Sulfonylureas Reduce fasting and PPG should be initiated at low doses

Sulfonylureas Reduce fasting and PPG should be initiated at low doses
Increased at 1- to 2-week intervals based on SMBG. Increase insulin acutely and thus should be taken shortly before a meal With chronic therapy, the insulin release is more sustained

Repaglinide Is not a sulfonylurea but also interacts with the ATP-sensitive potassium channel. short half-life usually given with or immediately before each meal to reduce meal-related glucose excursions.

Insulin secretagogues
Are well tolerated in general. All of these agents, have the potential to cause profound and persistent hypoglycemia, especially in elderly individuals.

Insulin secretagogues
Hypoglycemia is usually related to Delayed meals Increased physical activity Alcohol intake Renal insufficiency. Individuals who ingest an overdose of these agents develop prolonged and serious hypoglycemia and should be monitored closely in the hospital

Sulfonylureas Most sulfonylureas are metabolized in the liver to compounds that are cleared by the kidney. Their use in individuals with significant hepatic or renal dysfunction is not advisable. Weight gain, a common side effect of SUD, results from the increased insulin and improvement in glycemic control

Sulfonylureas Some sulfonylureas have significant drug interactions with other medications such as Alcohol Warfarin Aspirin ketoconazole a-glucosidase inhibitors Fluconazol

Biguanides: Mechanisms of Action
Treating to Target Biguanides: Mechanisms of Action 1. Intestine: glucose absorption 2. Muscle and adipose tissue: Biguanides  glucose utilization Insulin resistance Blood glucose 4. Liver: Biguanides  hepatic glucose output The primary therapeutic mechanisms of the biguanides are to decrease the production of glucose by the liver and to increase the insulin-mediated uptake of glucose into muscle tissue. Biguanides may also delay glucose absorption. Similarly to insulin secretagogues, biguanides typically lower HbA1c by 1.5 to two per cent (Luna. Am Fam Phys 2001;63: ). 3. Pancreas: insulin secretion Insulin resistance DeFronzo et al. J Clin Endocrinol Metab 1991;73: Stumvoll et al. N Engl J Med 1995;333:

BIGUANIDES Metformin Reduces hepatic glucose production through an undefined mechanism May improve peripheral glucose utilization slightly. Reduces fasting plasma glucose and insulin levels Improves the lipid profile Promotes modest weight loss.

Metformin The initial starting dose of 500 mg once or twice a day can be increased to 850 mg tid or 1000 mg bid. Because of its relatively slow onset of action and gastrointestinal symptoms with higher doses, the dose should be escalated every 2 to 3 weeks

L I V E R MUSCLE metformin metformin metformin interferes with
respiratory oxidation metformin metformin ADP = adenosine diphosphate; ATP = adenosine triphosphate; Ca++ = intracellular calcium levels; OAA = oxaloacetate; PEP = phosphoenolpyru vate; Pi = inorganic phosphate; TK = tyrosine kinase. From: Kirpichnikov: Ann Intern Med, Volume 137(1).July 2, enhances glucose uptake metformin reduces hepatic glucose output it acts in the mitochondria, where it interfers with respiratory oxidation substrate such as lactate, pyruvate, glycerol and amino acids are less able to undergo gluconeogenesis metformin enhances glucose uptake in insulin-sensitive tissue by increasing tyrosine kinase activity in insulin receptors and by enhancing glucose transporter (GLUT) trafficing to the cell membrane Figure 1. Mechanisms of metformin action on hepatic glucose production and muscle glucose consumption. Metformin decreases hepatic gluconeogenesis by interfering with respiratory oxidation in mitochondria. It suppresses gluconeogenesis from several substrates, including lactate, pyruvate, glycerol, and amino acids. In addition, metformin increases intramitochondrial levels of calcium (Ca++), a modulator of mitochondrial respiration. In insulin-sensitive tissues (such as skeletal muscle), metformin facilitates glucose transport by increasing tyrosine kinase activity in insulin receptors and enhancing glucose transporter (GLUT) trafficking to the cell membrane. ADP = adenosine diphosphate; ATP = adenosine triphosphate; Ca++ = intracellular calcium levels; OAA = oxaloacetate; PEP = phosphoenolpyruvate; Pi = inorganic phosphate; TK = tyrosine kinase. From: Kirpichnikov: Ann Intern Med, Volume 137(1).July 2, metformin MUSCLE

metformin metformin inhibits fatty acid production and oxidation
fatty acid-induced insulin resistance hepatic glucose production metformin Figure 2. Metformin and fatty acids. Metformin inhibits fatty acid (FA) production and oxidation, thereby reducing fatty acid-induced insulin resistance and hepatic glucose production. CoA = coenzyme A; CPT = carnitine palmitoyltransferase; FFA = free fatty acid; GLUT = glucose transporter; IGF-1 = insulin-like growth factor I; IRS-1 = insulin receptor substrate-1; OAA = oxaloacetate; PDH = pyruvate dehydrogenase; PFK = phosphofructokinase; PI-3 = phosphatidyl inositol From: Kirpichnikov: Ann Intern Med, Volume 137(1).July 2,

Metformin The major toxicity lactic acidosis
Metformin should not be used in patients with RF [creatinine >1.5 in men or >1.4 mg/dL in women] Any form of acidosis CHF Liver disease Severe hypoxia.

Metformin Metformin should be discontinued in patients
Who are seriously ill Patients who can take nothing orally Those receiving radiographic contrast

METFOMIN Some develop GI side effects (diarrhea, anorexia, nausea, and metallic taste) that can be minimized by gradual dose escalation. Drug is metabolized in the liver It should not be used in patients with liver disease or heavy ethanol intake

Alpha-Glucosidase Inhibitors: Mechanisms of Action
Treating to Target Alpha-Glucosidase Inhibitors: Mechanisms of Action 1. Intestine: glucose absorption 2. Muscle and adipose tissue: glucose uptake Insulin resistance Blood glucose Alpha-glucosidases are intestinal enzymes that break down starches into monosaccharides. Acarbose, a tetrasaccharide, is a reversible inhibitor of alpha-glucosidases. Treatment with acarbose delays the breakdown of starches into monosaccharides and their subsequent absorption into the circulation. Hence, the rise of plasma glucose is delayed enough to coincide with the delayed insulin response characteristic of type 2 diabetes. The result is that the postprandial rise in plasma glucose is effectively dampened. Alpha-glucosidase inhibitors typically lower HbA1c by 0.7 to 1.0 per cent, somewhat less than the other classes of oral agents (Luna. Am Fam Phys 2001;63: ). 4. Liver: hepatic glucose output Insulin resistance 3. Pancreas: insulin secretion Amatruda. From Diabetes Mellitus, Ch. 72,1996,p

a-GLUCOSIDASE INHIBITORS
a-Glucosidase inhibitors (acarbose and miglitol) reduce pp hyperglycemia by delaying glucose absorption They do not affect glucose utilization or insulin secretion. PP hyperglycemia, contributes significantly to the hyperglycemic state in type 2 DM.

These drugs, taken just before each meal, reduce glucose absorption by inhibiting the enzyme that cleaves oligosaccharides into simple sugars in the intestinal lumen.

Therapy should be initiated at a low dose (25 mg of acarbose or miglitol) with the evening meal and may be increased to a maximal dose over weeks to months (50 to 100 mg for acarbose or 50 mg for miglitol with each meal).

The major side effects (diarrhea, flatulence, abdominal distention) are related to increased delivery of oligosaccharides to large bowel a-Glucosidase inhibitors may increase SUD and increase hypoglycemia. Simultaneous treatment with bile acid resins and antacids should be avoided.

These agents should not be used in IBD Gastroparesis Creatinine >2.0 mg/dL. This agents is not as potent as other oral agents in lowering the HbA1c but is unique in that it reduces the PP glucose rise even in individuals with type 1 .

THIAZOLIDINEDIONES Thiazolidinediones represent a new class of agents that reduce insulin resistance. These drugs bind to a nuclear receptor (peroxisome proliferator-activated receptor, PPAR-g) that regulates gene transcription.

Glitazones Mechanism of Action
Direct stimulation of a family of receptors on the nuclear surface of cells that are responsible for lipid homeostasis (lowers triglycerides and FFA) PPAR family of receptors; nuclear transcription factors

Glitazones Mechanism of Action
peroxisome-proliferator-activated receptor-gamma PPAR - most important receptor isoform reduces TNF- and hepatic glucokinase expression (suppresses glucose output) Stimulate expression of genes responsible for production of GLUT-1 and GLUT-4 (increases insulin sensitivity 60%)

Thiazolidinediones: Mechanisms of Action
Treating to Target Thiazolidinediones: Mechanisms of Action Blood glucose Muscle and adipose tissue  insulin resistance  glucose uptake Rosiglitazone and pioglitazone belong to a new class of antidiabetic agents known as thiazolidinediones. Their mechanism of action is multifactorial. These compounds appear to be unique in their ability to decrease insulin resistance directly. There are several consequences: hepatic glucose production decreases, muscle and adipose tissue glucose uptake increases, and the demand on the pancreas for insulin is decreased. Liver  insulin resistance  hepatic glucose production Pancreas  demand for insulin secretion  beta-cell insulin content Balfour, et al. Drugs 1999;57: Whitcomb, et al. From Diabetes Mellitus, Ch. 74, p

Thiazolidinediones: Structures
Treating to Target Thiazolidinediones: Structures O Rosiglitazone NH CH3 S O N N O CH3 CH2 O This slide shows the structures of two commercially available thiazolidinediones. Pioglitazone NH S N O O

THIAZOLIDINEDIONES Agonists of this receptor
promote adipocyte differentiation may reduce insulin resistance in skeletal muscle indirectly. TZD reduce the fasting glucose by improving peripheral glucose utilization and insulin sensitivity

THIAZOLIDINEDIONES Circulating insulin decrease with use of the TZDs, indicating a reduction in insulin resistance. Therapeutic range for pioglitazone is 15 to 45 mg/d in a single daily dose and for rosiglitazone is 2 to 8 mg/d

THIAZOLIDINEDIONES TZD raise LDL and HDL slightly and lower TG by 10 to 15% TZD are associated with weight gain (1 to 2 kg) small reduction of HCT a mild increase in plasma volume. Cardiac function is not affected, but the incidence of peripheral edema is increased

THIAZOLIDINEDIONES They are contraindicated in patients with liver disease or CHF (class III or IV). TZD have been shown to induce ovulation in premenopausal women with polycystic ovary syndrome

INSULIN THERAPY IN TYPE 2 DM
Insulin should be considered as the initial therapy in type 2 DM, particularly in Lean individuals Severe weight loss Underlying renal or hepatic disease Individuals who are hospitalized Acutely ill

Insulin is usually initiated in a single dose of intermediate-acting (0.3 to 0.4 U/kg/day), given either before breakfast or just before bedtime (or ultralente at bedtime).

Since fasting hyperglycemia and increased hepatic glucose production are prominent features of type 2 bedtime insulin is more effective than a single dose of morning insulin.

Both morning and bedtime intermediate insulin may be used in combination with oral glucose-lowering agents (biguanides, a-glucosidase inhibitors, or thiazolidinediones).

