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The treatment of diabetes in advanced liver disease: change of a paradigm
Maria Letizia Petronib, Lucia Brodosib, Giulio Marchesinia,b,
Corresponding author
giulio.marchesini@unibo.it

Corresponding author.
a Department of Medical and Surgical Sciences, Alma Mater University, Bologna, Italy
b IRCCS Azienda Ospedaliera di Bologna Sant'Orsola-Malpighi, Bologna, Italy
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="para0001" class="elsevierStylePara elsevierViewall">The treatment of type 2 diabetes &#40;T2DM&#41; has entered a new era in the past 15 years&#46; After decades of stagnation&#44; novel drugs&#44; adding beneficial pleiotropic effects to their glucose lowering activity &#40;<a class="elsevierStyleCrossRef" href="#tbl0001">Table 1</a>&#41;&#44; entered the market and totally replaced the old drugs in treatment diagrams proposed by international societies <a class="elsevierStyleCrossRef" href="#bib0001">&#91;1&#93;</a>&#46; Also&#44; the use of metformin as an initial treatment of hyperglycemia has been challenged following the evidence that gliflozins &#40;sodium-glucose cotransporter-2 inhibitors &#8211; SGLT-2Is&#41; and glucagon-like peptide-1 receptor agonists &#40;GLP-1RAs&#41; may reduce the risk of heart and kidney disease progression&#44; the most common outcomes in patients with long-standing diabetes&#46; A large network meta-analysis comparing the effects of 5-year T2DM treatment with these new classes versus any other intervention in randomized controlled trials &#40;764 RCT&#44; a total of 421&#44;364 patients&#41; confirmed the superiority of these drugs <a class="elsevierStyleCrossRef" href="#bib0002">&#91;2&#93;</a>&#46; The risks of all-cause mortality&#44; cardiovascular mortality&#44; non-fatal myocardial infarction&#44; non-fatal stroke&#44; kidney failure and hospital admission for heart failure were all reduced <a class="elsevierStyleCrossRef" href="#bib0002">&#91;2&#93;</a>&#44; with differences between GLP-1RAs and SGLT-2Is and in relation to <span class="elsevierStyleItalic">a priori</span> severity of cardiovascular risk&#46; Changes in drug use are slowly being accepted in the community&#44; despite clinical inertia and budget restriction <a class="elsevierStyleCrossRef" href="#bib0003">&#91;3&#93;</a>&#46;</p><elsevierMultimedia ident="tbl0001"></elsevierMultimedia><p id="para0002" class="elsevierStylePara elsevierViewall">These beneficial effects prompt to reconsider the treatment of T2DM also in patients with liver disease&#44; a specific area of research where the risk of hepatotoxicity&#44; drug-drug interaction&#44; comorbidity and frailty commonly indicate the use of insulin as a preferred drug&#46; The questions now are&#58; 1&#41; May we confidently use these drugs in the presence of advanced liver disease&#63; 2&#41; Do these beneficial effects also occur in patients with T2DM and cirrhosis&#63; 3&#41; Is there any evidence that these drugs may also improve &#8211; or reduce the progression of &#8211; the underlying liver disease&#63;</p><p id="para0003" class="elsevierStylePara elsevierViewall">As to the first question&#44; all SGLT-2Is share similar pharmacokinetic characteristics&#46; Following oral administration and rapid absorption&#44; they undergo extensive hepatic metabolism via glucuronidation to inactive metabolites&#44; which are finally excreted by the kidney&#46; Their systemic exposure &#40;C<span class="elsevierStyleInf">max</span> and AUC<span class="elsevierStyleInf">&#8734;</span>&#41; increases with the severity of hepatic disease&#44; classified according to Child-Pugh score <a class="elsevierStyleCrossRef" href="#bib0004">&#91;4&#93;</a>&#44; but no signs of hepatotoxicity have ever been reported&#46; Nonetheless&#44; very few data are available&#44; and review articles suggest caution for use in patients with advanced liver disease <a class="elsevierStyleCrossRef" href="#bib0005">&#91;5&#93;</a> and even more in the presence of combined liver and renal failure&#46; No dose adjustment is suggested for patients up to Child-Pugh B class <a class="elsevierStyleCrossRef" href="#bib0006">&#91;6&#93;</a>&#46;</p><p id="para0004" class="elsevierStylePara elsevierViewall">Incretin-based