Oral diabetes Medications P. Akhavan, M.D

Agenda Advantages and disadvantages of oral antihyperglycemic agents Approaches to Glycemic Treatment (oral agent) Noninsulin antihyperglycemic agent in GDM Metformin's ability to lower A1C and decrease fasting plasma glucose is similar to that of sulfonylurea drugs. However, the UKPDS showed that those who received metformin had less hypoglycemia and weight gain than those who received sulfonylureas. Metformin must be avoided in patients with renal impairments, as those patients are at higher risk of experiencing lactic acidosis. However, metformin is an effective monotherapy and may be an ideal drug for overweight patients since it does not cause weight gain and has been seen to cause modest amounts of weight loss when first administered. Diarrhea and abdominal discomfort can be alleviated by changes in diet and slow increases in metformin dosage.

Biguanides 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

Biguanides 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 Metformin's ability to lower A1C and decrease fasting plasma glucose is similar to that of sulfonylurea drugs. However, the UKPDS showed that those who received metformin had less hypoglycemia and weight gain than those who received sulfonylureas. Metformin must be avoided in patients with renal impairments, as those patients are at higher risk of experiencing lactic acidosis. However, metformin is an effective monotherapy and may be an ideal drug for overweight patients since it does not cause weight gain and has been seen to cause modest amounts of weight loss when first administered. Diarrhea and abdominal discomfort can be alleviated by changes in diet and slow increases in metformin dosage.

Biguanides Metformin should not be administered when conditions predisposing to lactic acidosis are present. Such conditions include impaired renal function ,decreased tissue perfusion or hemodynamic instability due to infection or other causes, concurrent liver disease or alcohol abuse, and heart failure.

Biguanides Patients who are about to receive intravenous iodinated contrast material or undergo a surgical procedure should have metformin held until renal function and circulation can be established (normal urine output, normal serum creatinine, and no physical exam evidence of fluid overload or circulatory compromise). Serum creatinine is typically assessed two to three days after contrast administration Drug safe010;33:727

Sulfonylureas 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)

Sulfonylureas Disadvantages 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

although direct controlled clinical trials have not been performed 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. 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

Multivariable adjusted Kaplan–Meier plots demonstrating the cumulative mortality for the first glucose-lowering treatment course only according to previous myocardial infarction. Multivariable adjusted Kaplan–Meier plots demonstrating the cumulative mortality for the first glucose-lowering treatment course only 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

Meglitinides 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 Repaglinide 2-6 h glimipride 24h glibenclamide 12-24 h

Meglitinides Disadvantages Hypoglycemia (although may be less than with sulfonylureas if patient has a variable eating schedule) ↑ Weight Frequent dosing schedule ? Blunts myocardial ischemic repaglinid 0.5-16 mg-

Meglitinides ? Blunts myocardial ischemic There are no long-term studies of meglitinides to assess cardiovascular outcomes or mortality. Whether meglitinides are associated with poorer outcomes after a myocardial infarction is not known. However, since its mode of action is so similar to sulfonylureas, the same concern existspreconditioning The mechanism of action of repaglinide is similar to that of the sulfonylurea drugs: binding to beta cell receptors to stimulate insulin secretion. The major difference between the two drug classes is that meglitinides are shorter-acting, and are most effective when taken after meals in the presence of glucose. Adverse effects include weight gain and hypoglycemia. An additional drawback to this drug is the dosing schedule since it must be taken with meals.

Thiazolidinediones 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 Thiazolidinediones (TZDs) enhance insulin sensitivity in muscle and adipose tissue by binding to cell receptors,which leads to an increase in glucose transporter expression. TZDs encourage beta cells to respond more efficiently by lowering the amount of glucose and free fatty acids in the bloodstream, both of which are known to be detrimental to insulin secretion. Finally, these drugs reduce glucose production in the liver.

Thiazolidinediones Advantages No hypoglycemia Durability ↑ HDL-C ↓ Triglycerides (pioglitazone) ? ↓ CVD events(PROactive,pioglitazone) Pioglitazone 15-45

Thiazolidinediones Disadvantages ↑ Weight Edema/heart failure ↑ LDL-C (rosiglitazone) ? ↑ MI (meta-analyses, rosiglitazone Bone fractures

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 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

Meta-analyses of cohort studies found a similar increased risk of bladder cancer with pioglitazone use CMAJ 2012;55:187 Oncologist 2013;18:148

Thiazolidinediones 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.