CHOICE OF INITIAL GLUCOSE-LOWERING AGENT
most patients and physicians currently prefer oral glucose-lowering drugs as the initial pharmacologic approach. The level of hyperglycemia should influence the initial choice of therapy

Mild to moderate hyperglycemia [fasting plasma glucose < (200 to 250 mg/dL)] often respond well to a single oral glucose-lowering agent. More severe hyperglycemia [fasting plasma glucose > 250 mg/dL] may respond partially but are unlikely to achieve normoglycemia with oral monotherapy.

Some physicians begin insulin in individuals with severe hyperglycemia [fasting glucose > 250 to 300 mg/dL].

Insulin secretagogues biguanides a-glucosidase inhibitors thiazolidinediones insulin are approved for monotherapy of type 2 .

insulin secretagogues, biguanides, and TZD improve glycemic control to a similar degree (1 to 2% reduction in HbA1c) and are more effective than a-glucosidase inhibitors

insulin secretagogues and a-glucosidase inhibitors begin to lower the plasma glucose immediately glucose-lowering effects of the biguanides and TZD are delayed by several weeks to months

Biguanides a-glucosidase inhibitors TZD do not directly cause hypoglycemia

COMBINATION THERAPY WITH GLUCOSE-LOWERING AGENTS
Commonly used regimens include: (1) insulin secretagogue with metformin or TZD (2) SUD with a-glucosidase inhibitor (3) insulin with metformin or TZD. The combination of metformin and a TZD is also effective and complementary

Antihyperglycemic Agents: Major Sites of Action
Plasma glucose -Glucosidase Inhibitors Glitazones Carbohydrate Absorption Glucose Uptake (–) (+) Glucose Production GI tract Muscle/Fat (+) Injected Insulin Metformin (–) Liver (–) Slide 4-5 Antihyperglycemic Agents: Major Sites of Action The abnormalities in blood glucose regulation that characterize type 2 diabetes mellitus are complex and involve defects in insulin secretion as well as insulin resistance. The complexity of the metabolic defects in this condition has led to the development of therapeutic agents that affect different targets along the metabolic pathways involved. Plasma glucose may be lowered via the stimulation of insulin secretion by the sulfonylureas or the meglitinides, as well as by the stimulation of glucose uptake by muscle and fat, or by the decrease in hepatic production of glucose mediated by metformin or insulin. Acarbose and miglitol may decrease plasma glucose by slowing absorption of glucose from the gastrointestinal tract; the thiazolidinediones lower plasma glucose by enhancing tissue uptake of glucose. – + Insulin Secretion Sulfonylureas Meglitinides Insulin Secretion (+) Pancreas 4-5

Characteristics of an Ideal Basal Insulin
Closely mimic normal pancreatic basal insulin secretion No distinct peak effect Continued effect over 24 hours Reduce nocturnal hypoglycemia Once-daily administration for patient convenience Predictable absorption pattern

Pharmacokinetics of Current Insulin Preparations
Effective Onset Peak Duration Insulin lispro <15 min hr 3-4 hr Regular hr 2-3 hr 3-6 hr NPH 2-4 hr 6-10 hr hr Lente hr hr hr Ultralente 6-10 hr hr hr Glargine

The Basal/Bolus Insulin Concept
Basal Insulin Suppresses glucose production between meals and overnight Nearly constant levels 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 Ideally, for insulin replacement therapy, each component should come from a different insulin with a specific profile 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

Problems with Human Insulin Profiles
Short-acting insulin (regular insulin) Absorbed too slowly to match glucose peak Intermediate/Long-acting insulins (NPH, Lente, UL) Absorbed too quickly to mimic basal secretion These insulins have a peak effect Short duration of action- need for multiple injections 9

Meal Time (Bolus) Insulin
Regular insulin Dosed minutes prior to meal Longer duration of action (up to 4-6 hours) Can result in between-meal hypoglycemia New Rapid acting insulin analogues (Aspart, Lispro) Dose given immediately pre-meal Onset - 15 minutes, peak effect minutes Improved post-meal glucose control Limits risk of hypoglycemia

Activity Profile of Insulin Lispro
60 50 Normal insulin response Regular human insulin (injection 5 minutes before meals) Insulin Lispro (injection 5 minutes before meals)* * Aspart has similar profile Insulin (mU/L) 40 30 20 10 60 120 180 240 300 360 420 480 Meal Minutes Based on a study of 6 patients with type 1 diabetes and some residual b-cell function and 6 control subjects without diabetes Adapted from Pampanelli S et al. Diabetes Care 1995;18:

Insulin Aspart/Lispro
Ultra-short-acting insulin analogues Controls postprandial glucose excursions Compared with regular human insulin: Reduces incidence of hypoglycemia Questionable improvement in HbA1c Thorsby P et al. European Association for the Study of Diabetes Abstract 57 Home PD, et al. European Association for the Study of Diabetes Abstract 60

Available Basal Insulins
NPH, Lente Generally dosed twice daily (AM, PM or HS) Peak effect 4-8 hours after injection Ultralente has a peak effect variable pharmacokinetics human UL does not last 24 hours Glargine (Lantus) Once daily, no peak action

Pharmacokinetics of Insulin Glargine (Lantus®)
Compared with NPH insulin: Slower, more prolonged absorption Lack of peak serum concentration Allows for once-daily administration Intrapatient variability comparable with NPH insulin Less intrapatient variability than ultralente insulin Cannot be mixed in the same syringe with other insulins

Treatment strategies Single dose regimens Twice daily regimenes
Multiple daily injections

Conventional regimens
problems Lack of flexibilty Inadequate coverage of post-lunch glycemia Fasting hyperglycemia Nocturnal hypoglycemia

Problems with Human Insulin Profiles
Short-acting insulin (regular insulin) Absorbed too slowly to match glucose peak Intermediate/Long-acting insulins (NPH, Lente, UL) Absorbed too quickly to mimic basal secretion These insulins have a peak effect Short duration of action- need for multiple injections 9

Meal Time (Bolus) Insulin
Regular insulin Dosed minutes prior to meal Longer duration of action (up to 4-6 hours) Can result in between-meal hypoglycemia New Rapid acting insulin analogues (Aspart, Lispro) Dose given immediately pre-meal Onset - 15 minutes, peak effect minutes Improved post-meal glucose control Limits risk of hypoglycemia

Indications for Insulin Therapy in Type 2 Diabetes
Presence ketonuria in unstressed state Nonobese with persistently elevated glucose leveles (FBS greater than ) Symtpoms of polyuria, polydipsia and weight loss and hyperglycemia Severe hypertriglyceridemia Oral agent failure with or without symptomatic hyperglycemia GDM whose disease is not controlled with diet alone and women with type 2 diabetes who become pregnant

Rationale for Insulin Therapy in Type 2 Diabetes (1)
Peripheral resistance to insulin action and impaired pancreatic B-cell secretion are early and primary abnormalities Increased hepatic glucose production is a late and secondary manifestation

Progressive hyperglycemia  decrease in B-cell function in UKPDS deteriorated significantly in diet-treated group, from 53% at yr 1 to 26% at yr 6

in sulfonylurea group, an early increase in B-cell function from 45% to 78% in yr 1, but subsequently decreased to 52% in metformin group, B-cell function declined from 66% to 38% at yr 6 Over the course of 15 yrs, the proportion of patients using oral agents declines, and most will require exogenous insulin treatment

Benefits of Insulin Therapy in Type 2 Diabetes (1)
Improvement in insulin sensitivity Intensive insulin therapy for up to 4 weeks actually improves insulin sensitivity as measured by glucose-insulin clamp method presumably due to reduced glucose toxicity

Disadvantages of Insulin Therapy in Type 2 Diabetes
Hypoglycemia Weight gain Patient compliance and inconvenience

Patient Compliance and Inconvenience
Pain Pens with smaller and finer needles Discrete modes of administration Inconvenience Less invasive glucose monitoring system like the glucowatch and MiniMed Continuous Monitoring system

Insulin Preparation Rapid-acting insulin, short-acting preparations, long-acting insulins and ultra-long-acting insulins The site of insulin injection should be kept constant, because changing sits can change the pharmacokinetics, also, absorption can be highly variable, especially if lipohypertrophy is present

Monitoring Insulin Therapy (1)
Home glucose monitoring (HGM) Monitoring should normally coincide with the peak of a particular type of insulin (e.g. 1-3 hours after RI and 6-8 hours after NPH) to evaluate the efficacy of the dose and to avoid hypoglycemia Initially, check blood glucose level before meals, 2 hours after meals at bedtime, and occasionally at 3:00AM

Nonpharmacologic tools can be used to control excessive glucose levels Interval between the insulin injection and mealtime can be increased to allow sufficient time for insulin to become active Consuming fewer calories

Eliminating foods that cause rapid increases in blood glucose Spreading the calories over an extended period of time Exercising lightly after meal

Addition of Insulin to oral Agents (1)
Fasting blood glucose contributes more to daytime hyperglycemia than do postpraandial changes Fasting blood glucose concentration is highly correlated with the degree of hepatic glucose production during the early morning hours Hepatic glucose output is directly decreased by insulin and is indirectly inhibited by the ability of insulin to reduce adipose tissue lipolysis, with lower concentrations of free fatty acids and gluconeogenesis

Addition of Insulin to oral Agents (2)
The peak action of intermediate-acting insulin taken at bedtime also coincides with the onset of the dawn phenomenon (early morning resistance to insulin caused by diurnal variations in growth hormone and possible by norepinephrine levels) Reduce the postbreakfast glucose in addition to the fasting value

Insulin Treatment Strategies
Addition of Insulin to oral Agents Sulfonylurea plus Evening NPH Sulfonylurea plus Bedtime NPH Sulfonylurea plus Evening 70/30 Insulin Sulfonylurea plus Various Insulin Regimes Sulfonylurea plus Lispro Insulin Sulfonylurea plus Metformin plus Insulin

Selection of Patients Obese
Overt diabetes for less than 10 to 15 years Diagnosed with type 2 diabetes after age of 35 years Do not have FBG consistently over mg/dL Have evidence of endogenous insulin secretory ability

Dose Culculation Divide the average FBG by 18
Divided the body weight in kg by 10

Start Insulin Therapy in Patients failing OAA
Continue OAA at same dosage( eventually reduce) Add single evening insulin dose For thin patients (BMI < 25 kg/m2) – 5 to10 u NPH (bedtime) For obese patients (BMI > 25 kg/m2) – 10 to 15 u NPH (bedtime) or 70/30 (before dinner) Adjust dose by fasting self-monitored blood glucose (goal: mg//dL) Increase insulin dose weekly as needed Increase by 4 units if FBG > 140 mg/dL Increase by 2 units if FBG = mg/dL

Best time to give the evening injection of NPH
between 10 PM and midnight

Dose Adjustment If the daytime blood glucose concentrations start to become excessively low, the dose of oral medication must be reduced If the prelunch and predinner blood glucose remain excessively high, In the past, a more conventional two-injection/day insulin regimen has been used, discontinuing therapy with OAA Now, the use of insulin-sensitizing agents (metformin and the glitazones)

Practical Strategy to Implement a Multi-Injection Insulin Regimens
Dose Calculation Split-mixed regimen in obese patients uses 70/30 premixed insulin with an initial total daily dose ( u/kg) equally split between the prebreakfast and predinner meals Lower doses (total daily dose u/kg) in thin patients Dose Adjustment Dose is increased by 2-4 u increment every 3-4 days until the morning FPG and predinner blood glucose concentration are consistently in the range of mg/dL

Addition of Oral Agents to Insulin
Insulin plus Metformin Inuslin plus Glitazones Insulin plus Acarbose

Insulin Aspart/Lispro
Ultra-short-acting insulin analogues Controls postprandial glucose excursions Compared with regular human insulin: Reduces incidence of hypoglycemia Questionable improvement in HbA1c Thorsby P et al. European Association for the Study of Diabetes Abstract 57 Home PD, et al. European Association for the Study of Diabetes Abstract 60

Classification Gestational DM Pregestational DM

Etiology During pregnancy, the placenta is secreting diabetogenic hormones, which increase insulin production growth hormone corticotropin releasing hormone human placental lactogen progesterone

Etiology GDM occurs when the woman’s pancreas can not function sufficiently to overcome her relative insulin resistance and increased fuel consumption GDM defined by ACOG as “carbohydrate intolerance first recognized during pregnancy”

Risk Factors for GDM family history
pre-pregnancy weight of 110% of ideal body weight age >25 years old previous history of large baby (9 lbs.)

