An Update on Oral Hypoglycemic Agents -...
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An Update on Oral Hypoglycemic Agents Dr Foo Joo Pin Consultant Endocrinologist Specialist Endocrine Clinic For Diabetes, Thyroid and Hormones CAMDEN MEDICAL CENTRE
Transcript of An Update on Oral Hypoglycemic Agents -...
An Update on Oral Hypoglycemic Agents
Dr Foo Joo Pin Consultant Endocrinologist
Specialist Endocrine Clinic
For Diabetes, Thyroid and Hormones CAMDEN MEDICAL CENTRE
Scope
• Oral Agents
– Old – New
• Insulin Therapy
Pathogenesis of Type 2 Diabetes
HGP=hepatic glucose production.
Islet β-cell
Impaired Insulin Secretion
Increased HGP
Decreased Glucose Uptake
Increased Insulin Resistance
The Ominous Octet
Islet β-cell
Impaired Insulin Secretion
Neurotransmitter Dysfunction
Decreased Glucose Uptake
Islet α-cell
Increased Glucagon Secretion
Increased Lipolysis
Increased Glucose Reabsorption
Increased HGP
Decreased Incretin Effect
Diabetes Medications
1960 1995 2000 2005 2010
Insulin 1922
SUs 1946 / Metformin
1957
AGIs 1995
Glinides TZDs 1997
GLP1-A Exenatide Pramlintide
2005
DPP4-I Sitagliptin
2006
Liraglutide 2010
Patlak M. Breakthroughs in Bioscience 2002. http://www.faseb.org/Portals/0/PDFs/opa/diabetes.pdf Philippe J. Int J Clin Pract 2009;63:321-332
Saxagliptin 2009
SGLT2-I? Jan 2012
β-Cell Function Continues to Decline Regardless of Intervention in T2DM
T2DM=type 2 diabetes mellitus *β-cell function measured by homeostasis model assessment (HOMA) Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.
0
20
40
60
80
100
–5 –4 –3 –2 –1 0 1 2 3 4 5 6
Years Since Diagnosis
β-C
ell F
unct
ion
(%)*
Progressive loss of β-cell function occurs prior to diagnosis
Metformin (n=159)
Diet (n=110)
Sulfonylurea (n=511)
Presenter
Presentation Notes
β-Cell Function Continues to Decline Regardless of Intervention in T2DM Data from the UK Prospective Diabetes Study (UKPDS) 16 indicate that β-cell function declines over time regardless of therapy.1 This randomized controlled trial was designed to determine whether specific therapies carry certain advantages or disadvantages. Subjects comprised 4209 newly diagnosed type 2 diabetes mellitus (T2DM) patients who, after 3 months of diet therapy, were asymptomatic and had fasting plasma glucose (FPG) levels of 6.0–15.0 mmol/L. The study consisted of two main comparisons: (1) obese and nonobese patients allocated to conventional therapy (primarily with diet) or intensive therapy (with additional sulfonlyurea or insulin); (2) obese patients assigned to conventional therapy or to intensive therapy (with metformin, sulfonylurea or insulin). The data presented on this slide were derived from a subset of patients in the second comparison still on their initial therapy at 6 years—metformin (n=159, blue circles), a sulfonylurea (n=511, yellow squares), or diet (n=110, white triangles). Indeed, these data can be extrapolated to show that the progressive loss of β-cell function (dashed line) begins years before a diagnosis of T2DM is made. For all patients, β-cell function was assessed with homeostasis model assessment (HOMA), a mathematical formula that uses the fasting insulin and glucose measurements to assess the degree of β-cell function (and insulin resistance) that would account for a given person’s set of fasting insulin and glucose levels. Reference UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995; 44: 1249–1258.
Case 1
• 54 year old male, BMI: 28 • Hypertension, hyperlipidemia • No history of cardiovascular event • Routine health screen
– FPG 8.6 mmol/L – OGTT: 2hr glucose 14.4 mmol/L
• HbA1c: 8.5% • Liver, renal function normal • What will you do?
Nathan et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm. Diabetes Care 2006; 31:173-5.
