-220 mg/dL;PPG: 250-320 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• 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 DiabetesGoals

A1C < 7% Plasma glucose (mg/dL) Preprandial 70-130 mg/dL Peak PPG < 180 mg/dLBP < 130/80 mm HgLipids TC <200 mg/dL LDL <100 mg/dL (<70 mg/dL) TG <150 mg/dL HDL >40 mg/dL

Males >40 mg/dLFemales >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 45-65 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, bcps, fascp, cde, bc-adm professor (clinical)...

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