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Oral Anti-diabetic Drugs in Special Populations Presented by: Saeed Behradmanesh, M.D. Internist, Endocrinologist April 2017, Isfahan, IRAN Agenda & Topics: • • • • • OADs in Elderly OADs in Chronic Liver Diseases (CLD) OADs in Pregnancy OADs in Heart Diseases OADs in Kidney Dysfunction Main References: 1) The American Geriatrics Society (AGS) 2) The American Diabetes Association (ADA) 3) The Canadian Diabetes Association 4) the International Diabetes Federation (IDF) 5) The European Diabetes Working Party guidelines 6) UoToDate 7) Joslin Clinical Guidelines OADs in Elderly (≥ 60 y/o or ≥ 65 y/o ) The prevalence of T2DM continues to increase steadily as more people live longer and grow heavier. From 1995 to 2004, the overall prevalence of T2DM in nursing home residents increased from 16 to 23%. Zhang X, Decker FH, Luo H, et al. Trends in the prevalence and comorbidities of diabetes mellitus in nursing home residents in the United States: 1995-2004. J Am Geriatr Soc 2010; 58:724. Older adults are at high risk for: Polypharmacy Functional disabilities Common geriatric syndromes: • • • • • cognitive impairment depression urinary incontinence falls persistent pain Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults: a consensus report. J Am Geriatr Soc 2012; 60:2342. Older adults with diabetes are a heterogeneous population that includes: persons residing independently in communities, in assisted care facilities, or in nursing homes. They can be fit and healthy or frail with many comorbidities and functional disabilities. Functional categories of older people with diabetes Glycemic targets: •In the absence of any long-term clinical trial data in fit healthy older populations, an A1C goal of <7.5 % should be considered in medication-treated patients. •To achieve this goal, fasting and preprandial glucoses should be between 140 and 150 mg/dL. Wei N, Zheng H, Nathan DM. Empirically establishing blood glucose targets to achieve HbA1c goals. Diabetes Care 2014; 37:1048. The patient with advanced microvascular complications and/or major comorbid illness and/or a life expectancy of < 5 years should have an A1C target of 8-9%. Diabetes in Older Adult, DIABETES CARE, VOLUME 35, DECEMBER 2012, 2650-2664 IDF Global Guideline for Managing Older People with Type 2 Diabetes, 2013 IDF Global Guideline for Managing Older People with T2DM For fit older adults, metformin (in the absence of contraindications) should be initiated at the time of diabetes diagnosis. For patients who prefer to avoid medication and who have A1C near their individualized target, a 3-6 month trial of lifestyle modification before initiating metformin is reasonable. Treatment of T2DM in the older patients. UpToDate 2017 For patients with contraindications and/or intolerance to metformin, we suggest a short-acting sulfonylurea (e.g., glipizide) or a DPP-IV inhibitor as an alternative option. Diabetes Care Volume 40, Supplement 1, January 2017, S99-104 Metformin may be temporarily D/C before: procedures during hospitalizations when acute illness may compromise renal or liver function We tend not to use pioglitazone in older adults due the: risks of fluid retention weight gain increased macular risks of heart failure edema osteoporotic fracture . 1) Campanelli CM; American Geriatrics Society 2012 Beers Criteria Update Expert Panel. American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2012;60: 616–631 2) Diabetes Care Volume 40, Supplement 1, January 2017, S99-104 • DPP-4 inhibitors are: – once-a-day oral agents – with no risk of hypoglycemia – weight-neutral (when used as monotherapy) – may be attractive agents to use in older adults • DPP-4 inhibitors should only be used as monotherapy when the A1C level is relatively close to the goal level. • DPP-4 inhibitors, also, can be used as dual/triple therapy in older patients with T2DM. . 