Thiazolidinediones 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

Thiazolidinediones 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 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 Because AGIs work in the digestive tract, they are more effective at lowering postprandial glucose levels than fasting plasma glucose levels. On average, AGIs are less effective at lowering A1c levels than biguanides or sulfonylureas. What makes this class of drug attractive to patients and physicians is it's disassociation with weight gain and hypoglycemia. However, it is known to cause abdominal discomfort and diarrhea. AGIs are also rarely used as monotherapy because of their low efficacy.

Alpha-glucosidase Inhibitors Disadvantages Generally modest A1C efficacy Gastrointestinal side effects (flatulence, diarrhea) Frequent dosing schedule Because AGIs work in the digestive tract, they are more effective at lowering postprandial glucose levels than fasting plasma glucose levels. On average, AGIs are less effective at lowering A1c levels than biguanides or sulfonylureas. What makes this class of drug attractive to patients and physicians is it's disassociation with weight gain and hypoglycemia. However, it is known to cause abdominal discomfort and diarrhea. AGIs are also rarely used as monotherapy because of their low efficacy.

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% Sitagliptin 100

the efficacy and safety of adding sitagliptin or glimepiride to the metformin regimen Diabetes, Obesity and Metabolism 13: 160–168, 2011.

DPP-4 inhibitors Advantages No hypoglycemia Well tolerate

DPP-4 inhibitors Disadvantages Angioedema/urticaria and other immune-mediated dermatological effects ? ↑ Heart failure hospitalizations ? Acute pancreatitis

DPP-4 inhibitors In post-marketing reports, sitagliptin , saxagliptin, and alogliptin have been associated with hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome [ 118 ]. DPP-4 inhibitors are contraindicated in patients with a history of a serious hypersensitivity reaction after previous exposure [ 138 ]

DPP-4 inhibitors In addition, there have been postmarketing case reports of acute pancreatitis in patients using sitagliptin, saxagliptin , and alogliptin [ 50,132,133 ]. In a retrospective cohort study of a claims database, the incidence of acute pancreatitis in sitagliptin users was 5.6 cases per 1000 patient-years, which was similar to the incidence in the diabetic control group [ 52 ]..

DPP-4 inhibitors However, in a population-based case-control study using a large insurance database, treatment with GLP-1-based therapy (sitagliptin and exenatide) was associated with an increased risk of hospitalization for acute pancreatitis (adjusted OR 2.07, 95% CI 1.36-3.13) [ 51 ]. It is unclear if exposure to DPP-4 inhibitors or other drugs that act through GLP-1 play a causal role in the development of pancreatitis

DPP-4 inhibitors Pancreatitis should be considered in patients with persistent severe abdominal pain (with or without nausea), and DPP-4 inhibitors should be discontinued in such patients. DPP-4 inhibitors should be used with caution and with careful monitoring in patients with a history of pancreatitis .

SGLT2 Inhibitor Inhibits SGLT2 in the proximal nephron Blocks glucose reabsorption by the kidney, increasing glucosuria Lowers A1C by 0.6-0.8%

SGLT2 inhibitors Canagliflozin Dapagliflozin Empagliflozin Advantages No hypoglycemia ↓ Weight ( 2-3% body weight loss) ↓ Blood pressure

SGLT2 inhibitors Disadvantages Genitourinary infections Polyuria Volume depletion/hypotension/ dizziness ↑ LDL-C ↑ Creatinine (transient)

Bile acid sequestrants Colesevelam ? ↓ Hepatic glucose production ? ↑ Incretin levels Advantages (No hypoglycemia , ↓ LDL-C ) Disadvantages Generally modest A1C efficacy Constipation ↑ Triglycerides May ↓ absorption of other medications

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.

In a meta-analysis, metformin in type 1 diabetes was found to reduce insulin requirements (6.6 U/day, P<0.001) and led to small reductions in weight and total and LDL cholesterol but not to improved glycemic control (absolute A1C reduction 0.11%, P = 0.42)

Incretin-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 inhibitors There are insufficient data to recommend clinical use in type 1diabetes at this time

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 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 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 11. Langer O, Conway DL, Berkus MD, Xenakis EM-J, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134–1138 12. Rowan JA, Hague WM, Gao W, Battin MR,Moore MP; MiG Trial Investigators. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med 2008;358:2003–2015 13. Gui J, Liu Q, Feng L. Metformin versus insulin in the management of gestational diabetes: a meta-analysis. PLoS One 2013;8:e64585 14. Coustan DR. Pharmacological management of gestational diabetes: an overview. Diabetes Care 2007;30(Suppl. 2):S206–S208

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 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