therapies include GLP-1RAs and the dipeptidyl-peptidase-4 inhibitors &#40;DPP-4Is&#41;&#46; Both classes are scarcely metabolized by the liver and are mostly excreted unchanged by the kidney <a class="elsevierStyleCrossRef" href="#bib0007">&#91;7&#93;</a>&#44; which regulates systemic exposure &#40;with the notable exception of linagliptin&#41;&#46; DPP-4Is are safe and do not induce hypoglycemia&#44; but do not share the beneficial effects of GLP-1RAs on the cardiovascular and renal systems&#46; Therefore&#44; they are considered the second choice in the treatment algorithm&#46; On the contrary&#44; liraglutide and the long-acting weekly GLP-1RAs &#40;exenatide LAR&#44; dulaglutide and semaglutide&#41; qualify as potential treatment also in the presence of liver disease <a class="elsevierStyleCrossRef" href="#bib0008">&#91;8&#93;</a>&#44; considering their safety and efficacy <a class="elsevierStyleCrossRef" href="#bib0009">&#91;9&#93;</a>&#46; The only possible risk comes from the reported interaction of GLP-1RAs with beta-blocking agents for the prevention of recurrent bleeding <a class="elsevierStyleCrossRef" href="#bib0010">&#91;10&#93;</a>&#44; requiring further investigation&#46;</p><p id="para0005" class="elsevierStylePara elsevierViewall">As to the second question&#44; there are no systematic data on cardiovascular and renal disease progression in specific cohorts with T2DM and liver disease&#44; a group of patients largely identifiable as NASH-cirrhosis&#46; The beneficial effects of GLP-1RAs and SGLT-2Is have been extensively reproduced in large cohorts of patients with T2DM&#44; and most of them were expected to have non-alcoholic steatohepatitis &#40;NASH&#41; superimposed to T2DM&#46; Old studies identified liver failure or bleeding&#44; not cardiovascular events&#44; as most common cause of death in cirrhosis with T2DM <a class="elsevierStyleCrossRef" href="#bib0011">&#91;11&#93;</a>&#44; but the present epidemics of metabolic liver disease significantly increased the cardiovascular risk in the general population with advanced liver disease &#91;<a class="elsevierStyleCrossRef" href="#bib0012">12</a><a class="elsevierStyleCrossRef" href="#bib0013">13</a>&#93;&#46; Although liver disease was not systematically considered an exclusion criterion in cardiovascular and renal outcome trials <a class="elsevierStyleCrossRefs" href="#bib0014">&#91;14&#8211;23&#93;</a>&#44; probably very few enrolled patients might be classified as NASH-cirrhosis&#46; This is a very novel area of research that should be extensively investigated in the future&#46;</p><p id="para0006" class="elsevierStylePara elsevierViewall">The third question is far more intriguing&#46; GLP-1RAs have been extensively investigated as treatment for NASH&#44; but the results are inconclusive&#46; Liraglutide and semaglutide reduced steatosis and NASH <a class="elsevierStyleCrossRef" href="#bib0024">&#91;24&#93;</a>&#44; but failed to improve fibrosis &#91;<a class="elsevierStyleCrossRef" href="#bib0025">25</a><a class="elsevierStyleCrossRef" href="#bib0026">26</a>&#93;&#46; Similar effects on steatosis and liver biomarkers were observed with dulaglutide <a class="elsevierStyleCrossRef" href="#bib0027">&#91;27&#93;</a> and tirzepatide&#44; the dual GIP &#40;glucose-dependent insulinotropic peptide&#41;&#47;GLP-1RA <a class="elsevierStyleCrossRef" href="#bib0028">&#91;28&#93;</a>&#44; and data on fibrosis are being investigated&#46; SGLT-2Is similarly reduced steatosis <a class="elsevierStyleCrossRef" href="#bib0024">&#91;24&#93;</a>&#44; with no definite effect on fibrosis&#46; For both classes&#44; changes in steatosis and fibrosis biomarkers might stem from weight loss <a class="elsevierStyleCrossRef" href="#bib0029">&#91;29&#93;</a>&#44; favored by behavioral treatment <a class="elsevierStyleCrossRef" href="#bib0030">&#91;30&#93;</a>&#46; Beneficial effects might also be achieved by high dose semaglutide and tirzepatide&#44; causing 15&#37; mean weight reduction &#91;<a class="elsevierStyleCrossRef" href="#bib0031">31</a><a class="elsevierStyleCrossRef" href="#bib0032">32</a>&#93;&#44; provided that the negative effects of weight loss-associated sarcopenia are adequately corrected <a class="elsevierStyleCrossRef" href="#bib0033">&#91;33&#93;</a>&#46; A