1) Rotz ME, Ganetsky VS, Sen S, Thomas TF. Implications of incretin-based therapies on cardiovascular disease. Int J Clin Pract 2015;69:531–549 2) Diabetes Care Volume 40, Supplement 1, January 2017, S99-104 Repaglinide and nateglinide are short- acting secretagogues that act similarly to the SUs(weaker than SUs). They require more frequent administrations with meals than SUs and are more expensive. OADs in Chronic Liver Diseases Liver International (2016); pp: 932 - 948 © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd J Endocrinol Diabetes Obes 3(3) AGI(Acarbose) Liver toxicity of Acarbose is low (safe in compensated cirrhosis). Although there are no pharmacodynamic studies with acarbose in patients with hepatic insufficiency, its efficacy on hyperglycemia and its safety has been evaluated in patients with DM and CLD, alcoholic cirrhosis and mild hepatic encephalopathy. Its use was associated with a significant reduction of fasting and postprandial hyperglycemia, as well as HbA1c and Cpeptide in diabetic patients with compensated cirrhosis. Acarbose In is particularly useful in liver disease. cirrhotics there was also a reduction in blood ammonia levels, which paralleled an increase in bowel movement frequency. Acarbose is a safe and effective drug in cirrhotic patients with low-grade hepatic encephalopathy and T2DM mellitus. 1) Holstein A, Beil W. Oral antidiabetic drug metabolism: pharmacogenomics and drug interactions. Expert Opin Drug Metab Toxicol. 2009; 5: 225-241. 2) Tolman KG, Fonseca V, Dalpiaz A, Tan MH. Spectrum of liver disease in T2DM and management of patients with diabetes and liver disease. Diabetes Care. 2007; 30: 734-743. 3) Gentile S, Guarino G, Romano M, Alagia IA, Fierro M, Annunziata S, et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol. 2005; 3: 184-191. TZDs (Glitazones) The administration of pioglitazone and rosiglitazone for the treatment of NAFLD (presumably without cirrhosis) with or without DM has yielded conflicting results. Both improve serum transaminase levels and IR though improvement of inflammation and hepatic fibrosis is inconsistent. •Although both have low hepatotoxicity, in patients with serum transaminases 2.5 times above the upper limit of normal and compensated cirrhosis, they should be used with careful monitoring. •If the enzymes increase or remain at the same level several days after introduction, the drug should be discontinued. •Its use in patients with Child-Pugh stage C (& B?) cirrhosis should be avoided. • Although available clinical data show no evidence of TZD-induced hepatotoxicity , it is recommended that: – TZDs not be initiated in patients exhibiting clinical evidence of active liver disease or increased serum transaminase levels (ALT > X 2.5 ULN) SUs Glibenclamide (glyburide), Glipizide, Glimepiride and Gliclazide are metabolized in the liver and eliminated through bile and kidney. Hepatotoxicity has been reported with glibenclamide and gliclazide. Their use is not recommended in severe hepatic impairment. Meglitinides Both agents are metabolized in the liver. Repaglinide is rapidly eliminated through the bile and its rate of elimination is significantly reduced in patients with CLD. Repaglinide & Nateglinide have not been associated with hepatotoxicity. Repaglinide may induce hypoglycemia and it is contraindicated in patients with advanced liver insufficiency. The pharmacodynamics of Nateglinide is not altered in patients with CLD and is thus expected to be safer. Metformin Metformin does not undergo hepatic metabolism and is excreted unchanged by tubular secretion and glomerular filtration in the urine. As metformin is not metabolized via the hepatic CYP450 system, its pharmacokinetic characteristics do not expose patients to drug– drug interactions. There are no clinically relevant metabolic interactions reported with metformin. There are only a few reported cases of hepatotoxic side effects for metformin. There may be an increased risk of developing lactic acidosis in the setting of severe and advanced impaired liver function. Metformin has been associated with a reduced risk of HCC(1). Two recent studies have shown that this drug reduced incidence of liver complications and increased survival of patients with liver cirrhosis. In one study, a significant reduction in the incidence of hepatocellular carcinoma and liver complications was observed in patients with DM and HCV cirrhosis after treatment of an average period of 5.7 years(2). In another study, the long-term survival of diabetic patients with liver cirrhosis who continued taking metformin was longer than the ones who stopped it. 1. 