Biguanides
• Metformin, Metformin XR (500-1000 g ON) • Reduce hepatic gluconeogenesis – activate Adenosine
Monophosphate protein Kinase (intracellular energy sensor)
• Increased insulin-mediated muscle glucose uptake
• Decrease fatty acid oxidation – reduce energy supply for gluconeogenesis
• Non-glycemic effect – loss of appetite, lower fasting hyperinsulinemia, facilitate weight loss
• Possibly best OHGA for CV risk reduction – Selvin E, Bolen S, Hsin-Chieh Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes
medications: A systematic review. Arch Intern Med. 2008;168:2070-2080.
Biguanides - Metformin
• Risk of Lactic Acidosis < 1 per 100000 (Very rare)
• Caution in Renal Failure
– CCT of < 30 ml/min/1.73 m – contraindicated – CCT of 30-60 ml/min/1.73m – use with caution – CCT of > 60 ml/min/1.73m – safe Establishing pragmatic estimated GFR thresholds to guide metformin prescribing.Shaw JS; Wilmot
RL; Kilpatrick ES Diabet Med. 2007 Oct;24(10):1160-3. Epub 2007 Aug 2.
Other Oral Agents
• Sulphonyureas • Glinides • Αlpha-glucosidase Inhibitors • TZDs • DPP IV Inhibitors • (GLP-1 Agonist) • SGLT2 Inhibitor
Sulfonylureas
• Tolbutamide, glipizide, gliclazide, glimepiride, glibenclamide
• ATP-sensitive potassium channel in plasma membrane of β-cell • SUR, Kir6.2
• Activation closes K channels → depolarization of β-cell → Ca++ influx
which promotes insulin release
• Potency of a sulfonylurea is a function of its binding affinity to the receptor: glibenclamide the most potent, tolbutamide the least
• Side Effects: hypoglycemia, weight gain
Sulfonylureas
Glinides
• Repaglinide, Nateglinide
• Stimulate insulin secretion • bind to a different site within the sulfonylurea receptor (SUR1 subunit)
• Shorter circulating half-life than sulfonylureas
• Must be administered more frequently:
– 15 mins before each meal
• Weight gain, hypoglycemia – incidence somewhat lower than sulphonylureas
Alpha Glucosidase Inhibitor
• Acarbose, miglitol, voglibose
• Competitive inhibitors of small intestine brush border enzymes alpha-glucosidases -hydrolyze oligosaccharides and polysaccharides to monosaccharides
• Carbohydrate absorption and digestion are delayed and prolonged throughout the small intestine
• Reduction of the postprandial plasma glucose elevation in both type 1 and type 2 diabetes mellitus
• Glucose lowering effect modest
• GI Side effects
TZDs
Thiazolidinediones
• Side Effects: weight gain and fluid retention, with peripheral edema and a twofold increased risk for congestive heart failure, hepatotoxicity (troglitazone)
• Increased fracture risk
– Meier C, Kraenzlin ME, Bodmer M, et al.:Use of thiazolidinediones and fracture risk. Arch Intern Med 168:820–825, 2008
• Risk of Cardiovascular death
– Nissen SE, Wolski K: Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471, 2007
Pioglitazone and Bladder Ca
• Preclinical : bladder Ca in rats • PROactive trial : 14 vs 5 cases in pioglit • Using FDA adverse event reporting : risk of
bladder Ca higher with piog users HR 1.22 (1.05-1.43) in French Study
• June 2011 France and Germany suspend use
• EMA’s Committee for Medicinal Products : benefits outweigh risk and piog continues to be valid option for treating certain T2DM Lancet 378:1543-1545, Nov 2011
Incretin based Therapy
Nauck et al. Diabetologia. 1986
Incretin effect on insulin secretion
Oral glucose load Intravenous glucose infusion
Time (min) In
sulin
(mU
/l)
80
60
40
20
0 180 60 120 0
Time (min)
Insu
lin (m
U/l)
80
60
40
20
0 180 60 120 0
Incretin effect
Control subjects (n=8) People with Type 2 diabetes (n=14)
GLP-1: effects in humans
GLP-1 is secreted from L-cells of the jejunum
and ileum
That in turn…
• Stimulates glucose- dependent insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
Long-term effects in animal models:
• Increase of β-cell mass and improved β-cell function
• Improves insulin sensitivity
• Leads to a reduction of food intake
After food ingestion…
Drucker. Curr Pharm Des. 2001 Drucker. Mol Endocrinol. 2003
Inhibition of DPP-4 Increases Active GLP-1
GLP-1 inactive
(>80% of pool)
Active GLP-1
Meal
DPP-4
Intestinal GLP-1 release
GLP-1 t½=1–2 min
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1 Adapted from Rothenberg P, et al. Diabetes. 2000; 49(suppl 1): A39. Abstract 160-OR. Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126-1131.