Risk Factors history of abnormal glucose tolerance
ethnic group with higher incidence of Diabetes Mellitus Type 2 previous unexplained perinatal loss or malformed child mother was large at birth

GDM associated with increased incidence of:
Preeclampsia Hydramnios Fetal macrosomia Birth trauma Operative deliveries Later development of DM in mother

GLOBAL SCREENING ? OR SELECTIVE SCREENING

Screening Selective suggested by ADA Universal
done at weeks in all women may do earlier if suspicious

LOW RISK GROUP Member of an ethnic group with a low prevalence of GDM.
No known diabetes in first-degree relatives. Age < 25 years. Weight normal before pregnancy. No history of abnormal glucose metabolism. No history of poor obstetric outcome.

Screening Test *1-h PG (50gr) At 24-28 WK PG > 140 mg /dl
*Fasting is not required.

Definitive test PG > 140 mg/dl *Perform 3-GTT (100g)
*Overnight fast of at least 8h but not more than 14h is required.

NDDG Criteria For GTT Time Venous plasma Fasting 105 mg/dl 1 hour
*If two values are met or exceeded, GDM is diagnosed

*New Criteria Time mg/dl Fasting 95 1h 180 2h 155 3h 140
* By carpenter & coustan.

PG < 140mg/dl Non- diabetic Repeat screening test if glycosuria,toxemia or hydramnios develops,if fetus is large at 32 WK,or if maternal age >33 years,or if maternal weight >120% IBW

Blood glucose goals Fasting 65-85 mg/dl 1-h postprandial 140-150 mg/dl

*Fasting < 90mg/dl Institute calculated diet . Monitor FBS & 1 hr PC. 1 hr PC < 120 mg/dl Continue diet *During GTT

*Fasting > 90 mg/dl **1 hr PC > 120 mg/dl Hospitalized patient to initiate insulin or use intensive outpatient program * During GTT ** After short term diet trial.

Management Metabolic control Diet Medication Fetal evaluation
Delivery considerations Post-partum

Recommended Daily Caloric Intake
Prepregnancy weight status Kcal/kg/d Recommended weight gain (kg) Desirable body weight 30 11-16 >120% desirable body weight 24 7 <80% desirable body weight 36 to 40 18

*Daily caloric distribution
40% to %50 CHO,%20 protein, %30 fat meal Calories (%) Breakfast 10-15(%33 CHO) Snack 0-10 Lunch 20-30(%45 CHO) Dinner 30-40(%40 CHO) *Avoid fasting in excess of 4 to 5 h during the waking hours.

INSULIN PROTOCOLE

*Insulin Requirement Total insulin Time(WK) 0.7u/kg 6-18 0.8u/kg 18-26
26-36 1.0u/kg 36-40 * Initial calculation.

*FBS > 90mg/dl NPH 0.15u/kg (Bedtime)
*Normal postprandial blood sugar.

1.5u/10gr CHO (prebreakfast) 1.0u/ 10gr CHO (prelunch & dinner)
*Postprandial Blood Glucose Regular Insulin 1.5u/10gr CHO (prebreakfast) 1.0u/ 10gr CHO (prelunch & dinner) * Normal FBS.

FBS & *PP NPH , %45 of total dose Regular , %55 of total dose
* Postprandial

+ NPH Regular %30 prebreakfast % 16.5 perlunch %15 bedtime
%16.5 predinner %30 prebreakfast %15 bedtime

Monitoring of diabetic control
SMBG(*at least 4 times/day ) Hb A1C every 4 to 6 WK (in pregestational DM ). Urinary ketone (every morning & if BG>150). *premeal, bedtime & twice weekly 1h pp.

Postprtum course of the GDM
%98 of all gestational diabetic women revert to normoglycemia postpartum. Probability that DM will recur in each subsequent pregnancy is about %90. There is %60 chance of manifesting DM within 20 years.

At 6-12 WK postpartum all patient who had GDM should be reclassified
FBS mg/dl Diagnosis > 126(on two occasions) DM Impaired fasting glucose < 110 Normal

Incretin therapies

Incretin therapies Physiologic defects associated with Type 2 diabetes
β-Cell dysfunction Inadequate insulin secretion and glucagon over-secretion The role of incretins in normal physiology Approaches to incretin therapy GLP-1 analogues DPP-4 inhibitors Incretin therapies Type 2 diabetes is characterised by hyperglycaemia that is attributable, in part, to pancreatic β-cell dysfunction. β-cell dysfunction eventually leads to inadequate insulin secretion, which contributes to elevated blood glucose concentrations. In addition, -cell dysfunction leads to glucagon over-secretion, which also elevates blood glucose levels due to increased hepatic glucose output. Incretins are gut peptides that potentiate insulin secretion during eating. Glucagon-like peptide-1 (GLP-1) is an incretin that has been demonstrated to stimulate glucose-dependent insulin secretion and inhibit glucagon secretion. However, GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), rendering it inactive [Drucker, 2006; Nauck et al, 1993]. This presentation will describe the mechanisms of action of GLP-1 replacement therapy, as well as of inhibitors of DPP-4 that enhance endogenous GLP-1 activity by reducing the rate of GLP-1 degradation. First, we will start with an overview of the physiological defects associated with Type 2 diabetes. REFERENCES Drucker DJ. Cell Metab. 2006;3: Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W. Diabetologia. 1993;36: DPP-4=dipeptidyl peptidase-4 GLP-1=glucagon-like peptide-1

Islet β-cell function (HOMA %B) in the UKPDS
Sulfonylurea Conservative (primarily diet) Islet β-cell function (%) Metformin 100 Non-overweight Overweight 80 60 40 Islet β-cell function (HOMA %B) in the UKPDS This slide shows the progressive loss in β-cell function among newly diagnosed people with Type 2 diabetes over the first 6 years of the United Kingdom Prospective Diabetes Study (UKPDS). This study included over 1800 participants who were treated with diet alone, sulfonylurea, or, for obese participants with poorly controlled symptoms, a combination of sulfonylurea plus metformin. The percent β-cell function was estimated using the homeostasis model assessment method. In this graph, we see a slight to significant increase in β-cell function in the first year of this study on all therapies (sulfonylurea, P<0.01) . However, for all treatment groups, there was thereafter a continuing decline in function, statistically significant at year 6 compared with year 1 (P<0.01). These results demonstrate the temporal limitations of diet, sulfonylurea, and metformin therapy in the treatment of Type 2 diabetes. REFERENCE U.K. Prospective Diabetes Study Group. Diabetes. 1995;44: 20 Loss ~4% per year 1 2 3 4 5 6 1 2 3 4 5 6 Years from randomization HOMA=homeostasis model assessment; UKPDS=United Kingdom Prospective Diabetes Study UKPDS Group. Diabetes. 1995

β-Cell mass is sustained by continual birth and death of cells by neogenesis and apoptosis
Nestin-positive intra-islet progenitor Duct-derived progenitor Undifferentiated cells Differentiated cells α-Cell β-Cell Duct cell Neogenesis (birth) Apoptosis (death) GLP-1 Lumen β-Cell mass is sustained by continual birth and death of cells by neogenesis and apoptosis This slide shows the dynamic state of the pancreas. In normal adult islet cells, β-cell mass is maintained by a balance between the generation of new cells and cell death by apoptosis. In adult rodents, it is estimated that the entire β-cell mass is renewed every 30 to 40 days. Much of our knowledge of β-cell function is based on rodent models; the corroboration of these results in humans has been limited by available opportunities for human pancreatic tissue evaluation. Although the ability of β-cells to renew appears to diminish rapidly in the mouse following birth, models of pancreatic injury suggest that high rates of β-cell regeneration are possible and involve mechanisms other than existing cell replication, such as neogenesis (a process by which undifferentiated cells are transformed to functioning β-cells). New, undifferentiated cells are thought to originate from either pancreatic duct-derived progenitor cells or Nestin-positive intra-islet progenitor cells located within the islets themselves. Nestin is a stem cell-specific marker. A variety of factors may influence the differentiation of progenitor cells into endocrine cells, including the role of the incretin hormone GLP-1 which has been shown to trigger both β-cell proliferation and differentiation. REFERENCE Kemp DM, Thomas MK, Habener JF. Rev Endocr Metab Disord. 2003;4:5-17. Activin A Betacellulin Hepatocyte growth factor GLP-1 Pancreatic duct 30–40 days Kemp et al. Rev Endocr Metab Disord. 2003

β-Cell mass in Type 2 diabetes
-50% -63% β-Cell mass in Type 2 diabetes This slide shows the outcomes of a retrospective autopsy study that assessed human pancreatic β-cell mass in lean and obese subjects (n=124). Cases were categorized based on recent fasting plasma glucose (FPG) measurements as non-diabetic (ND), impaired fasting glucose (IFG), or Type 2 diabetes. For inclusion, cases were required to have had at least one FPG in the year prior to death. Cases were categorized as obese (body mass index [BMI] >27 kg/m2) or lean (BMI <25 kg/m2) and further classified as: ND (FPG <6.1 mmol/l [<110 mg/dl]); IFG (FPG= mmol/l [ mg/dl]); or Type 2 diabetes (FPG >7.0 mmol/l [>126 mg/dl]). Relative β-cell volume percentage was used to estimate β-cell mass. Obese subjects with IFG or Type 2 diabetes had relative β-cell volumes of 40% (P<0.05) and 63% (P<0.01), respectivelyrepresenting a lower relative β-cell volume compared with ND-obese cases. Lean subjects with Type 2 diabetes cases had 41% less relative β-cell volume compared with ND cases (P<0.05). The ND-obese subgroup had approximately 50% greater β-cell volume compared with ND-lean (P=0.05), which may have been a result of the younger age at death for obese-ND (66.9 yr) compared with lean-ND (78.1 yr) cases. These results illustrate the link between β-cell mass, IFG, and Type 2 diabetes. REFERENCE Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Diabetes. 2003;52: Obese Lean ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus Butler et al. Diabetes. 2003