2. 3. Donadon V, Balbi M, Mas MD, Casarin P, Zanette G. Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease. Liver Int 2010; 30: 750-8. Nkontchou G, Cosson E, Aout M, Mahmoudi A, et al. Impact of metformin on the prognosis of cirrhosis induced by viral hepatitis C in diabetic patients. J Clin Endocrinol Metab 2011; 96: 2601-8. Therneau TM, Roberts LR, et al. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival o patients with diabetes. Hepatology 2014; 60: 2008-16. Reduction in mortality was also significant in patients with stages B and C of Child Pugh. No patient developed lactic acidosis during a follow up period of 26.8 months (3). The low incidence of lactic acidosis reported in these studies is encouraging, though caution should still be taken when considering its use in patients with advanced liver failure. Incretin-based therapies Both types of drugs are barely metabolized in the liver and are excreted unchanged by the kidney; thus, they seem to be safe in cirrhotic patients. Their pharmacodynamic characteristics have been assessed in patients with varying degrees of hepatic impairment and their safety has been assessed in studies comprising large number of individuals. Inhibitors of DPP-4 showed only minimal pharmacokinetic changes in patients with varying degrees of hepatic impairment. No DPP-4 inhibitor has been shown to inhibit or to induce hepatic CYP-mediated drug metabolism. Unlike sitagliptin and vildagliptin, linagliptin is excreted in bile (enterohepatic). Sitagliptin is eliminated almost entirely by the kidneys; saxagliptin and vildagliptin are metabolized in the liver. In pharmacokinetic studies, patients with moderate or severe hepatic impairment showed no increase of drug exposure after administration of multiple doses of Sitagliptin, compared to normal controls; thus, no dose adjustment is required. Accordingly, the number of clinically significant drug-drug interactions is minimal. It is hypothesized that in NAFLD the DPP-4 enzymatic activity is increased which might contribute to the development of T2DM and metabolic deterioration. DPP-4 inhibitors might offer prevention of further metabolic deterioration, especially in NAFLD. A case–control study, using sitagliptin 50 mg/day for 48 weeks, showed no significant changes of average AST and ALT levels during follow up. Sitagliptin showed effectiveness and safety for the treatment of T2DM complicated with HCV- positive chronic liver disease. Arase Y, Suzuki F, Kobayashi M, Suzuki Y, et al. Efficacy and safety of sitagliptin therapy for diabetes complicated by chronic liver disease caused by HCV: Hepatol Res. 2011; 41:524-529. Sitagliptin resulted in a significant decrease in ballooning and NASH scores. These effects were accompanied by a significant reduction in body mass index, AST, and ALT levels. Yilmaz Y, Yonal O, Deyneli O, Celikel CA, Kalayci C, Duman DG. Effects of sitagliptin in diabetic patients with NASH. Acta Gastroenterol Belg. 2012; 75: 240-244. Patients with liver disease and DM may be benefited with incretin-based therapies due to their low liver toxicity and wide tolerance. However, no study of long term effectiveness and safety has been published to date. They seem to be well tolerated in patients with mild and moderate liver function impairment, though they should be cautiously administered in patients with advanced liver disease. OADs in Pregnancy • T2DM • GDM ENDOCRINE PRACTICE Vol 21 No. 4 April 2015 D/C OADs. Start insulin. An exception is metformin, which may be continued during the 1st TM in patients with PCOS or T2DM, and anovulatory infertility. Metformin should not be used beyond the 1st TM or in lieu of insulin until randomized controlled studies evaluating safety and efficacy have been completed. Metformin crosses the placenta and achieves therapeutic levels in the fetus. Presently, there are no long term randomized controlled safety data in infants whose mother’s were treated with metformin in pregnancy. Other oral medications have not been adequately studied for the treatment of preexisting T2DM in pregnancy. There is inadequate safety information about the use of GLP-1RA, DPP-4 inhibitors, AGIs, and SGLT2 inhibitors in pregnancy. They should therefore not be used in pregnancy . J Clin Endocrinol Metab, November 2013, 98(11):4227–4249 OADs in Heart Diseases 1) Stable/Unstable Angina Pectoris 2) Acute Coronary Syndrome (ACS) 3) Heart Failure Acarbose Initial reviews of the placebo- controlled studies suggested that acarbose use was associated with a significantly lower risk of myocardial infarction and other cardiovascular events. A more comprehensive review of the literature was unable to find a difference in cardiovascular risk associated with any AGI, including acarbose. Acarbose does not appear to increase the risk of adverse cardiovascular events. There is no any contraindication for prescription of Acarbose in patients with stable/unstable angina & HF. Metformin Renal dysfunction and heart failure have been longstanding contraindications for metformin use because of the perceived risk of lactic acidosis. However, there is good evidence that metformin is used in patients with these contraindications, with no change in the incidence of lactic acidosis. Moreover, observational studies have demonstrated that metformin use in patients with heart failure is associated with a lower risk of cardiovascular morbidity and mortality. It is also important to note that none of the patients allocated to metformin use in the UKPDS study developed lactic acidosis. • Metformin: Safe in stable/unstable angina pectoris Not recommend in ACS Safe in HF class I & II (NYHA) May be safe in HF class III, (concomitant with aggressive treatment for HF) Contraindicated in HF class IV TZDs (Glitazones) In 2007 evidence emerged linking rosiglitazone to an increased risk of myocardial infarction and death. Hospitalization or death attributable to heart failure was significantly higher in patients allocated to rosiglitazone use. Although pioglitazone does not appear to have the same level of cardiovascular risk as rosiglitazone, there appears to be a higher risk of fractures and cancer. TZDs are also associated with fluid retention and significant weight gain. TZDs, especially rosiglitazone, increase the risk of heart failure, stroke, and AMI and therefore should be avoided in patients at risk of cardiovascular disease. Insulin Secretagogues Given the uncertainty surrounding SU cardiovascular safety, it is not surprising that there have been numerous observational studies and post hoc analyses of randomized controlled trials examining this issue. Collectively, these studies provide some evidence that risk of cardiovascular events may be higher in people taking SUs compared with other OADs. A systematic review and meta-analysis of these data reported that glyburide (glibenclamide) had the highest risk among SUs. Current evidence suggests that SU use is associated with an increased risk of adverse cardiovascular events. This risk varies among individual drugs, with the lowest risk associated with gliclazide. Gangji AS, Cukierman T, Gerstein HC, Goldsmith CH, Clase CM. A systematic review and meta-analysis of hypoglycemia and cardiovascular events: a comparison of glyburide with other secretagogues and with insulin. Diabetes Care. 2007;30:389-394. Dipeptidyl peptidase 4 inhibitors Cardiovascular safety studies mandated in the 2008 FDA requirements must demonstrate that a new antidiabetic drug is safe, or in other words, does not increase the risk of cardiovascular events beyond an acceptable threshold. Three cardiovascular safety trials of DPP-4 inhibitors have been published and a fourth study is ongoing, with results expected in 2018. Regarding the primary outcome of cardiovascular safety, all three studies demonstrated noninferiority vs placebo. The DPP‒4 inhibitors and SGLT-2 inhibitors do not appear to increase the risk of adverse cardiovascular events, though the evidence to support this premise is still evolving. Safety Announcement [ 4-5-2016, 4 June 2016 ] A U.S. Food and Drug Administration (FDA) safety review has found that T2DM medicines containing saxagliptin and alogliptin may increase the risk of heart failure, particularly in patients who already have heart or kidney disease. OADs in Kidney Dysfunction Clinical Diabetes & Endocrinology, 2015,1:2 Impaired eGFR Dialysis Patients Thanks a lot for your attention.