Oral diabetes Medications Oral diabetes Medications

P. Akhavan, M.D

AgendaAgenda

• Advantages and disadvantages of oral antihyperglycemic agents

• Approaches to Glycemic Treatment (oral agent)

• Noninsulin antihyperglycemic agent in GDM

BiguanidesBiguanides

Activates AMP-kinase(? other) • ↓ Hepatic glucose production increase

insulin-mediated peripheral glucose uptake

Efficacy :Reduce A1C 1.0-2.0%

Advantages : Extensive experience

No hypoglycemia ,↓ CVD events (UKPDS)

No weight gain, with possible modest weight loss

BiguanidesBiguanides Disadvantages

• Gastrointestinal side effects (diarrhea abdominal cramping)

• Vitamin B12 deficiency• Lactic acidosis risk (rare)

• Multiple contraindications: CKD, acidosis, hypoxia, dehydration, etc

Ann InternMed 2011;154:602–613

SulfonylureasSulfonylureas Closes KATP channels on beta-cell

plasma membranes• ↑ Insulin secretion

Efficacy– Decrease fasting plasma glucose 60-70 mg/dl – Reduce A1C by 1.0-2.0%

Advantages• Extensive experiencec • ↓ Microvascular risk(UKPDS)

SulfonylureasSulfonylureasDisadvantages

• Hypoglycemia

Shorter acting sulfonylureas, such as glipizide and gliclazide, are less likely to cause hypoglycemia than the older, long-acting sulfonylureas and therefore are the preferred sulfonylureas, especially in older patients.

• ? Blunts myocardial ischemic

Gliclazide are selective for the pancreatic sulfonylurea receptors over the cardiac receptors

• Do not appear to be associated with increased cardiovascular mortality compared with metformin or other diabetes medications,

although direct controlled clinical trials have not been performed

j clin Endocrinol Metab 2010;95:4993

Eur heart j 2010;32:1900

Hazard ratios (95% CI) for different endpoints in relation to monotherapies with different glucose-lowering agents according to previous myocardial infarction.

Schramm T K et al. Eur Heart J 2011;32:1900-1908

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2011. For permissions please email: journals.permissions@oup.com

MeglitinidesMeglitinides• Closes KATP channels on beta-cell plasma

membranes • ↑ Insulin secretion Efficacy

– Decreases peak postprandial glucose– Decreases plasma glucose 60-70 mg/dl – Reduce A1C 1.0-2.0%

Advantages • Postprandial glucose excursions • Dosing flexibility

MeglitinidesMeglitinides

Disadvantages

o Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule)

o ↑ Weight

o Frequent dosing schedule

o ? Blunts myocardial ischemic

ThiazolidinedionesThiazolidinediones

• Activates the nuclear transcription factor PPAR-g

• ↑ Insulin sensitivity

Efficacy– Decrease fasting plasma glucose ~35-40

mg/dl – Reduce A1C ~0.5-1.4%– 6 weeks for maximum effect

ThiazolidinedionesThiazolidinediones

Advantages

• No hypoglycemia• Durability • ↑ HDL-C• ↓ Triglycerides (pioglitazone) • ? ↓ CVD events(PROactive,pioglitazone)

ThiazolidinedionesThiazolidinediones

Disadvantages

• ↑ Weight

• Edema/heart failure

• ↑ LDL-C (rosiglitazone) ?

• ↑ MI (meta-analyses, rosiglitazone

• Bone fractures

• Bone fracture• Bone fracture

In a large population-based study using the UK-based General Practice Research Database, both pioglitazone (OR 2.59, 95% CI 0.96-7.01) and rosiglitazone (OR 2.38, 95% CI 1.39-4.09) were associated with low-trauma fracture in men and women

intern Med 2008;168;8220

• bladder cancer• bladder cancer

In the PROactive trial , there were more cases of bladder cancer (14 versus 5) in the pioglitazone than placebo group .

Drug saf 2009;32:187

In a10-year observational study of pioglitazone use in patients with diabetes,

there was not a significant association between pioglitazone exposure and bladder cancer among patients with median duration of therapy of two years (HR for bladder cancer 1.2, 95% CI 0.9-1.5) .

However, the risk of bladder cancer was significantly increased in those with the longest exposure to pioglitazone and to those exposed to the highest cumulative dose.

Diabetes care 2011;34916

ThiazolidinedionesThiazolidinediones • In data from several double blind trials with

rrosiglitazon and pioglitazone involving over 5000 patients, fewer than 0.3 percent of patients had alanine aminotransferase levels more than three times the upper limit of normal and no patients had values more than 10 times the upper limit of normal.

ThiazolidinedionesThiazolidinediones

• US FDA currently recommends that patients receiving pioglitazone or rosiglitazone undergo baseline testing followed by periodic monitoring of liver function based upon clinical judgment.

Diabetes care 2002;25:815

ThiazolidinedionesThiazolidinediones

Macular edema has been reported in patients taking thiazolidinediones, though the frequency of occurrence is unknown .

