Download Oral Anti-diabetic Drugs in Special Populations

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.