recent report compared the effectiveness of antidiabetic agents at reducing the risk of hepatic decompensation &#40;hospitalization for ascites&#44; bacterial peritonitis&#44; hepatorenal syndrome&#44; hepatic encephalopathy&#44; bleeding varices&#41; in T2DM with cirrhosis &#40;60&#37; NASH-cirrhosis&#41;&#44; based on a large US commercial claims dataset <a class="elsevierStyleCrossRef" href="#bib0009">&#91;9&#93;</a>&#46; After accurate propensity-score matching&#44; patients receiving GLP-1RAs experienced lower rates of decompensation compared with DPP-4Is or sulphonylureas &#40;HR 0&#46;68&#44; 95&#37;CI 0&#46;53-0&#46;88&#59; and HR 0&#46;64&#44; 95&#37;CI 0&#46;48-0&#46;84&#41;&#44; respectively&#41;&#44; whereas no differences were observed between the cohorts treated with GLP-1RAs and SGLT-2Is&#46; A role of SGLT-2Is in decompensated cirrhosis is also being explored in adequately powered trials&#44; following anecdotal reports of control of refractory ascites&#44; hydrothorax and peripheral edema &#91;<a class="elsevierStyleCrossRef" href="#bib0034">34&#44;</a><a class="elsevierStyleCrossRef" href="#bib0035">35</a>&#93;&#46; With the limits of possible bias inherent to observational studies&#44; these drugs appear to be safe and effective for T2DM treatment in cirrhosis&#46;</p><p id="para0007" class="elsevierStylePara elsevierViewall">In conclusion&#44; a large body of evidence is accumulating for a systematic use of novel antidiabetic drugs&#44; namely GLP-1RAs and SGLT-2Is&#44; also in subjects with cirrhosis&#44; as well as in candidates for liver transplantation <a class="elsevierStyleCrossRef" href="#bib0036">&#91;36&#93;</a>&#44; a population at very high risk of cardiovascular and renal disease&#46; These novel drugs might be effectively associated with metformin and&#47;or pioglitazone&#46; Metformin continuation in cirrhosis with T2DM&#44; in the safe renal function area&#44; improved survival <a class="elsevierStyleCrossRef" href="#bib0037">&#91;37&#93;</a> and also reduced the risk of primary liver cancer <a class="elsevierStyleCrossRef" href="#bib0038">&#91;38&#93;</a>&#44; whereas pioglitazone remains the only drug associated with reduced risk of NASH fibrosis <a class="elsevierStyleCrossRef" href="#bib0039">&#91;39&#93;</a>&#46;</p></span>"
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                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0002"><li class="elsevierStyleListItem" id="celistitem0005"><span class="elsevierStyleLabel">&#8226;</span><p id="para0012" class="elsevierStylePara elsevierViewall">Rare abdominal discomfort</p></li><li class="elsevierStyleListItem" id="celistitem0006"><span class="elsevierStyleLabel">&#8226;</span><p id="para0013" class="elsevierStylePara elsevierViewall">Dose tapering and suspension in the presence of CKD grade 4-5</p></li><li class="elsevierStyleListItem" id="celistitem0007"><span class="elsevierStyleLabel">&#8226;</span><p id="para0014" class="elsevierStylePara elsevierViewall">Risk of lactic acidosis</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0007"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Sulphonylureas and glinides&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0008"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0003"><li class="elsevierStyleListItem" id="celistitem0008"><span class="elsevierStyleLabel">&#8226;</span><p id="para0015" class="elsevierStylePara elsevierViewall">Potent control of glucose levels</p></li><li class="elsevierStyleListItem" id="celistitem0009"><span class="elsevierStyleLabel">&#8226;</span><p id="para0016" class="elsevierStylePara elsevierViewall">Intra-class difference in terms of renal or hepatic metabolism</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0009"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0004"><li class="elsevierStyleListItem" id="celistitem0010"><span class="elsevierStyleLabel">&#8226;</span><p id="para0017" class="elsevierStylePara elsevierViewall">Risk of hypoglycemia</p></li><li class="elsevierStyleListItem" id="celistitem0011"><span class="elsevierStyleLabel">&#8226;</span><p id="para0018" class="elsevierStylePara elsevierViewall">Increased CV risk</p></li><li class="elsevierStyleListItem" id="celistitem0012"><span