Presenter
Presentation Notes
Inhibition of DPP-4 Increases Active GLP-1 Released by intestinal L-cells in response to ingested food (upper left), glucagon-like peptide-1 (GLP-1) is rapidly and extensively inactivated (lower right).1 The active amide is rapidly attacked at its N-terminus by dipeptidyl peptidase-4 (DPP-4), leaving the inactive metabolite GLP-1(9–36) and giving the active amide a half-life of only 1–2 minutes.2 Since DPP-4 is the only enzyme that can inactivate GLP-1, it was hypothesized that inhibition of DPP-4 may preserve intact (active) GLP-1 and improve metabolic control in treatment of T2DM. In an early study with DPP-4 inhibitor NVP-DPP728 12 healthy subjects fasted overnight and then ate a standardized breakfast 30 minutes after receiving single oral doses of placebo or the active drug.3 The active drug increased the subjects’ plasma levels of prandial active GLP-1, with concomitant reduction in prandial glucose exposure. These findings, reported in year 2000, were the first to provide direct evidence that inhibition of DPP-4 could be a viable pharmacologic approach for potentiating the activity of endogenous GLP-1 in humans.3
Newer Agents - Incretin DPP4 inhibitors (PO) GLP 1 – Agonist (SC)
Sitagliptan (Januvia®), Merck & Co, 2006 FDA
Vildagliptan (Galvus®), Novartis, 2008 EU
Saxagliptin (Onglyza®), Bristol Myers, 2009 FDA
Linagliptan (Tradjenta®) Eli Lilly, 2011 FDA
Dutogliptin, Phenomix Corp, Phase III
Gemigliptin, LG Life Sciences, Korea
Alogliptin, Takeda, FDA susp
Exenatide (Byetta®), Eli Lilly, 2005
Liraglutide (Victoza®), Novo Nordisk, 2010
Exenatide LAR, Phase III
Taspoglutide, Ispen and Roche, Phase III (Sept 10 : halted due to serious hypersensit and GI)
Alibiglutide, GSK, Phase III
AVE0010
DPP4 Inhibitors Side effects
• Low risk of hypoglycaemia, Weight neutral
• ? Immune effect - Effect on other DPP4 substrates
– Increased risk of nasopharyngitis RR 1.2, UTI RR1.5, Headache RR 1.4 in meta-analysis of sitag and vilda
• Pancreatitis : 88 cases with sitagliptan (post-marketing). 5.6 cases per 1000 patient years – similar to diabetic control group. 56 cases with saxagliptan (till Sept 2011)
• Hepatic dysfunction (Vilda) uncommon check LFT 3/12ly
• Skin : Sitaglip & saxa : Hypersensitivity reports, incl anaphy/ angioed/ SJS with sita (post-marketing)
– Serious skin reactions in animals (Vilda / Saxa)
– Skin lesion in healthy adults with higher doses Vilda
GLP-1 Agonists Exenatide Liraglutide Exenatide LAR
Dose 5mcg bd, 10mcg bd
Given within 60min prior to meals
0.6 mg od, 1.2mg od, 1.8mg od (more LOW, same A1C lowering c.f 1.2mg)
No need to give in rln meals
2.0 mg once a week
Indications Monotherapy (2009)
Add-on to Met, SU, SU+Met, TZD (+- Met)
NOT with Insulin (altho studied before)
Monotherapy
Add-on to Met, SU, Met+SU, TZD+Met
NOT with insulin
A1C lowering
Greater A1C reduction cf exenatide 1.12 vs 0.79%
Greater A1C reduction cf exenatide 1.9% vs 1.5%
Side Effects
Nausea Vomiting
Lost of Weight
Pancreatitis
(similar SE / LOW to exenatide)
Benign and malignant thyroid C-cell tumors (rats
Similar LOW to exenatide Less frequent nausea c.f daily dose (26% vs 50%)
Stimulation of calcitonin release in rats (same as liraglutide, but not exenatide) ?tumorigenesis potential