Excessive hepatic glucose production in Type 2 diabetes
Insulin; IR Hepatic glucose output Glucagon Fasting & postprandial hyperglycaemia Excessive hepatic glucose production in Type 2 diabetes In addition to lost β-cell function and mass, Type 2 diabetes is also characterised by excessive hepatic glucose production. This slide shows that excessive hepatic glucose production, which is mediated by glucagon, contributes to both fasting and postprandial hyperglycaemia. Increased insulin resistance reduces glucose uptake by peripheral tissues and further exacerbates hyperglycaemia. REFERENCE Toft-Nielsen M, Damholt M, Madsbad S, et al. J Clin Endocrinol Metab. 2001;86: Plasma glucose concentration IR=insulin resistance

Normal subects n=11; Type 2 diabetes n=12
Insulin and glucagon dynamics in response to meals in normal subjects and Type 2 diabetes 20.0 18.3 16.6 15.0 13.3 6.1 4.4 140 130 120 110 100 90 60 30 Glucose (mmol/l) Insulin (mU/l) Glucagon (ng/l) Meal Type 2 diabetes Normal subjects Delayed/depressed insulin response Insulin and glucagon dynamics in response to meals in normal subjects and Type 2 diabetes This slide illustrates a study that measured plasma glucose, insulin, and glucagon response in individuals without (normal subjects) and with Type 2 diabetes. The study was conducted after an overnight fast followed by a high-carbohydrate meal. Plasma glucose concentrations rose from 12.7 mmol/l (228 mg/dl), pre-meal, to 19.9 mmol/l (358 mg/dl) in individuals with Type 2 diabetes compared with an increase from 4.7 mmol/l (84 mg/dl) to a peak of 7.6 mmol/l (137 mg/dl) in normal subjects. Insulin levels rose in normal individuals from a fasting level of 13 mU/l to a peak of 136 mU/l at 45 minutes. The insulin response in individuals with Type 2 diabetes was depressed, with a modest increase from a fasting level of 21 mU/l to a peak of 50 mU/l at 60 minutes. In normal individuals, plasma glucagon began to fall from the fasting value of 126 ng/l (126 pg/ml) within 30 minutes of the start of the meal and reached a significantly lower concentration of 90 ng/l (90 pg/ml) at 90 minutes (P<0.01). Plasma glucagon concentrations in those with Type 2 diabetes did not fall in response to the meal, despite the sharp increase in plasma glucose. These results demonstrate the delayed and suppressed insulin response to rising plasma glucose concentrations in individuals with Type 2 diabetes. Importantly, it also shows the lack of postprandial suppression of glucagon in Type 2 diabetes following a meal; this stands in marked contrast to the rapid fall in glucagon levels among normal subjects. The combined effect of decreased insulin secretion and glucagon over-secretion in Type 2 diabetes leads to fasting hyperglycaemia and increases postprandial hyperglycaemia. REFERENCE Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. N Engl J Med. 1970;283: Nonsuppressed glucagon Time (min) -60 60 120 180 240 Müller et al. N Engl J Med. 1970 Normal subects n=11; Type 2 diabetes n=12

Action of glucagon Raises blood glucose
Low blood glucose promotes glucagon release from a-cells of pancreas Glycogen Glucose Glucagon stimulates breakdown of glycogen Action of glucagon This slide depicts the action of glucagon on hepatic glycogen metabolism. Triggered by low blood glucose concentrations, glucagon is released from the α-cells of the pancreas into the blood. In the liver, glucagon stimulates the breakdown of glycogen to glucose, which elevates blood glucose levels. Raises blood glucose

β-Cell function and glucagon in Type 2 diabetes
Loss of β-cell function and glucagon over- secretion both play key roles in Type 2 diabetes development Progressive β-cell decline is coupled with inadequate insulin secretion Glucagon is not suppressed during the postprandial period Hepatic glucose production is increased during the fasting period and is not suppressed during the postprandial period β-Cell function and glucagon in Type 2 diabetes There is a progressive decline in β-cell function in Type 2 diabetes [UKPDS, 1995]. Coupled with increased insulin sensitivity in peripheral tissues and an eventual decline in β-cell-stimulated insulin production, reduced β-cell response is a primary contributor to the development of diabetes, and later the main determinant of disease progression. Glucagon also plays a contributing role to the hyperglycaemic condition characteristic of Type 2 diabetes. Plasma glucagon levels are elevated in Type 2 diabetes, and glucagon is not suppressed in the postprandial state; this results in increased hepatic glucose production in the fasting state and a failure to suppress this in the postprandial period [Müller et al, 1970]. Loss of β-cell function and glucagon over-secretion are key components in Type 2 diabetes pathophysiology. REFERENCES Müller WA, Faloona GR, Aguilar-Parada E, Unger RH. N Engl J Med. 1970;283: U.K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16. Diabetes. 1995;44:

β-cell dysfunction Inadequate insulin secretion and glucagon over-secretion The role of incretins in normal physiology Approaches to incretin therapy GLP-1 analogues DPP-4 inhibitors Incretin therapies We have reviewed the effects of β-cell dysfunction, inadequate insulin secretion, and glucagon over-secretion in Type 2 diabetes. Now we will turn our attention to the role of gut peptides, known as incretins, and their potential therapeutic role in Type 2 diabetes.

GLP-1: effects in humans
Stimulates glucose- dependent insulin secretion After food ingestion… Suppresses glucagon secretion Slows gastric emptying Leads to a reduction of food intake GLP-1 is secreted from L-cells of the jejunum and ileum Improves insulin sensitivity GLP-1: effects in humans GLP-1 is an incretin secreted from enteroendocrine cells in response to nutrient ingestion. GLP-1 is released from gut L-cells, the majority of which are located in the distal ileum and colon. Plasma levels of GLP-1 rise rapidly within minutes of food intake and well before digested nutrients make contact with the distal L-cells; this suggests that nutrient-induced signals from the duodenum and jejunum are relayed to the distal ileum and colon. The release of GLP-1 appears to be biphasic. The first response occurs shortly after food ingestion followed by a second response which is more likely associated with direct contact between nutrients and L-cells [Drucker, 2001]. Starting at the islet cell level, GLP-1 potentiates insulin release from β-cells to promote cellular uptake of glucose; it also inhibits glucagon secretion from α-cells, which, in turn, reduces hepatic glucose output [Drucker, 2001]. Furthermore, GLP-1 acts beyond the pancreas to trigger a cascade of physiological events. By inhibiting gastric emptying (which is postulated to reduce the rate of nutrient absorption), GLP-1 slows the rate of glucose appearance in the blood; this, in turn, appears to reduce insulin secretion requirements. The reduction in appetite observed with GLP-1 treatment may also be associated with inhibited gastric emptying [Drucker, 2001]. GLP-1 may also enhance insulin sensitivity and increase glucose uptake by peripheral tissues, independent of insulin secretion [Drucker, 2006]. In addition to these short-term metabolic effects, GLP-1 may also trigger long-term changes in β-cell mass and function. Studies in rodent models have demonstrated that GLP-1 stimulates β-cell mass by mechanisms that include increased cellular differentiation, islet cell proliferation, and reduced cellular apoptosis [Drucker, 2003]. REFERENCES Drucker DJ. Cell Metab. 2006;3: Drucker DJ. Curr Pharm Des. 2001;7: Drucker DJ. Mol Endocrinol. 2003;17: Long-term effects in animal models: That in turn… Increase of β-cell mass and improved β-cell function Drucker. Curr Pharm Des. 2001 Drucker. Mol Endocrinol. 2003

People with Type 2 diabetes (n=14)
Incretin effect on insulin secretion Control subjects (n=8) People with Type 2 diabetes (n=14) 80 60 40 20 80 Incretin effect 60 Insulin (mU/l) Insulin (mU/l) 40 20 Incretin effect on insulin secretion This slide illustrates the incretin response of 14 individuals diagnosed with Type 2 diabetes and 8 weight-matched, metabolically healthy individuals (control group) [Nauck et al, 1986]. The incretin response is represented as the difference in the secretory response of insulin between oral glucose ingestion and intravenous glucose infusion. The intravenous test consisted of glucose infusions calculated to mimic glucose concentration profiles associated with oral glucose ingestion [Nauck et al, 1986]. The first graph shows the incretin response of normal individuals and indicates that a large proportion of the insulin response in healthy individuals is incretin-mediated. Insulin secretion is stimulated by elevated plasma glucose as well as the incretin effect. The intravenous infusion stimulates the insulin response due to elevated plasma glucose in the absence of an oral glucose load. The sharply enhanced insulin response to an oral glucose load is a result of gut-associated insulin secretion, stimulated by incretins [Drucker, 2006; Nauck et al, 1986]. The second graph shows the incretin response in individuals with Type 2 diabetes. The incretion response was found to be markedly reduced or even absent in individuals with Type 2 diabetes (P≤0.05 vs normal individuals). The reduced incretin response in Type 2 diabetes indicates the potential for incretin therapy in treating this disease [Nauck et al, 1986]. REFERENCES Drucker DJ. Cell Metab. 2006;3: Nauck M, Stöckmann R, Ebert RF, Creutzfeldt W. Diabetologia. 1986;29:46-52. 60 120 180 60 120 180 Time (min) Time (min) Oral glucose load Intravenous glucose infusion Nauck et al. Diabetologia. 1986

Postprandial GLP-1 levels are decreased in people with IGT and Type 2 diabetes
Meal 20 15 10 5 * * * * * * * NGT IGT GLP-1 (pmol/l) * T2DM Postprandial GLP-1 levels are decreased in people with IGT and Type 2 diabetes This slide illustrates plasma GLP-1 response to meal ingestion in age- and weight-matched individuals with normal glucose tolerance (NGT) compared with individuals with impaired glucose tolerance (IGT) and Type 2 diabetes (n=102). The meal test began 3 days after discontinuation of oral glucose-lowering medication and following an overnight fast. Blood was sampled before the start of the meal and over 4 hours post-meal. Plasma GLP-1 levels rose shortly after meal ingestion in all groups. GLP-1 concentrations were significantly lower in the Type 2 diabetes group compared with the NGT group beginning at 60 minutes and continuing for an additional 90 minutes (P<0.05). A similar trend was apparent for IGT compared with NGT. These results demonstrate that the meal-stimulated GLP-1 response is depressed in individuals with both Type 2 diabetes and IGT compared with their NGT counterparts. REFERENCE Toft-Nielsen M, Damholt M, Madsbad S, et al. J Clin Endocrinol Metab. 2001;86: 60 120 180 240 *P<0.05 T2DM vs NGT Time (min) Toft-Nielsen et al. J Clin Endocrinol Metab. 2001 IGT=impaired glucose tolerance; NGT=normal glucose tolerance