class="elsevierStyleLabel">&#8226;</span><p id="para0019" class="elsevierStylePara elsevierViewall">Weight gain</p></li><li class="elsevierStyleListItem" id="celistitem0013"><span class="elsevierStyleLabel">&#8226;</span><p id="para0020" class="elsevierStylePara elsevierViewall">Low durability</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0010"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Pioglitazone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0011"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0005"><li class="elsevierStyleListItem" id="celistitem0014"><span class="elsevierStyleLabel">&#8226;</span><p id="para0021" class="elsevierStylePara elsevierViewall">Moderate control of glucose levels</p></li><li class="elsevierStyleListItem" id="celistitem0015"><span class="elsevierStyleLabel">&#8226;</span><p id="para0022" class="elsevierStylePara elsevierViewall">CV and cerebrovascular protection</p></li><li class="elsevierStyleListItem" id="celistitem0016"><span class="elsevierStyleLabel">&#8226;</span><p id="para0023" class="elsevierStylePara elsevierViewall">Very low risk of hypoglycemia</p></li><li class="elsevierStyleListItem" id="celistitem0017"><span class="elsevierStyleLabel">&#8226;</span><p id="para0024" class="elsevierStylePara elsevierViewall">Reduced progression of NASH fibrosis</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0012"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0006"><li class="elsevierStyleListItem" id="celistitem0018"><span class="elsevierStyleLabel">&#8226;</span><p id="para0025" class="elsevierStylePara elsevierViewall">Weight gain</p></li><li class="elsevierStyleListItem" id="celistitem0019"><span class="elsevierStyleLabel">&#8226;</span><p id="para0026" class="elsevierStylePara elsevierViewall">Heart failure risk</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0013"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">AGIs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0014"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0007"><li class="elsevierStyleListItem" id="celistitem0020"><span class="elsevierStyleLabel">&#8226;</span><p id="para0027" class="elsevierStylePara elsevierViewall">Modest post-prandial glucose control</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0015"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0008"><li class="elsevierStyleListItem" id="celistitem0021"><span class="elsevierStyleLabel">&#8226;</span><p id="para0028" class="elsevierStylePara elsevierViewall">Abdominal discomfort</p></li><li class="elsevierStyleListItem" id="celistitem0022"><span class="elsevierStyleLabel">&#8226;</span><p id="para0029" class="elsevierStylePara elsevierViewall">Low compliance</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0016"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">Insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0017"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0009"><li class="elsevierStyleListItem" id="celistitem0023"><span class="elsevierStyleLabel">&#8226;</span><p id="para0030" class="elsevierStylePara elsevierViewall">Maximum control of glucose levels</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0018"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0010"><li class="elsevierStyleListItem" id="celistitem0024"><span class="elsevierStyleLabel">&#8226;</span><p id="para0031" class="elsevierStylePara elsevierViewall">Weight gain</p></li><li class="elsevierStyleListItem" id="celistitem0025"><span class="elsevierStyleLabel">&#8226;</span><p id="para0032" class="elsevierStylePara elsevierViewall">High risk of hypoglycemia</p></li><li class="elsevierStyleListItem" id="celistitem0026"><span class="elsevierStyleLabel">&#8226;</span><p id="para0033" class="elsevierStylePara elsevierViewall">Low compliance and high burden with intensive treatment</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0019"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">DPP-4Is&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0020"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0011"><li class="elsevierStyleListItem" id="celistitem0027"><span class="elsevierStyleLabel">&#8226;</span><p id="para0034" class="elsevierStylePara elsevierViewall">Moderate