Contraind Hx / FHx Medullary Thy Ca, MEN 2A/B
• Renal Glucose Reabsorption in the Proximal Tubule
1. Adapted from Bays H. Curr Med Res Opin. 2009;25(3):671-81. 2. Wright EM, et al. J Int Med. 2007;261:32-43.
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• Glucose is freely filtered at the glomerulus and is reabsorbed via active transport mechanisms in the proximal convoluted tubule1
• Up to 180 g glucose filtered/24 h2
GLUCOSE REABSORPTION
NO GLUCOSE
Glomerulus Proximal tubule
S1 S2
S3
GLUCOSE FILTRATION
Collecting duct ~90%
~10%
Sodium Glucose Transporter 2 (SGLT2) Inhibition: A Novel Approach to Reduce Hyperglycemia
• SGLT2 inhibition decreases plasma glucose by increasing urinary glucose excretion • Canagliflozin / dapagliflozin is a potent, selective inhibitor of SGLT2
Rothenberg PL et al. Presented at European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden.
Presenter
Presentation Notes
Plasma glucose (PG), filtered in the kidney glomeruli, is reabsorbed into the systemic circulation by sodium glucose transporters (SGLTs) in the proximal tubule. The majority of filtered glucose is reabsorbed by SGLT2, a high-capacity, low-affinity transporter found in the early segment (S1 and S2) of the proximal tubule. The remaining glucose is reabsorbed by SGLT1, a low-capacity, high-affinity transporter found in the late segment (S3) of the proximal tubule. SGLT2 inhibitors block glucose reabsorption, increasing urinary glucose excretion. Canagliflozin is a potent and selective SGLT2 inhibitor. Glucosuria leads to loss of ~80-100 g of glucose/day (~3-4 g/h) in subjects with type 2 diabetes mellitus. Substantive decrease in net glucose entering the system lowers plasma glucose. Loss of “caloric equivalents” of ~300-400 cal/day. Rothenberg PL et al. Presented at European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden. Washburn W. et al. Evolution of sodium glucose co-transporter 2 inhibitors as antidiabetic agents. Expert Opin. Ther. Patents 2009; 19 (11): p14851499. Idris I. et al. Sodium–glucose co-transporter 2 inhibitors: an emerging new class of oral antidiabetic drug. Diabetes, Obesity and Metabolism 2009; 11: p79–88. Sha S. et al. Canagliflozin, a Novel Inhibitor of Sodium Glucose Co-transporter 2, Improved Glucose Control in Subjects With Type 2 Diabetes and Was Well Tolerated. Presented at American Diabetes Association 2010; June 2529: Orlando, Florida.
• The Renal Glucose Threhold (RTG) is Increased in Subjects with Type 2 Diabetes
Polidori D et al. 2010. Abstract 2186-PO. American Diabetes Association. June 25-29, 2010; Orlando, Florida. Polidori D et al. 2010. Presented at: European Association for the Study of Diabetes. September 20-24, 2010; Stockholm, Sweden.