Patients at greatest risk seem to be those who are also at risk for peripheral edema

Alpha-glucosidase InhibitorsAlpha-glucosidase Inhibitors

• Inhibits intestinal a-glucosidase • Slows intestinal carbohydrate

digestion/absorption

Efficacy : Decrease A1C 0.5-0.8%

Advantages • No hypoglycemia • ↓Postprandial glucose excursions • ? ↓ CVD events(STOP-NIDDM) • Nonsystemic

Alpha-glucosidase InhibitorsAlpha-glucosidase Inhibitors

Disadvantages • Generally modest A1C efficacy• Gastrointestinal side effects (flatulence,

diarrhea)• Frequent dosing schedule

DPP-4 inhibitors DPP-4 inhibitors• Inhibits DPP-4 activity, increasing

postprandial active incretin (GLP-1, GIP)

concentrations

• ↑ Insulin secretion(glucose-dependent)• ↓ Glucagon secretion (glucose-dependent)

efficacy :

Reduce A1C ~0.5-0.8%

the efficacy and safety of adding sitagliptin or glimepiride to the metformin regimen the efficacy and safety of adding sitagliptin or glimepiride to the metformin regimen

Diabetes, Obesity and Metabolism 13: 160–168, 2011.

DPP-4 inhibitorsDPP-4 inhibitors Advantages • No hypoglycemia • Well tolerate

DPP-4 inhibitors DPP-4 inhibitors

Disadvantages • Angioedema/urticaria and other immune-

mediated dermatological effects

• ? ↑ Heart failure hospitalizations

• ? Acute pancreatitis

SGLT2 InhibitorSGLT2 Inhibitor

• Inhibits SGLT2 in the proximal nephron

• Blocks glucose reabsorption by the kidney, increasing glucosuria

• Lowers A1C by 0.6-0.8%

SGLT2 inhibitors SGLT2 inhibitorsCanagliflozin DapagliflozinEmpagliflozin

Advantages• No hypoglycemia

• ↓ Weight ( 2-3% body weight loss)

• ↓ Blood pressure

SGLT2 inhibitors SGLT2 inhibitors

Disadvantages

• Genitourinary infections • Polyuria• Volume depletion/hypotension/ dizziness• ↑ LDL-C • ↑ Creatinine (transient)

Oral diabetes Medications in type 1 diabetes

Oral diabetes Medications in type 1 diabetes

• Metformin

Adding metformin to insulin therapy may reduce insulin requirements and improve metabolic control in overweight/obese patients with poorly controlled type 1 diabetes.

Incretin-Based TherapiesIncretin-Based Therapies

• Therapies approved for the treatment of type 2 diabetes are currently being evaluated in type 1 diabetes.

• GLP-1 agonists and DPP-4 inhibitors are not currently FDA approved for those with type 1 diabetes, but are being studied in this population.

SGLT2 inhibitorsSGLT2 inhibitors

• There are insufficient data to recommend clinical use in type 1diabetes at this time

Antihyperglycemic therapy in type 2 diabetes

Antihyperglycemic therapy in type 2 diabetes

• A patient-centered approach should be used to guide choice of pharmacological agents.

• Consider initiating combination insulin injectable therapy when blood glucose is>300–350 mg/dL and/or A1C is >10–12%.

• For all patients, consider initiating therapy with a dual combination when A1C is >9% to more expeditiously achieve the target A1C level

• A comparative effectiveness meta-analysis suggests that overall each new class of noninsulin agents added to initial therapy lowers A1C around 0.9–1.1%.

Ann Intern Med 2011;154:602–613

• Rapid-acting secretagogues (meglitinides) may be used instead of sulfonylureas in patients with irregular meal schedules or who develop late postprandial hypoglycemia on a sulfonylurea effects.

• Other drugs not shown in the figure (e.g., a-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide) may be tried in specific situations, but are generally not favored due to modest efficacy, the frequency of administration,and/or side effects

Noninsulin antihyperglycemic agent in GDMNoninsulin antihyperglycemic agent in GDM

• Randomized controlled trials support the efficacy and short-term safety of glyburide (11) (pregnancy category B) and metformin (12,13) (pregnancy category B) for the treatment of GDM.

• However, both agents cross the placenta, and long-term safety data are not available (14).

Diabetes Care 2015;38

Insulin is the preferred agent for management of diabetes in pregnancy because of the lack of long-term safety data for noninsulin agents.

Diabetes Care 2015;38

Metformin therapy can be used for glycemic control only for those women with gestational diabetes

who do not have satisfactory glycemic control despite medical nutrition therapy

and who refuse or cannot use insulin and are not in the first trimester.

Endocrine Society, 2013

• Breastfeeding women with overt diabetes

successfully using metformin or glyburide therapy during pregnancy should continue to use these medications, when necessary, during breastfeeding.

Endocrine Society, 2013

• Metformin use by the breastfeeding woman vs. formula feeding appears to have no adverse effects on infant growth, motor-social development, and intercurrent illness during the first 6 months of life .

• Glyburide was not detected in breast milk, and hypoglycemia was not observed in nursing infants of women using glyburide