control of glucose levels</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0021"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0012"><li class="elsevierStyleListItem" id="celistitem0028"><span class="elsevierStyleLabel">&#8226;</span><p id="para0035" class="elsevierStylePara elsevierViewall">Negligible adverse events</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0022"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">GLP-1RAs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0023"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0013"><li class="elsevierStyleListItem" id="celistitem0029"><span class="elsevierStyleLabel">&#8226;</span><p id="para0036" class="elsevierStylePara elsevierViewall">Potent control of glucose levels &#40;valid alternative to insulin treatment&#41;</p></li><li class="elsevierStyleListItem" id="celistitem0030"><span class="elsevierStyleLabel">&#8226;</span><p id="para0037" class="elsevierStylePara elsevierViewall">Reduced CV and renal disease progression</p></li><li class="elsevierStyleListItem" id="celistitem0031"><span class="elsevierStyleLabel">&#8226;</span><p id="para0038" class="elsevierStylePara elsevierViewall">Important weight loss</p></li><li class="elsevierStyleListItem" id="celistitem0032"><span class="elsevierStyleLabel">&#8226;</span><p id="para0039" class="elsevierStylePara elsevierViewall">Very low risk of hypoglycemia</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0024"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0014"><li class="elsevierStyleListItem" id="celistitem0033"><span class="elsevierStyleLabel">&#8226;</span><p id="para0040" class="elsevierStylePara elsevierViewall">Nausea and abdominal discomfort &#40;relatively high discontinuation rate&#41;</p></li><li class="elsevierStyleListItem" id="celistitem0034"><span class="elsevierStyleLabel">&#8226;</span><p id="para0041" class="elsevierStylePara elsevierViewall">Possible risk of weight loss-induced sarcopenia</p></li><li class="elsevierStyleListItem" id="celistitem0035"><span class="elsevierStyleLabel">&#8226;</span><p id="para0042" class="elsevierStylePara elsevierViewall">Limited use in advanced CKD</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><a name="en0025"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top">SGLT-2Is&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0026"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0015"><li class="elsevierStyleListItem" id="celistitem0036"><span class="elsevierStyleLabel">&#8226;</span><p id="para0043" class="elsevierStylePara elsevierViewall">Moderate control of glucose levels</p></li><li class="elsevierStyleListItem" id="celistitem0037"><span class="elsevierStyleLabel">&#8226;</span><p id="para0044" class="elsevierStylePara elsevierViewall">Reduced risk of CV and renal disease progression</p></li><li class="elsevierStyleListItem" id="celistitem0038"><span class="elsevierStyleLabel">&#8226;</span><p id="para0045" class="elsevierStylePara elsevierViewall">Prevention of heart failure</p></li><li class="elsevierStyleListItem" id="celistitem0039"><span class="elsevierStyleLabel">&#8226;</span><p id="para0046" class="elsevierStylePara elsevierViewall">Modest weight loss</p></li><li class="elsevierStyleListItem" id="celistitem0040"><span class="elsevierStyleLabel">&#8226;</span><p id="para0047" class="elsevierStylePara elsevierViewall">Very low risk of hypoglycemia</p></li><li class="elsevierStyleListItem" id="celistitem0041"><span class="elsevierStyleLabel">&#8226;</span><p id="para0048" class="elsevierStylePara elsevierViewall">Long-term durability</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><a name="en0027"></a><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="top"><ul class="elsevierStyleList" id="celist0016"><li class="elsevierStyleListItem" id="celistitem0042"><span class="elsevierStyleLabel">&#8226;</span><p id="para0049" class="elsevierStylePara elsevierViewall">Polyuria causing low compliance</p></li><li class="elsevierStyleListItem" id="celistitem0043"><span class="elsevierStyleLabel">&#8226;</span><p id="para0050" class="elsevierStylePara elsevierViewall">Risk of genital and urinary infections</p></li><li class="elsevierStyleListItem" id="celistitem0044"><span class="elsevierStyleLabel">&#8226;</span><p id="para0051" class="elsevierStylePara elsevierViewall">Low effectiveness in advanced CKD</p></li></ul>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spara001" class="elsevierStyleSimplePara elsevierViewall">Agents for diabetes treatment and their clinical effects&#46; The last three classes have been added to the spectrum of available treatment in the past 15 years&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "cebibsec1"