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Uri
nar
y G
luco
se E
xcre
tion
(g
/day
)
0
75
100
50
150
Plasma Glucose (mmol/L)
125
25
4 6 8 16 10 14
Below RTG minimal glucosuria occurs
12
Healthy RTG
T2DM RTG
Above RTG glucosuria occurs
~13.8 mmol/L ~10 mmol/L
• Renal glucose reabsorption is increased in diabetes, which could contribute to further increasing plasma glucose levels
Case 2
• 54 year old male,BMI: 28 • Hypertension, Hyperlipidemia • No history of cardiovascular event • Known diabetes for 3 years • No microvascular complications • No history of cardiovascular event • Receiving metformin 850mg tds • HbA1C 8.4% • Renal and liver function normal • What next?
Other Oral Agents
• Sulphonyureas • Glinides • Αlpha-glucosidase Inhibitors • TZDs • DPP IV Inhibitors • (GLP-1 Agonist) • SGLT2 inhibitor
Considerations
• A: Age • B: Body weight • C: Complications, Comorbidities, Cost • D: Duration
β-Cell Function Continues to Decline Regardless of Intervention in T2DM
T2DM=type 2 diabetes mellitus *β-cell function measured by homeostasis model assessment (HOMA) Adapted from UKPDS Group. Diabetes. 1995; 44: 1249–1258.
0
20
40
60
80
100
–5 –4 –3 –2 –1 0 1 2 3 4 5 6
Years Since Diagnosis
β-C
ell F
unct
ion
(%)*
Progressive loss of β-cell function occurs prior to diagnosis
Metformin (n=159)
Diet (n=110)
Sulfonylurea (n=511)
Presenter
Presentation Notes
β-Cell Function Continues to Decline Regardless of Intervention in T2DM Data from the UK Prospective Diabetes Study (UKPDS) 16 indicate that β-cell function declines over time regardless of therapy.1 This randomized controlled trial was designed to determine whether specific therapies carry certain advantages or disadvantages. Subjects comprised 4209 newly diagnosed type 2 diabetes mellitus (T2DM) patients who, after 3 months of diet therapy, were asymptomatic and had fasting plasma glucose (FPG) levels of 6.0–15.0 mmol/L. The study consisted of two main comparisons: (1) obese and nonobese patients allocated to conventional therapy (primarily with diet) or intensive therapy (with additional sulfonlyurea or insulin); (2) obese patients assigned to conventional therapy or to intensive therapy (with metformin, sulfonylurea or insulin). The data presented on this slide were derived from a subset of patients in the second comparison still on their initial therapy at 6 years—metformin (n=159, blue circles), a sulfonylurea (n=511, yellow squares), or diet (n=110, white triangles). Indeed, these data can be extrapolated to show that the progressive loss of β-cell function (dashed line) begins years before a diagnosis of T2DM is made. For all patients, β-cell function was assessed with homeostasis model assessment (HOMA), a mathematical formula that uses the fasting insulin and glucose measurements to assess the degree of β-cell function (and insulin resistance) that would account for a given person’s set of fasting insulin and glucose levels. Reference UK Prospective Diabetes Study Group. UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes. 1995; 44: 1249–1258.
Do Not Be Afraid of Insulin
Starting Basal Insulin
• Continue oral agents at same dose • Add single bedtime insulin (10U or 0.1U/kg)
• NPH • Glargine • Detemir
• Adjust dose according to fasting glucose
• Watch for nocturnal hypoglycemia
Case 3
• 54 year old male, obese, hypertensive, type 2 diabetes • Known diabetes for 10 years • No microvascular complications • No history of cardiovascular event • Receiving metformin 850mg tds, glipizide 10mg bd
• HbA1C: 8.5%. • Liver, renal function normal
• What will be the next treatment option?
Key points of Statement EASD/ADA • Unless there are prevalent contraindications, metformin is
the optimal first-line drug. • After metformin, there are limited data to guide us.
Combination therapy with an additional 1–2 oral or injectable agents is reasonable, aiming to minimize side effects where possible.
• Ultimately, many patients will require insulin therapy alone or in combination with other agents to maintain glucose control.
• All treatment decisions, where possible, should be made in conjunction with the patient, focusing on his/her preferences, needs, and values.
“There are in fact two things, science and opinion; the former begets knowledge, the latter ignorance.”
- Hippocrates
Thank you