Normalisation of diurnal plasma glucose concentrations by continuous IV GLP-1 infusion (1.2 pmol/kg/min) 16 T2DM 12 T2DM + GLP-1 Glucose (mmol/l) 8 Controls Normalisation of diurnal plasma glucose concentrations by continuous IV GLP-1 infusion (1.2 pmol/kg/min) This graph shows the plasma glucose response of individuals with Type 2 diabetes (n=7) to 19 hours of continuous GLP-1 or saline infusion. Age- and weight-matched non-diabetic individuals (controls, n=6) received saline infusion. Oral glucose-lowering medications were discontinued prior to the test, and the last meal prior to the test was completed by 1900 hours. When infused with saline, individuals with Type 2 diabetes exhibited hyperglycaemia during both the basal and postprandial periods. Median overnight (2400 to 0800 h) glucose concentration was 7.8 mmol/l (140.5 mg/dl) during saline infusion, but GLP-1 infusion reduced this to 5.1 mmol/l (91.9 mg/dl) (P<0.02), which was similar to the saline-infused control group (5.6 mmol/l [100.9 mg/dl]). Average daytime glucose concentrations were 11.0 mmol/l (198.2 mg/dl) in saline-infused Type 2 diabetes individuals, and GLP-1 infusion decreased this to 7.6 mmol/l (136.9 mg/dl) (P<0.02); this was also similar to the control group glucose (6.7 mmol/l [120.7 mg/dl]). This study demonstrates that GLP-1 infusion greatly improves both fasting and postprandial glucose concentrations in individuals with Type 2 diabetes. Although continuous GLP-1 infusion was not judged to be a practical therapy, continuous administration using a long-acting subcutaneous formulation or another route was proposed as a potential therapeutic application for Type 2 diabetes. REFERENCE Rachman J, Barrow BA, Levy JC, Turner RC. Diabetologia. 1997;40: 4 Breakfast Lunch Snack 2200 0200 0600 1000 1400 1600 Clock time (hours) Rachman et al. Diabetologia. 1997

Therapeutic effect of GLP-1 in people with Type 2 diabetes
Glucose (mmol/l) C-peptide (nmol/l) Glucagon (pmol/l) 17.5 3.0 30 GLP-1 infusion GLP-1 infusion GLP-1 infusion 15 2.5 * 25 12.5 2.0 20 10 * 1.5 15 * 7.5 * Therapeutic effect of GLP-1 in people with Type 2 diabetes This study evaluated the effect of GLP-1 or saline infusion on plasma glucose, C-peptide (a measure of insulin secretion), and glucagon response in individuals with Type 2 diabetes. The study evaluated 10 individuals whose type 2 diabetes was inadequately controlled using diet and medication. All oral glucose-lowering medications were discontinued prior to the test, which was preceded by an overnight fast [Nauck et al, 1986; Nauck et al, 1993]. These graphs illustrate the improved glucose, C-peptide, and glucagon response to GLP-1 infusion compared with saline placebo. Plasma glucose decreased sharply in response to GLP-1 infusion (P<0.05). As FPG values approached normal, C-peptide, which was higher with GLP-1 compared with saline throughout the infusion (P<0.05), began to decrease as well. Plasma glucagon initially decreased (P<0.05) in response to GLP-1 but returned to baseline levels as plasma glucose returned to normal fasting levels [Nauck et al, 1993]. These results demonstrate that even in individuals with poorly controlled Type 2 diabetes, GLP-1 replacement can reduce FPG to a near-normal state [Nauck et al, 1993]. REFERENCES Nauck M, Stöckmann R, Ebert R, Creutzfeldt W. Diabetologia. 1986;29:46-52. Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W. Diabetologia. 1993;36: * 1.0 10 5 * * * * * GLP-1 Saline 0.5 5 * 2.5 * 0.0 –30 60 120 180 240 –30 60 120 180 240 –30 60 120 180 240 Time (min) Time (min) Time (min) *P<0.05 Nauck et al. Diabetologia. 1993

GLP-1 preserves human islet morphology and function in cultured islets in vitro
Control + GLP-1 Day 1 Day 3 GLP-1 preserves human islet morphology and function in cultured islets in vitro This study investigated the potential mechanisms of possible longer-term effects of GLP-1 by measuring its influence on the viability and function of freshly isolated human islet cells. This slide shows the morphology of control and GLP-1-treated islet cultures over time. Islets were cultured in a medium containing 6-mmol/l glucose, and at the end of each 1-, 3- and 5-day period, a glucose-induced secretion test was performed by changing the culture medium from 6- to 15-mmol/l glucose. Islets cultured for 1 day maintained their spherical 3-dimensional (3-D) structure. As the number of culture days increased, many islets cells lost their 3-D structure; this was attributable to the disappearance of their surrounding acellular membrane. Islets treated with GLP-1 maintained their 3-D structure for longer periods of time. By day 5, control cultures had approximately 45% fewer islets with a preserved 3-D structure compared with an approximately 15% reduction for islets in GLP-1-treated cultures (P<0.01). Although the data are not shown here, GLP-1 cultures also showed higher insulin secretion responses on all 3 days of the test (P<0.05). These results demonstrate the positive influence of GLP-1 on morphology preservation and insulin secretion of cultured islet cells and suggest a potential mechanism for possible longer-term effects of GLP-1 on islet cell function. REFERENCE Farilla L, Bulotta A, Hirshberg B, et al. Endocrinology. 2003;144: Day 5 Farilla et al. Endocrinology. 2003

Effect of GLP-1 on β-cell mass in Zucker diabetic fatty rats
β-Cell proliferation β-Cell apoptosis 16 2.5 30 P<0.05 P<0.01 2.0 12 20 1.5 P<0.001 β-Cell mass (mg) 8 Proliferating β-cells (%) Apoptotic β-cells (%) 1.0 10 Effect of GLP-1 on β-cell mass in Zucker diabetic fatty rats This study investigated the effect of GLP-1 on β-cell mass as well as the underlying mechanisms that may influence changes in cell mass: proliferation and apoptosis. Zucker diabetic fatty (ZDF) rats were used as the model because they develop diabetes at approximately 10 weeks of age, with the clinical onset of diabetes dependent on increased cell apoptosis. The experiment began with a 2-day continuous infusion of saline (control, n=8) or GLP-1 (n=8). On day 7 of the study, rats were killed and pancreatic tissue was harvested for histological examination. This slide illustrates the effect of GLP-1 infusion on β-cell mass. ZDF rats treated with GLP-1 exhibited a 1.6-fold expansion in islet cell mass compared with controls (P<0.01). The increase in mass was accompanied by a 1.4-fold increase in the number of actively dividing cells (P<0.05). The largest observed effect was on cell apoptosis: GLP-1 treatment produced a 3.6-fold decrease in the number of apoptotic cells compared with the control group (P<0.01). These results suggest that one potential mechanism for the possible longer-term effects of GLP-1 is an expansion of β-cell mass that results from increased cell proliferation and decreased cell apoptosis. REFERENCE Farilla L, Hui H, Bertolotto C. Endocrinology. 2002;143: 4 0.5 Control GLP-1 treated Control GLP-1 treated Control GLP-1 treated Farilla et al. Endocrinology. 2002

Summary of the incretin effect
GLP-1 and GIP are the major incretin gut hormones released in response to food ingestion GLP-1 and GIP enhance insulin secretion from β-cells in a glucose-dependent manner GLP-1 suppresses glucagon release from α-cells in a glucose-dependent manner The incretin effect is attributed to intestinal derived factors, GLP-1 and GIP The incretin effect is diminished in Type 2 diabetes GIP is not a therapeutic target: although its levels are normal in Type 2 diabetes, GIP is functionally ineffective Summary of the incretin effect GLP-1 and glucose-dependent insulinotropic peptide (GIP) are the primary incretins released from the gut in response to nutrient digestion. GLP-1 was identified after GIP when researchers discovered that removal of GIP from gut extracts did not eliminate the incretin effect [Drucker, 2006]. Both GLP-1 and GIP exert postprandial glycaemic control by potentiating insulin secretion from β-cells; however, the glucoregulatory properties of GLP-1 are broader than those of GIP. GLP-1 suppresses glucagon release from α-cells which provides both fasting and postprandial glycaemic control [Drucker, 2006; Nauck et al, 1993]. The incretin effect is attributed to GLP-1 and GIP released from the gut, and the loss of glucoregulatory control in Type 2 diabetes is associated with a diminished incretin effect. Incretin therapy is a current focus in the treatment of Type 2 diabetes, although GIP is not a therapeutic target. Even though GIP levels are normal in Type 2 diabetes, GIP is functionally ineffective in Type 2 diabetes in stimulating insulin secretion [Drucker, 2006; Nauck et al, 1986]. REFERENCES Drucker DJ. Cell Metab. 2006;3: Nauck M, Stöckmann R, Ebert R, Creutzfeldt W. Diabetologia. 1986;29:46-52. Nauck MA, Kleine N, Ørskov C, Holst JJ, Willms B, Creutzfeldt W. Diabetologia. 1993;36: GIP=glucose-dependent insulinotropic peptide

β-cell dysfunction Inadequate insulin secretion and glucagon over-secretion The role of incretins in normal physiology Approaches to incretin therapy GLP-1 analogues DPP-4 inhibitors Incretin therapies Key factors contributing to Type 2 diabetes are loss of β-cell function, inadequate insulin secretion, and glucagon over-secretion. Research indicates that incretin therapy can mitigate these factors and that the incretin GLP-1 holds therapeutic promise [Toft-Nielsen et al, 2001]. Current approaches to incretin therapy include the development of molecular analogues of GLP-1 that have a longer bioactive life than natural GLP-1 [Gallwitz, 2006]. Another approach involves extending the bioactive life of natural GLP-1. This includes the identification of compounds that block the action of the enzyme DPP-4, which degrades GLP-1 to inactive forms shortly after its release from the gut [Gallwitz, 2006]. REFERENCES Gallwitz B. Eur Endocr Dis. June 2006:43-46. Toft-Nielsen M, Damholt MB, Madsbad S, et al. J Clin Endocrinol Metab. 2001;86:

Degradation of GLP-1 Enzymatic cleavage of GLP-1 by DPP-4 inactivates GLP-1 DPP-4 GLP-1 30 Des-HA-GLP-1 (inactive) 1 2 Degradation of GLP-1 GLP-1 is a 30 amino acid peptide. This peptide is rapidly degraded by the enzyme DPP-4, present in human serum and universally expressed on endothelial cells. DPP-4 hydrolyses the peptide between alanine in position 2 and the remainder of the amino acid chain. After cleavage, the resulting peptide fragment does not exhibit incretin activity [Gallwitz et al, 1994; Mentlein et al, 1993]. GLP-1 exerts its insulinotropic effects by binding to receptors on β-cells. One approach to improving GLP-1 activity is through the administration of incretin mimetics. These compounds are molecular analogues of GLP-1 which have the ability to activate β-cell receptors but which are structurally different enough to reduce or prevent degradation by DPP-4. A second approach involves the use of incretin enhancers; these prolong the bioactivity of GLP-1 by inhibiting the action of DPP-4 [Drucker 2006; Drucker 2001]. REFERENCES Drucker DJ. Cell Metab. 2006;3: Drucker DJ. Curr Pharm Des. 2001;7: Gallwitz B, Witt M, Paetzold G, et al. Eur J Biochem. 1994;225: Mentlein R, Gallwitz B, Schmidt WE. Eur J Biochem. 1993;214: Two possible solutions to utilize GLP-1 action therapeutically: Long-acting DPP-4-resistant GLP-1 analogues / incretin mimetics DPP-4 inhibitors / incretin enhancers Mentlein et al. Eur J Biochem. 1993; Gallwitz et al. Eur J Biochem. 1994

GLP-1 enhancement Injectables Oral agents
GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: exenatide liraglutide Injectables Block DPP-4, the enzyme that degrades GLP-1: sitagliptin vildagliptin Oral agents GLP-1 enhancement Postprandial plasma levels of GLP-1 are depressed in Type 2 diabetes, indicating an impaired GLP-1 response to nutrient ingestion. For this reason, continuous GLP-1 infusion therapy has proven useful in short-term studies but is not a practical long-term therapy. The effort to identify effective forms of GLP-1 administration is challenged by its extremely short half-life (the enzyme DPP-4 degrades GLP-1 rapidly following its release from gut cells) [Drucker 2006; Drucker 2001]. Much research has focused on compounds with molecular structures and incretin activity that are similar to GLP-1, but which have longer half-lives because they are not degraded by DPP-4 or are resistant to DPP-4. These compounds include exenatide and liraglutide, which are injectable treatments. Another approach is to identify compounds that inhibit the activity of DPP-4, thus prolonging the half-life of naturally occurring GLP-1. Two oral agents that act as DPP-4 inhibitors are sitagliptin and vildagliptin [Gallwitz, 2006]. REFERENCES Drucker DJ. Cell Metab. 2006;3: Drucker DJ. Curr Pharm Des. 2001;7: Gallwitz B. Eur Endocr Dis. June 2006:43-46. Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

Exenatide and first-phase insulin response in Type 2 diabetes
Exenatide vs healthy Exenatide vs placebo P=0.0002 P=0.0029 Time (min) Insulin secretion (pmol•kg-1•min-1) Healthy subjects, placebo Type 2 diabetes, placebo Type 2 diabetes, exenatide Exenatide and first-phase insulin response in Type 2 diabetes Exenatide is a synthetic form of the naturally occurring peptide exendin-4, originally discovered in the salivary glands of the Gila monster. This 39-unit peptide shares a similar amino acid sequence with GLP-1, but unlike GLP-1, it is not degraded by the enzyme DPP-4. The half-life of exenatide is about 3 hours (compared with less than 5 minutes for GLP-1) [Fehse et al, 2005; Gallwitz, 2006; Meier et al, 2004]. One goal of this study was to assess both first- and second-phase insulin response in individuals with Type 2 diabetes (n=13) treated with exenatide or saline infusion compared with weight- and age-matched saline-infused (n=12) healthy individuals. All oral glucose-lowering medications were discontinued prior to the test, and an intravenous glucose bolus was administered to all participants [Fehse et al, 2005]. When an intravenous glucose challenge followed saline infusion, individuals with Type 2 diabetes, in comparison with healthy individuals, exhibited a sharply reduced insulin response in the first 10 minutes (first phase) and during the remainder of the study (second phase). In contrast, when the same individuals were infused with exenatide, their first-phase insulin response was higher compared with saline (P<0.05) and similar to the healthy group. Second-phase insulin response was also increased with exenatide infusion compared with saline infusion in both individuals with Type 2 diabetes and healthy individuals (P<0.001) [Fehse et al, 2005]. These results corroborate our understanding that an underlying cause of hyperglycaemia in Type 2 diabetes is an inadequate first- and second-phase insulin response resulting from reduced β-cell insulin secretion. They also show the promise of exenatide to compensate for this depressed insulin response. REFERENCES Fehse F, Trautmann M, Holst JJ, et al. J Clin Endocrinol Metab. 2005;90: Gallwitz B. Eur Endocr Dis. June 2006:43-46. Meier JJ, Nauck MA, Kranz D, et al. Diabetes. 2004;53: Mean (SE); N=25 Fehse et al. J Clin Endocrinol Metab. 2005

Buse et al. Diabetes Care. 2004 DeFronzo et al. Diabetes Care. 2005
Summary of HbA1c changes with exendin oral agent therapy 30-Week, randomized, placebo-controlled trials Placebo Exendin-4 5 μg Exendin-4 10 μg  HbA1c (%) 0.5 0.23% 0.12% 0.08% 0.0 -0.5 -0.46% -0.40% * -0.55% * * -0.77% -0.86% -1.0 -0.78% * * * Summary of HbA1c changes with exendin-4 + oral agent therapy: 30-week randomized, placebo-controlled trials Traditional sulfonylurea and metformin therapies are useful in controlling hyperglycaemia but do not address the progressive loss of β-cell function in Type 2 diabetes. Sulfonylurea treatment stimulates insulin secretion from remaining functional β-cells, and metformin increases the insulin sensitivity of peripheral tissues. However, the loss of β-cell function over time can diminish or negate these beneficial effects [Gallwitz, 2006]. This slide shows the outcomes of three clinical studies (total n=1446) comparing the effect of sulfonylurea and/or metformin treatment, alone or in combination with twice-daily injections of exendin-4, 5 or 10 μg. These results show the percent change in HbA1c following 30 weeks of treatment [Buse et al, 2004; DeFronzo et al, 2005; Kendall et al, 2005]. All three trials were randomized, blinded, and placebo-controlled and had similar designs, including a 4-week lead-in period during which all participants received subcutaneous injections of placebo twice daily, followed by a 30-week treatment period. Those taking metformin or sulfonylurea were taking the maximally effective dose for at least 3 months before the study began. Values shown are for the intent to treat population [Buse et al, 2004; DeFronzo et al, 2005; Kendall et al, 2005]. In all three trials, significant improvements in baseline HbA1c were observed with the 5- and 10-μg doses of exendin-4 compared with placebo (P<0.01) [Buse et al, 2004; DeFronzo et al, 2005; Kendall et al, 2005]. The incidence of serious treatment-emergent adverse events was low in all trials and similar between exendin-4 and placebo groups. The most frequent adverse event associated with exendin-4 was nausea. In both trials that included sulfonylurea treatment, the incidence of mild-to moderate hypoglycaemia increased with exendin-4 compared with placebo [Buse et al, 2004; DeFronzo et al, 2005; Kendall et al, 2005]. REFERENCES Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, for the Exenatide-113 Clinical Study Group. Diabetes Care. 2004;27: DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Diabetes Care. 2005;28: Gallwitz B. Eur Endocr Dis. June 2006:43-46. Kendall DM, Riddle MC, Rosenstock J, et al. Diabetes Care. 2005;28: -1.5 Exendin-4 + SU (n=377) Exendin-4 + Met (n=336) Exendin-4 + SU + Met (n=733) *P<0.01 vs placebo Met=metformin; SU=sulfonylurea Buse et al. Diabetes Care. 2004 DeFronzo et al. Diabetes Care. 2005 Kendall et al. Diabetes Care. 2005

Changes in body weight over time with exenatide
Placebo  μg exenatide bd 5 μg bd  μg exenatide bd 10 μg bd  μg exenatide bd Placebo-Controlled Trials -1 Open-Label Extension (All subjects: 10 μg bd) -2 Mean weight change (kg ± SEM) -3 Changes in body weight over time with exenatide This graph shows changes in body weight observed during the clinical and open-label extension trials of exenatide evaluated in combination with metformin. Prior to the start of the study, all participants were taking the maximally effective dose of metformin. For the first 30 weeks of the study, participants were assigned to continue metformin monotherapy or metformin plus exenatide 5 or 10 μg twice daily. After week 30, all those who elected to continue received metformin plus exenatide 5 μg twice daily for 4 weeks and then 10-μg exenatide twice daily through week 82 [DeFronzo et al, 2005; Ratner et al, 2006]. A steady decline in body weight was observed on both exenatide doses for the first 30 weeks of the study. Compared with placebo (-0.3 kg), body weight loss on exenatide was -1.6 kg (P<0.05) for exenatide 5 μg twice daily and -2.8 kg for exenatide 10 μg twice daily (P<0.001) [DeFronzo et al, 2005]. Following week 30, when all participants received exenatide, a progressive mean reduction in body weight was observed throughout the remainder of the study [Ratner et al, 2006]. Nausea was the most frequent serious adverse event; it was observed more frequently in both exenatide treatments compared with placebo. However, there was no correlation between change in body weight and nausea duration during the first 30 weeks of the study, and the participants treated with exenatide who did not experience nausea also lost weight [DeFronzo et al, 2005]. The incidence of nausea declined over the course of the trial, but the reduction in body weight was progressive [Ratner et al, 2006]. REFERENCES DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Diabetes Care. 2005;28: Ratner RE, Maggs D, Nielsen LL, et al. Diabetes Obes Metab. 2006;8: -4 -5 10 20 30 40 50 60 70 80 90 Time (week) N=92; completer cohort; 82-week data; weight change was a secondary endpoint. Baseline weight: placebo=98 kg, 5 μg=98 kg, 10 μg=100 kg. Ratner et al. Diabetes Obes Metab. 2006; Data on file, Amylin Pharmaceuticals, Inc.

Incidence of nausea with exenatide in large phase 3 clinical studies
5 10 15 20 25 30 35 0-4 >4-8 >8-12 >12-16 >16-20 >20-24 >24-28 >28 Time (week) % Incidence of nausea Placebo 5-μg exenatide bd 10-μg exenatide bd Dose increased from 5 μg to 10 μg at week 4 Incidence of nausea with exenatide in large phase 3 clinical studies This chart shows the combined incidence of nausea from three efficacy trials that evaluated exenatide added to metformin and/or sulfonylurea therapy. In all trials, the most frequent adverse event was nausea, with a higher and dose-dependent incidence observed in the exenatide-treated group compared with placebo (44% vs 18%) [Byetta PI]. This nausea was generally mild to moderate in nature and, compared with later weeks of the trials, was reported at a higher rate in the first 8 weeks of exenatide treatment [Buse et al, 2004; Byetta PI; DeFronzo et al, 2005; Kendall et al, 2005]. The incidence of withdrawal due to nausea was 3% for the exenatide-treated group compared with <1% for placebo. Because exenatide has not been studied in people with severe gastrointestinal disease (including gastroparesis), it is not recommended for use by these individuals [Byetta PI]. REFERENCES Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, for the Exenatide-113 Clinical Study Group. Diabetes Care. 2004;27: Byetta prescribing information. Available at: Accessed January 7, 2007. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Diabetes Care. 2005;28: Kendall DM, Riddle MC, Rosenstock J, et al. Diabetes Care. 2005;28: Intent-to-treat 30-week data; N=1446 Data on file, Amylin Pharmaceuticals, Inc

Liraglutide: -cell function in Type 2 diabetes
50 * P<0.0001 40 * 30 * Mean change in β-cell function (HOMA, %) 20 10 Liraglutide: ß-cell function in type 2 diabetes Liraglutide is a long-acting GLP-1 analogue. The primary objective of this study was to evaluate the effect of liraglutide as monotherapy or as add-on therapy to metformin on several glycaemic parameters including β-cell function (estimated by the HOMA method). Individuals diagnosed with Type 2 diabetes for at least 1 year (HbA1c 8%-13%) started or maintained metformin 1000 mg twice daily for 2 weeks prior to the start of the experiment. Baseline data were collected at the start of the 5-week double-blind experiment when patients were randomized to one of four treatments: liraglutide monotherapy, metformin monotherapy, liraglutide plus metformin, or metformin plus the sulfonylurea glimepiride. The liraglutide dose was increased weekly from 0.5 mg up to 2.0 mg injected once daily. This chart shows the percent improvement in β-cell function after 5 weeks of treatment compared with baseline. The largest improvement was noted with the combination of liraglutide plus metformin followed by liraglutide monotherapy. Since loss of β-cell function is a key factor in the progression of Type 2 diabetes, these results indicate that the GLP-1 analogue liraglutide may reduce or prevent disease progression. REFERENCE Nauck MA, Hompesch M, Filipczak R, Le TDT, Zdravkovic M, Gumprecht J. Exp Clin Endocrinol Diabetes. 2006;114: -10 P<0.0001 Liraglutide (n=36) Liraglutide + metformin (n=36) Metformin (n=36) Metformin + glimepiride (n=36) *P< vs baseline Nauck et al. Diabetes Nauck et al. Exp Clin Endocrinol Diabetes. 2006

Diagram of how DPP-4 inhibition might be expected to improve blood glucose control
Increase insulin secretion Decrease glucagon release Increase insulin secretion Decrease glucagon release Active GLP-1 Active GLP-1 DPP-4 DPP-4 inhibitor X Glucose control improved Inactive GLP-1 Inactive GLP-1 Glucose control Diagram of how DPP-4 inhibition might be expected to improve blood glucose control DPP-4 is an enzyme that inactivates GLP-1 by cleaving it into peptide fragments that lack GLP-1 activity. GLP-1 is rapidly degraded by DPP-4 following release from the gut. The next section of this slide kit will discuss therapeutic approaches to Type 2 diabetes that potentiate DPP-4 inhibition. REFERENCE Drucker DJ. Curr Pharm Des. 2001;7:

Sitagliptin improves both fasting and post-meal glucose in monotherapy vs placebo
Fasting Glucose Post-meal Glucose  FPG* = -1.0 mmol/l (P<0.001) in 2-hr PPG* = -2.6 mmol/l (P<0.001) 16 10.5 10.0 14 9.5 Plasma glucose (mmol/l) Plasma glucose (mmol/l) 12 9.0 Baseline Baseline Sitagliptin improves both fasting and post-meal glucose in monotherapy vs placebo Sitagliptin is an orally administered GLP-1-enhancing agent that is a highly selective inhibitor of the enzyme DPP-4 and has minimal inhibitory effects on other enzymes in the DPP family of enzymes. The first graph on this slide shows the results of a large-scale efficacy trial of sitagliptin monotherapy in individuals with Type 2 diabetes. The design included a 2-week placebo baseline period followed by a 24-week treatment that compared sitagliptin 100 mg once daily with placebo. No other oral glucose-lowering agents were used. Fasting plasma glucose decreased rapidly with sitagliptin compared with placebo (net decrease mmol/l [-17.1 mg/dl], P<0.001). Meal tolerance tests were conducted both at baseline and following 24 weeks of sitagliptin treatment. The difference in post-meal glucose response compared with baseline in shown in the second graph. Sitagliptin treatment substantially reduced glucose at 1 and 2 hours post-meal (net decrease -2.6 mmol/l [-46.7 mg/dl], P<0.001). These results indicate that sitagliptin monotherapy improves glucose control in both the fasting and postprandial state. REFERENCE Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, for the Sitagliptin Study 021 Group. Diabetes Care. 2006;29: 24 weeks 24 weeks 10 8.5 Placebo (n=247) Sitagliptin 100 mg (n=234) Placebo (n=204) Sitagliptin (n=201) 8.0 8 3 6 12 18 24 60 120 60 120 Time (weeks) Time (minutes) *Least-squares (LS) mean difference from placebo after 24 weeks Aschner et al. Diabetes Care. 2006

Sitagliptin improves the β-cell response to glucose: monotherapy studies
Pooled Monotherapy Studies – Subset With Frequently Sampled MTT Model-based assessment of β-cell function 1400 Sitagliptin 100 mg od Placebo Baseline Baseline 1200 End-Treatment End-Treatment 1000 Insulin secretion (pmol/min) 800 600 Sitagliptin improves the β-cell response to glucose: monotherapy studies A subset of people from the sitagliptin monotherapy trial underwent meal tolerance tests at baseline (placebo treatment) and following 12 and 24 weeks of treatment with sitagliptin 100 mg once daily or placebo. This graph shows the relationship between mean insulin secretion rate and blood glucose concentrations; this is a commonly used method to estimate β-cell function [Aschner et al, 2006; Stein, 2006]. Following 24 weeks of sitagliptin treatment, the β-cell secretory response to glucose was significantly higher compared with the response in the placebo group [Aschner et al, 2006]. These results indicate that improved glucose control with sitagliptin may be mediated, in part, by its positive effect on β-cell function. REFERENCES Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, for the Sitagliptin Study 021 Group. Diabetes Care. 2006;29: Stein P. Late-breaking clinical presentation at: American Diabetes Association 66th Annual Scientific Sessions; June 10-14, 2006; Washington, DC. 400 200 9 10 11 12 13 14 Glucose concentration (mmol/l) MTT=meal tolerance test Aschner et al. Diabetes Care. 2006; Stein. ADA Late-breaking clinical presentation

Sitagliptin added to metformin improves 24-hour glucose profile in Type 2 diabetes
Placebo + metformin (n=13) Sitagliptin 50 mg bd + metformin (n=15) Breakfast Lunch Dinner 13 Dose 1 7:30 Dose 2 18:30 Difference in 24-hour mean glucose: -1.8 mmol/l (-32.8 mg/dl), P<0.001 12 11 10 Glucose (mmol/l) 9 8 Sitagliptin added to metformin improves 24-hour glucose profile in Type 2 diabetes This study evaluated the efficacy of sitagliptin in combination with metformin in individuals whose hyperglycaemia was inadequately controlled by metformin alone. It has been posited that adding sitagliptin to metformin therapy may enhance glucose control by combining metformin’s insulin-sensitising effect with sitagliptin’s GLP-1 enhancement [Brazg et al, 2007; Gallwitz, 2006]. Study participants were treated with metformin plus placebo or sitagliptin 50 mg twice daily during a 4-week period; at the close of the study, each participant’s 24-hour glucose profile was measured [Brazg et al, 2007]. Sitaglitpin combined with metformin produced substantially lower glucose concentrations in both the postprandial and fasting states compared with metformin montherapy. The decrease in 24-hour mean glucose for the sitagliptin-treated group compared with metformin monotherapy was -1.8 mmol/l (-32.8 mg/dl) (P<0.001) [Brazg et al, 2007]. These results demonstrate that the addition of sitagliptin to metformin improves glycaemic control compared with metformin monotherapy. REFERENCES Brazg R, Xu L, Dalla Man C, Cobelli C, Thomas K, Stein PP. Diabetes Obes Metab. 2007;9: Gallwitz B. Eur Endocr Dis. June 2006:43-46. 7 6 8:00 Day 1 13:00 19:00 0:00 Day 2 7:30 Time Brazg et al. Diabetes Obes Metab. 2007

Sitagliptin once daily lowers HbA1c when added to metformin or pioglitazone
Add-on to Metformin Study Add-on to Pioglitazone Study  in HbA1c vs Pbo* = -0.65% (P<0.001)  in HbA1c vs Pbo* = -0.70% (P<0.001) 8.2 Placebo (n=174) Sitagliptin 100 mg (n=163) 7.0 7.2 7.4 7.6 7.8 8.0 8.2 6 12 18 24 Time (weeks) HbA 1c (%) 8.0 7.8 (%) 1c 7.6 HbA 7.4 Sitagliptin once daily lowers HbA1c when added to metformin or pioglitazone Metformin and pioglitazone improve glycemic control by increasing insulin sensitivity in peripheral tissues [AHFS Drug Information, 2004; Gallwitz, 2006]. These large-scale efficacy trials tested the effect of sitagliptin 100 mg once daily added to metformin or pioglitazone in individuals with a mean HbA1c of ~8.0 % [Charbonnel et al, 2006; Rosenstock et al, 2006]. The first graph illustrates the rapid and progressive HbA1c response to sitagliptin added to metformin. The addition of sitagliptin decreased HbA1c by -0.65% (P<0.001) over the 24-week treatment period [Charbonnel et al, 2006]. Likewise, the response to sitagliptin when added to pioglitazone monotherapy was rapid and progressive, with a net HbA1c reduction of -0.70% (P<0.001) over the 24-week treatment period [Rosenstock et al, 2006]. These results indicate that the addition of sitagliptin improves glycaemic control in individuals whose hyperglycaemia is inadequately controlled by metformin or pioglitazone monotherapy. REFERENCES American Hospital Formulary Service Drug Information Available at Accessed December 28, 2006. Gallwitz B. Eur Endocr Dis. June 2006:43-46. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, for the Sitagliptin Study 020 Group. Diabetes Care. 2006;29: Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, for the Sitagliptin Study 019 Group. Clin Ther. 2006;28: 7.2 Placebo (n=224) Sitagliptin 100 mg (n=453) 7.0 6 12 18 24 Time (weeks) *Placebo-subtracted difference in LS means Charbonnel et al. Diabetes Care. 2006; Rosenstock et al. Clin Ther. 2006

Safety and tolerability profile: once-daily sitagliptin vs glipizide
 between groups = –2.5 kg (P<0.001) Change in body weight 86 88 90 92 94 12 24 38 52 Time (weeks) Body weight (kg) Sitagliptin 100 mg (n=382) Glipizide (n=411) 4.9% 32% 10 20 30 40 50 Hypoglycaemia P<0.001 Week 52 Incidence (%) Glipizide (n=584) Sitagliptin 100 mg (n=588) Safety and tolerability profile: once-daily sitagliptin vs glipizide This 52-week, randomized, parallel-group study compared the efficacy and safety of sitagliptin (100 mg once daily, n=588) with glipizide (5-20 mg/day, n=584) in individuals with Type 2 diabetes inadequately controlled with metformin monotherapy. The addition of sitagliptin or glipizide to metformin provided similar reductions in HbA1c at 52 weeks (-0.67 % change from baseline HbA1c of 7.5 %). At 52 weeks, relative to baseline, sitagliptin-treated individuals had significant weight loss and glipizide-treated individuals had significant weight gain, with a between-group difference of -2.5 kg (P<0.001). The incidence of hypoglycaemia was significantly higher with glipizide than with sitagliptin. In the glipizide-treated group, 187 (32.0%) individuals reported 657 episodes of hypoglycaemia; in the sitagliptin-treated group, 29 (4.9%) individuals reported 50 episodes (P<0.001). These results indicate that the addition of sitagliptin to patients inadequately controlled on metformin monotherapy improves glycaemic control without the higher risk of hypoglycaemia and weight gain associated with glipizide. REFERENCE Nauck MA, Meininger G, Sheng D, Terranella L, and Stein PP for the Sitagliptin Study 024 Group. Diabetes Obes Metab. 2007;9: Stein. ADA Late-breaking clinical presentation; Nauck et al. Diabetes Obes Metab. 2007

Sustained reduction in HbA1c during 1-year treatment with vildagliptin in Type 2 diabetes
9.5 9.0 Vildagliptin Metformin 8.5 Mean HbA1c (%) 8.0 7.5 7.0 Sustained reduction in HbA1c during 1-year treatment with vildagliptin in Type 2 diabetes Vildagliptin is an orally administered GLP-1-enhancing agent that selectively inhibits the action of DPP-4, the enzyme responsible for GLP-1 inactivation [Mari et al, 2005]. This study compared the efficacy of vildagliptin 100 mg (50 mg twice daily, n=526) with metformin 2000 mg (1000 mg twice daily, n=254) in drug-naive individuals with Type 2 diabetes [Dejager et al, 2006]. This graph shows the results of the 4-week baseline period (no treatment applied) followed by a 52-week treatment period with either metformin or vildagliptin. A rapid and sustained decrease in HbA1c was apparent in both groups. The overall decrease in HbA1c from baseline was -1.0% and -1.4% for vildagliptin and metformin, respectively [Dejager et al, 2006]. The results demonstrate that substantial and sustained reductions in HbA1c can be achieved with either vildagliptin or metformin monotherapy in drug-naive individuals with Type 2 diabetes. REFERENCES Dejager S, Lebeaut A, Couturier A, Schweizer A. Paper presented at: American Diabetes Association 66th Annual Scientific Sessions; June 9-13, 2006; Washington, DC. Abstract 120-OR. Mari A, Sallas WM, He YL, et al. J Clin Endocrinol Metab. 2005;90: 6.5 -4 4 8 12 16 20 24 28 32 36 40 44 48 52 Time (wk) Dejager et al. ADA Abstract 120-OR

Vildagliptin added to metformin improves glycaemic control
Vildagliptin 50 mg od & metformin Vildagliptin 50 mg bd & metformin Placebo & metformin 11.0 8.5 10.0 8.0 HbA1c (%) FPG (mmol/l) Vildagliptin added to metformin improves glycaemic control This study compared the efficacy of two doses of vildagliptin (50 mg once daily and 50 mg twice daily) added to metformin with metformin plus placebo (n=416). Prior to the start of this study, all participants had received a stable daily metformin dose of ~2000 mg/day over a period of 17 months. A rapid and sustained improvement in HbA1c was observed in participants receiving either dose of vildagliptin compared with those receiving metformin plus placebo. The mean observed HbA1c reduction for vildagliptin compared with metformin was -0.7% (50 mg once daily) and 1.1% (50 mg twice daily) (P<0.001 for both vs placebo). FPG also decreased by 0.8 mmol/l and 1.7 mmol/l with vildagliptin 50 mg once and twice daily, respectively, compared with metformin plus placebo (P<0.01). These results indicate that the addition of vildagliptin to metformin improves glycaemic control in individuals with Type 2 diabetes with previous exposure to metformin. REFERENCE Garber A, Camisasca RP, Ehrsam E, Collober-Maugeais C, Rochotte E, Lebeaut A. Paper presented at: American Diabetes Association 66th Annual Scientific Sessions; June 10-14, 2006; Washington, DC. Abstract 121-OR. 9.0 7.5 7.0 8.0 -8 -4 4 8 12 16 20 24 -8 -4 4 8 12 16 20 24 Time (weeks) Time (weeks) Garber et al. ADA Abstract 121-OR

Vildagliptin added to insulin improves HbA1c
9.0 Vildagliptin 50 mg + insulin Vildagliptin 50 mg bd + insulin Pbo + insulin 8.5 ∆ HbA1c -0.4 ± 0.1, P=0.001 Mean HbA1c (%) 8.0 Vildagliptin added to insulin improves HbA1c This 60-week study evaluated the effect of vildagliptin in individuals with insulin-requiring Type 2 diabetes. The experiment consisted of three distinct periods. In the first 8-week period (baseline), all participants received only insulin therapy. During the 24-week core study period, participants received either 50-mg vildagliptin twice daily added to insulin therapy (n=125) or continued insulin monotherapy (n=131). For the 28-week extension period, 96 participants continued with vildagliptin plus insulin therapy, and 104 participants formerly allocated to insulin monotherapy switched to vildagliptin 50 mg once daily plus insulin. During the core study period, vildagliptin 50 mg twice daily plus insulin decreased HbA1c from baseline by -0.5% compared with -0.2% in participants treated with insulin alone (P <0.05). Participants who later switched from insulin monotherapy to vildagliptin 50 mg once daily plus insulin experienced a prompt and sustained -0.4% decrease in HbA1c over the 28-week study extension period compared with week 24 (P <0.001). Participants continuing to take the same vildagliptin plus insulin therapy throughout the extension period sustained the HbA1c improvements noted during the first 24 weeks of the study. These results demonstrate the efficacy of vildagliptin added to insulin in the management of people with Type 2 diabetes with more advanced islet β-cell deficiency. REFERENCE Fonseca V, Dejager S, Albrecht D, Shao Q, Schweizer A. Paper presented at: 42nd EASD Annual Meeting; September 14-17, 2006; Copenhagen, Denmark, and Malmo, Sweden. Abstract PS 62: 0802. 7.5 7.0 Time (weeks) Fonseca et al. EASD Abstract PS 62: 0802

Effect of vildagliptin on the day-time plasma glucagon profile
(ng/l) 125 100 Day 0 75 Day 28 Effect of vildagliptin on the day-time plasma glucagon profile This study assessed the effect of vildagliptin on a variety of predictors of glycaemic control, including glucagon, in individuals not previously treated with oral glucose-lowering agents. Three post-meal tests were conducted on day 0 prior to randomization to vildagliptin (100 mg twice daily, n=9) or placebo (n=11) and following 1 and 28 days of treatment. Glucagon levels tended to be lower after 28 days of vildagliptin treatment compared with pretreatment baseline. However, this change was not significantly different from placebo. These results suggest that one of the mechanisms by which vildagliptin improves glycaemic control may be associated with reduced glucagon levels. REFERENCE Mari A, Sallas WM, He YL, et al. J Clin Endocrinol Metab. 2005;90: 50 0700 1100 1700 2100 Time (h) Mari et al. J Clin Endocrinol Metab. 2005

Effect of vildagliptin and rosiglitazone monotherapy on body weight
3.0 2.5 1.6 1.7 2.0 1.5 Mean weight change from baseline (kg) 1.0 0.5 0.0 -0.5 Effect of vildagliptin and rosiglitazone monotherapy on body weight This 24-week, double-blind, randomized, parallel-group trial compared monotherapy with vildagliptin (100 mg daily, n=519) with rosiglitazone (8 mg daily, n=267) in drug-naive individuals with Type 2 diabetes. Mean baseline BMI was 32.2  5.7 kg/m2 in the vildagliptin-treated group and 32.9  6.0 kg/m2 in the rosiglitazone-treated group. By the end of the study period, both treatments had significantly reduced HbA1c to a similar extent. Significant reductions in FPG from baseline were observed with both treatments, although FPG decreased more with rosiglitazone (-2.3 mmol/l [-41.4 mg/dl]) than with vildagliptin (-1.3 mmol/l [-23.4 mg/dl]). In the overall cohort, body weight did not change in the vildagliptin-treated group (-0.3 kg) from baseline but increased significantly with rosiglitazone (+1.6 kg) (P<0.001 vs vildagliptin). In the more severely obese individuals (BMI 35 kg/m2), a larger decrease in body weight was seen with vildagliptin (-1.1 kg) whereas the weight gain with rosiglitazone (+1.7 kg) was similar to the overall cohort. These results suggest that vildagliptin may be a treatment to consider in Type 2 diabetes when body weight is a concern. REFERENCE Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Diabetes Care. 2007;30: -1.0 -0.3 -1.5 -1.1 -2.0 Primary ITT population BMI ≥35 kg/m2 subgroup n= Vildagliptin 100 mg od Rosiglitazone 8 mg od Rosenstock et al. Diabetes Care. 2007

Incretin mimetics and DPP-4 inhibitors: major differences
Properties/effect Incretin mimetics DPP-4 inhibitors Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect Yes Unknown Restitution of insulin secretion (2 phases) Yes (exenatide) Hypoglycaemia No Maintained counter-regulation by glucagon in hypoglycaemia Not tested Inhibition of gastric emptying Marginal Effect on body weight Weight loss Weight neutral Side effects Nausea None observed Administration Subcutaneous Oral Incretin mimetics and DPP-4 inhibitors: major differences Incretin mimetics and DPP-4 inhibitors improve glycaemic control in Type 2 diabetes; however, their mechanisms of action and associated side effects are somewhat different [Gallwitz, 2006]. Incretin mimetics are molecular analogues of GLP-1. Their stimulatory influence on glucose-dependent insulin secretion is exclusively a function of their action on GLP-1 receptors. It has been posited that the effect of DPP-4 inhibitors on insulin secretion may be broader because DPP-4 is involved in the degradation of many peptide hormones, including GIP and pituitary adenylate cyclase-activating polypeptide (PACAP), which also potentiate glucose-dependent insulin secretion [Ahren et al, 2005; Drucker, 2006; Gallwitz, 2006; Jamen et al, 2002]. Restoration of first- and second-phase insulin response has been demonstrated with both exenatide and DPP-4 inhibitors. When used as monotherapy, incretin mimetics and DPP-4 inhibitors do not increase the incidence of hypoglycaemia. Counter-regulation of hypoglycaemia by glucagon is maintained with incretin mimetics; however, this has not been adequately tested with DPP-4 inhibitors [Gallwitz, 2006]. Incretin mimetics may exert a portion of their glucoregulatory control through the inhibition of gastric emptying (which slows the rate of nutrient absorption and, thus, the need for insulin secretion). Weight loss has been observed in clinical trials with incretin mimetics, while DPP-4 inhibitors have been weight neutral in clinical trials [Drucker, 2001; Gallwitz, 2006], and some of the effect of incretin mimetics on HbA1c levels may be due to the weight loss. Like GLP-1, incretin mimetics are peptides and, thus, must be administered by daily injection (although longer-acting formulations are being developed). DPP-4 inhibitors are orally active [Gallwitz, 2006]. Testing of incretin mimetics and DPP-4 inhibitors has been limited to trials that typically lasted 1 year or less. The long term effects of incretin mimetics and DPP-4 inhibitors will need to be followed in clinical practice [Gallwitz, 2006]. REFERENCES Ahrén B, Hughes TE. Endocrinology. 2005;146: Drucker DJ. Curr Pharm Des. 2001;7: Drucker DJ. Cell Metab. 2006;3: Gallwitz B. Eur Endocr Dis. June 2006:43-46. Jamen F, Puech R, Bockaert J, Brabet P, Bertrand G. Endocrinology. 2002;143: Gallwitz. Eur Endocr Dis. 2006

Sulfonylureas Reduce fasting and PPG should be initiated at low doses

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Sulfonylureas Reduce fasting and PPG should be initiated at low doses

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Presentation on theme: "Sulfonylureas Reduce fasting and PPG should be initiated at low doses"— Presentation transcript:

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