          "bibliografiaReferencia" => array:39 [
            0 => array:3 [
              "identificador" => "bib0001"
              "etiqueta" => "&#91;1&#93;"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "9&#46; Pharmacologic approaches to glycemic treatment&#58; Standards of Medical Care in Diabetes-2022"
                      "autores" => array:1 [
                        0 => array:3 [
                          "colaboracion" => "American Diabetes Association Professional Practice Committee"
                          "etal" => true
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                            2 => "G Bakris"
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                      "Revista" => array:6 [
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                        "fecha" => "2022"
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                        "link" => array:1 [
                          0 => array:2 [
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                            "web" => "Medline"
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            1 => array:3 [
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                    0 => array:2 [
                      "titulo" => "Sodium-glucose cotransporter protein-2 &#40;SGLT-2&#41; inhibitors and glucagon-like peptide-1 &#40;GLP-1&#41; receptor agonists for type 2 diabetes&#58; systematic review and network meta-analysis of randomised controlled trials"
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                          "etal" => true
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                      "titulo" => "A view on the quality of diabetes care in Italy and the role of Diabetes Clinics from the 2018 ARNO Diabetes Observatory"
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                    0 => array:2 [
                      "titulo" => "Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease"
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                      "titulo" => "The treatment of diabetes mellitus of patients with chronic liver disease"
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                            0 => "D Garcia-Compean"
                            1 => "JA Gonzalez-Gonzalez"
                            2 => "FJ Lavalle-Gonzalez"
                            3 => "EI Gonzalez-Moreno"
                            4 => "HJ Maldonado-Garza"
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                    0 => array:2 [
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                      "titulo" => "Effects of Child-Pugh B cirrhosis on pharmacokinetics of tofogliflozin&#44; a new sodium-glucose co-transporter &#40;SGLT2&#41; inhibitor"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
                            0 => "H Yamada"
                            1 => "H Ohira"
                            2 => "F Ikegami"
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                    0 => array:2 [
                      "doi" => "10.1055/a-1202-0818"
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                      "titulo" => "Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes"
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                    0 => array:2 [
                      "doi" => "10.1007/s40262-014-0198-2"
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                          "etal" => false
                          "autores" => array:3 [
                            0 => "SM Morris"
                            1 => "MJ Armstrong"
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                      "doi" => "10.1016/j.cgh.2021.09.023"
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos