Diabetes mellitus type 2 medical therapy: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Diabetes mellitus type 2}} | {{Diabetes mellitus type 2}} | ||
{{CMG}}; {{AE}} | {{CMG}}; {{AE}} {{MehdiP}}{{Anahita}} {{JA}} | ||
==Overview== | ==Overview== | ||
The main goals of treatment are | The main goals of [[treatment]] are to eliminate [[hyperglycemic]] [[symptoms]], control the long term [[complications]] and improve the patient's quality of life. [[Diabetes mellitus type 2]] is initially treated by life style modification and [[weight loss]], especially in [[obese]] patients. [[Metformin]] is the first line pharmacologic [[therapy]] that is usually started once the diagnosis is confirmed unless [[Contraindication|contraindications]] exist. Nevertheless, in patients presented with high [[HbA1C]]/fasting [[blood sugar]] levels or if glycemic goals are not achieved, a second agent must be added to [[metformin]]. A wide range of options are available to add as [[combination therapy]] based on the patient's condition and [[Comorbidity|comorbidities]]. | ||
Diabetes mellitus type 2 is | ==Pharmacologic therapy== | ||
===Inpatients=== | |||
{{main|Diabetes Care in the Hospital Setting}} | |||
===Outpatients=== | |||
A [[network meta-analysis]] summarizes the risks and benefits of available medications for [[diabetes mellitus type 2]]<ref name="pmid37024129">{{cite journal| author=Shi Q, Nong K, Vandvik PO, Guyatt GH, Schnell O, Rydén L | display-authors=etal| title=Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials. | journal=BMJ | year= 2023 | volume= 381 | issue= | pages= e074068 | pmid=37024129 | doi=10.1136/bmj-2022-074068 | pmc=10077111 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=37024129 }} </ref>. | |||
*Medical [[therapy]] starts with [[metformin]] [[monotherapy]] unless there is a [[contraindication]] for it. In the following conditions, treatment starts with dual [[therapy]]:<ref name="pmid24145991">{{cite journal |vauthors=Qaseem A, Hopkins RH, Sweet DE, Starkey M, Shekelle P |title=Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians |journal=Ann. Intern. Med. |volume=159 |issue=12 |pages=835–47 |year=2013 |pmid=24145991 |doi=10.7326/0003-4819-159-12-201312170-00726 |url=}}</ref><ref name="pmid27979887">{{cite journal |vauthors= |title=Standards of Medical Care in Diabetes-2017: Summary of Revisions |journal=Diabetes Care |volume=40 |issue=Suppl 1 |pages=S4–S5 |year=2017 |pmid=27979887 |doi=10.2337/dc17-S003 |url=}}</ref><ref name="pmid12145243">{{cite journal |vauthors=Colagiuri S, Cull CA, Holman RR |title=Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes?: U.K. prospective diabetes study 61 |journal=Diabetes Care |volume=25 |issue=8 |pages=1410–7 |year=2002 |pmid=12145243 |doi= |url=}}</ref><ref name="pmid1441492">{{cite journal |vauthors=Davidson MB |title=Successful treatment of markedly symptomatic patients with type II diabetes mellitus using high doses of sulfonylurea agents |journal=West. J. Med. |volume=157 |issue=2 |pages=199–200 |year=1992 |pmid=1441492 |pmc=1011263 |doi= |url=}}</ref><ref name="pmid27088241">{{cite journal |vauthors=Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S |title=Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis |journal=Ann. Intern. Med. |volume=164 |issue=11 |pages=740–51 |year=2016 |pmid=27088241 |doi=10.7326/M15-2650 |url=}}</ref><ref name="pmid27434443">{{cite journal |vauthors=Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, Natale P, Saglimbene V, Badve SV, Cho Y, Nadeau-Fredette AC, Burke M, Faruque L, Lloyd A, Ahmad N, Liu Y, Tiv S, Wiebe N, Strippoli GF |title=Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis |journal=JAMA |volume=316 |issue=3 |pages=313–24 |year=2016 |pmid=27434443 |doi=10.1001/jama.2016.9400 |url=}}</ref> | |||
**If [[HbA1C]] is greater than 9, start with dual oral blood [[glucose]] lowering agent. | |||
**If [[HbA1C]] is greater than 10 or [[blood glucose]] is more than 300 mg/dl or patient is markedly [[symptomatic]], consider [[combination therapy]] with [[insulin]]. | |||
*The most effective class of drugs for reducing death are probably [[SGLT2|sodium glucose transporter 2]] ([[SGLT2]]) inhibitors or [[GLP-1]] receptor [[agonist|agonists]].<ref>GitHub Contributors. Hypertonic Saline for Bronchiolitis: a living systematic review. GitHub. Available at http://openmetaanalysis.github.io/Diabetes-mellitus-type-2-mortality-prevention-with-pharmacotherapy/. Accessed June 11, 2018.</ref> | |||
===Metformin=== | ===Metformin=== | ||
Metformin is effective and | |||
* [[Metformin]] is effective, safe and inexpensive. | |||
*It may reduce risk of [[cardiovascular]] events and death. | |||
*Patients should be advised to stop the [[medication]] in cases of [[nausea]], [[vomiting]] or [[dehydration]]. | |||
* [[Metformin]] is capable of decreasing the [[body weight]] but it's effect on [[muscle]] mass is unclear.<ref name="pmid31372016">{{cite journal| author=Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D| title=Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship. | journal=Diabetes Metab Syndr Obes | year= 2019 | volume= 12 | issue= | pages= 1057-1072 | pmid=31372016 | doi=10.2147/DMSO.S186600 | pmc=6630094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31372016 }}</ref> | |||
* A systemic [[review]], observing 34,000 patients in total concluded that [[Metformin]] is as safe as other [[Anti-diabetic drug|anti-diabetic]] treatments in diabetic patients with [[Congestive heart failure|heart failure.]]<ref name="EurichWeir2013">{{cite journal|last1=Eurich|first1=Dean T.|last2=Weir|first2=Daniala L.|last3=Majumdar|first3=Sumit R.|last4=Tsuyuki|first4=Ross T.|last5=Johnson|first5=Jeffrey A.|last6=Tjosvold|first6=Lisa|last7=Vanderloo|first7=Saskia E.|last8=McAlister|first8=Finlay A.|title=Comparative Safety and Effectiveness of Metformin in Patients With Diabetes Mellitus and Heart Failure|journal=Circulation: Heart Failure|volume=6|issue=3|year=2013|pages=395–402|issn=1941-3289|doi=10.1161/CIRCHEARTFAILURE.112.000162}}</ref> | |||
* Some studies demonstrated lower risk of [[Mortality rate|mortality]] in [[Diabetes mellitus|diabetic]] patients with concurrent [[Chronic obstructive pulmonary disease|COPD]] or [[Asthma]] who were taking [[Metformin]] compared to non-users.<ref name="pmid30761687">{{cite journal| author=Mendy A, Gopal R, Alcorn JF, Forno E| title=Reduced mortality from lower respiratory tract disease in adult diabetic patients treated with metformin. | journal=Respirology | year= 2019 | volume= 24 | issue= 7 | pages= 646-651 | pmid=30761687 | doi=10.1111/resp.13486 | pmc=6579707 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30761687 }}</ref> | |||
* [[Metformin]] use in [[diabetes mellitus|diabetic]] patients with [[sepsis]], [[tuberculosis]] and [[Chronic obstructive pulmonary disease]] [[Chronic obstructive pulmonary disease|(COPD]]) were associated with lower [[mortality rate]].<ref name="LiangDing2019">{{cite journal|last1=Liang|first1=Huoyan|last2=Ding|first2=Xianfei|last3=Li|first3=Lifeng|last4=Wang|first4=Tian|last5=Kan|first5=Quancheng|last6=Wang|first6=Lexin|last7=Sun|first7=Tongwen|title=Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies|journal=Critical Care|volume=23|issue=1|year=2019|issn=1364-8535|doi=10.1186/s13054-019-2346-4}}</ref><ref name="SinghKhunti2020">{{cite journal|last1=Singh|first1=Awadhesh Kumar|last2=Khunti|first2=Kamlesh|title=Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review|journal=Diabetes Research and Clinical Practice|volume=165|year=2020|pages=108266|issn=01688227|doi=10.1016/j.diabres.2020.108266}}</ref> | |||
*One of the possible effects of [[Metformin]] is [[Gut flora|gut microbiota]] alteration, which results in Tauroursodeoxycholic acid (TUDCA) and Glycoursodeoxycholic Acid (GUDCA) elevation. Since both TUDCA and GUDCA act as intestinal [[farnesoid X receptor]] ([[Farnesoid X receptor|FXR]]) [[Receptor antagonist|antagonists]], they can be effective in [[hyperglycemia]] [[treatment]].<ref name="WuZhou2020">{{cite journal|last1=Wu|first1=Yingjie|last2=Zhou|first2=An|last3=Tang|first3=Li|last4=Lei|first4=Yuanyuan|last5=Tang|first5=Bo|last6=Zhang|first6=Linjing|title=Bile Acids: Key Regulators and Novel Treatment Targets for Type 2 Diabetes|journal=Journal of Diabetes Research|volume=2020|year=2020|pages=1–11|issn=2314-6745|doi=10.1155/2020/6138438}}</ref> | |||
==== Contraindications ==== | |||
*As of June 2020, The US Food and Drug Administration ([[Food and Drug Administration|FDA]]) recalls [[extended-release metformin]] which is made by few pharma companies due to detection of high levels of [[N-Nitrosodimethylamine]] ([[N-Nitrosodimethylamine|NDMA]]).<ref name="pmid9167101">{{cite journal| author=Sulkin TV, Bosman D, Krentz AJ| title=Contraindications to metformin therapy in patients with NIDDM. | journal=Diabetes Care | year= 1997 | volume= 20 | issue= 6 | pages= 925-8 | pmid=9167101 | doi=10.2337/diacare.20.6.925 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9167101 }} </ref><ref name="pmid16283245">{{cite journal| author=Holstein A, Stumvoll M| title=Contraindications can damage your health--is metformin a case in point? | journal=Diabetologia | year= 2005 | volume= 48 | issue= 12 | pages= 2454-9 | pmid=16283245 | doi=10.1007/s00125-005-0026-1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16283245 }} </ref> | |||
*[[N-Nitrosodimethylamine]] ([[N-Nitrosodimethylamine|NDMA]]) is a [[Carcinogen|carcinogenic]] agent when exposed in higher levels leads to [[cancer]]. | |||
*The following are the pharma companies that the [[FDA]] recalls the [[Metformin extended release|extended-release metformin:]] | |||
**Lupin | |||
**Apotex Corp | |||
**Actavis | |||
**Time-Cap Labs, Inc | |||
**Amneal | |||
*[[Contraindication|Contraindications]] to [[metformin]] include, [[heart failure]], [[liver failure]], [[GFR]] ≤30 and [[metabolic acidosis]]. | |||
{| class="wikitable" | |||
|+,[[Randomized controlled trial]] comparing initial doses for metformin<ref name="pmid9428832">{{cite journal| author=Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL| title=Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. | journal=Am J Med | year= 1997 | volume= 103 | issue= 6 | pages= 491-7 | pmid=9428832 | doi=10.1016/s0002-9343(97)00254-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9428832 }} </ref>. | |||
! style="text-align: center;" | Total duration was 14 weeks with at least 8 weeks on final dose. | |||
! style="text-align: center;" | Placebo | |||
! style="text-align: center;" | 500 mg once daily | |||
! style="text-align: center;" | 1000 mg | |||
(500 mg twice daily) | |||
! style="text-align: center;" | 1500 mg | |||
(500 mg thrice daily) | |||
! style="text-align: center;" | 2000 mg | |||
(1000 mg twice daily) | |||
! style="text-align: center;" | 2500 mg | |||
(1000 am, 500 lunch, 1000 at supper daily | |||
|- | |||
| Any [[Gastrointestinal tract|GI]] [[Adverse drug reaction|ADR]] | |||
| style="text-align: center;" | 13% | |||
| style="text-align: center;" | 16% | |||
| style="text-align: center;" | 29% | |||
| style="text-align: center;" | 24% | |||
| style="text-align: center;" | 23% | |||
| style="text-align: center;" | 29% | |||
|- | |||
| [[Diarrhea]] | |||
| style="text-align: center;" | 5% | |||
| style="text-align: center;" | 8% | |||
| style="text-align: center;" | 21% | |||
| style="text-align: center;" | 12% | |||
| style="text-align: center;" | 19% | |||
| style="text-align: center;" | 14% | |||
|- | |||
| [[HbA1c]] change | |||
| style="text-align: center;" | + 1.2 | |||
| style="text-align: center;" | + 0.3 | |||
| style="text-align: center;" | + 0.1 | |||
| style="text-align: center;" | - 0.5 | |||
| style="text-align: center;" | - 0.8 | |||
| style="text-align: center;" | - 0.04 | |||
|- | |||
| colspan="7" |'''Source''': {{cite journal| author=Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL| title=Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial. | journal=Am J Med | year= 1997 | volume= 103 | issue= 6 | pages= 491-7 | pmid=9428832 | doi=10.1016/s0002-9343(97)00254-4 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9428832 }} | |||
|} | |||
===Insulin=== | |||
* The lack of inexpensive, generic [[insulin]] may lead to underuse of insulin<ref name="pmid30508012">{{cite journal| author=Herkert D, Vijayakumar P, Luo J, Schwartz JI, Rabin TL, DeFilippo E et al.| title=Cost-Related Insulin Underuse Among Patients With Diabetes. | journal=JAMA Intern Med | year= 2018 | volume= | issue= | pages= | pmid=30508012 | doi=10.1001/jamainternmed.2018.5008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30508012 }} </ref> and occurs for unusual reasons<ref name="pmid25785977">{{cite journal| author=Greene JA, Riggs KR| title=Why is there no generic insulin? Historical origins of a modern problem. | journal=N Engl J Med | year= 2015 | volume= 372 | issue= 12 | pages= 1171-5 | pmid=25785977 | doi=10.1056/NEJMms1411398 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=25785977 }} </ref>. | |||
* The [[insulin]] [[analogue|analogues]] may not provide a meaningful advantage<ref name="pmid30694321">{{cite journal| author=Luo J, Khan NF, Manetti T, Rose J, Kaloghlian A, Gadhe B et al.| title=Implementation of a Health Plan Program for Switching From Analogue to Human Insulin and Glycemic Control Among Medicare Beneficiaries With Type 2 Diabetes. | journal=JAMA | year= 2019 | volume= 321 | issue= 4 | pages= 374-384 | pmid=30694321 | doi=10.1001/jama.2018.21364 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30694321 }} </ref><ref name="pmid29936529">{{cite journal| author=Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ| title=Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes. | journal=JAMA | year= 2018 | volume= 320 | issue= 1 | pages= 53-62 | pmid=29936529 | doi=10.1001/jama.2018.7993 | pmc=6134432 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29936529 }} </ref><ref name="pmid17443605">{{cite journal| author=Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J et al.| title=Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. | journal=Cochrane Database Syst Rev | year= 2007 | volume= | issue= 2 | pages= CD005613 | pmid=17443605 | doi=10.1002/14651858.CD005613.pub3 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17443605 }} [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=17764137 Review in: ACP J Club. 2007 Sep-Oct;147(2):46] </ref>. | |||
* Although [[Insulin]] increases the [[body weight]], some data suggest that it is capable of increasing the [[muscle]] mass.<ref name="pmid313720162">{{cite journal| author=Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D| title=Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship. | journal=Diabetes Metab Syndr Obes | year= 2019 | volume= 12 | issue= | pages= 1057-1072 | pmid=31372016 | doi=10.2147/DMSO.S186600 | pmc=6630094 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=31372016 }}</ref> | |||
* A [[meta-analysis]] of [[randomized controlled trial]]s by the [[Cochrane Collaboration]] found "only a minor clinical benefit of [[treatment]] with long-acting [[insulin]] [[analogue|analogues]] for patients with [[diabetes mellitus type 2]]" compared to human [[insulin]]<ref name="pmid17443605">{{cite journal |author=Horvath K ''et al.'' |title=Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus |journal=Cochrane database of systematic reviews (Online) |volume= |pages=CD005613 |year=2007 |pmid=17443605}}</ref> More recent [[randomized controlled trial]]s have found no differences with glargine<ref name="pmid18936501">{{cite journal |author=Esposito K ''et al.'' |title=Addition of neutral protamine lispro insulin or insulin glargine to oral type 2 diabetes regimens for patients with suboptimal glycemic control: a randomized trial |journal=Ann Intern Med |volume=149 |pages=531–9|year=2008 |pmid=18936501 |doi= |url= |issn=}}</ref> and have found that although long acting insulins were less effective, they were associated with less hypoglycemia.<ref name="pmid17890232">{{cite journal |author=Holman RR ''et al.'' |title=Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes |journal=N Engl J Med |volume=357 |pages=1716–30 |year=2007 |pmid=17890232 |doi=10.1056/NEJMoa075392|url=http://content.nejm.org/cgi/pmidlookup?view=short&pmid=17890232&promo=ONFLNS19 |issn=}}</ref> | |||
* Premixed combinations of [[insulin]], human or [[analogue]], have similar reductions in [[HbA1c]]<ref name="pmid18794553">{{cite journal| author=Qayyum R, Bolen S, Maruthur N, Feldman L, Wilson LM, Marinopoulos SS et al.| title=Systematic review: comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes. | journal=Ann Intern Med | year= 2008 | volume= 149 | issue= 8 | pages= 549-59 | pmid=18794553 | doi= | pmc=4762020 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18794553 }} </ref>. A [[Cohort study|cohort]] study likewise found similar rates of hypoglycemia<ref name="pmid29936529">{{cite journal| author=Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ| title=Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes. | journal=JAMA | year= 2018 | volume= 320 | issue= 1 | pages= 53-62 | pmid=29936529 | doi=10.1001/jama.2018.7993 | pmc=6134432 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29936529 }} </ref>. | |||
====Bedtime insulin==== | |||
For [[Diabetes mellitus type 2]]: | |||
*Initially, a [[randomized controlled trial]] found that adding bedtime [[insulin]] to patients failed oral [[medication|medications]] is more effective ''and'' with less [[weight gain]] than using multiple dose [[insulin]].<ref name="pmid1406860">{{cite journal |author=Yki-Järvinen H, Kauppila M, Kujansuu E, ''et al'' |title=Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus |journal=N. Engl. J. Med. |volume=327 |issue=20 |pages=1426-33 |year=1992 |pmid=1406860|doi=|url=http://content.nejm.org/cgi/content/abstract/327/20/1426}}</ref> Nightly insulin combines better with [[metformin]] that with [[sulfonylurea]]s.<ref name="pmid10068412">{{cite journal |author=Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M |title=Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial |journal=Ann. Intern. Med. |volume=130 |issue=5|pages=389–96 |year=1999 |pmid=10068412 |doi=|url=http://www.annals.org/cgi/content/full/130/5/389}}</ref> | |||
* More recently, the Cochrane Collaboration concluded: "hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with insulin detemir instead of NPH insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted"<ref name="pmid33166419">{{cite journal| author=Semlitsch T, Engler J, Siebenhofer A, Jeitler K, Berghold A, Horvath K| title=(Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus. | journal=Cochrane Database Syst Rev | year= 2020 | volume= 11 | issue= | pages= CD005613 | pmid=33166419 | doi=10.1002/14651858.CD005613.pub4 | pmc=8095010 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=33166419 }} </ref>. | |||
* Kaiser Permanente, in a large cohort study, found no benefit from long-acting insulin analogues compared to human NPH insulin<ref name="pmid29936529">{{cite journal| author=Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ| title=Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes. | journal=JAMA | year= 2018 | volume= 320 | issue= 1 | pages= 53-62 | pmid=29936529 | doi=10.1001/jama.2018.7993 | pmc=6134432 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29936529 }} [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=32182291 Review in: J Fam Pract. 2020 Mar;69(2):94-95] </ref>. | |||
; Dosing | |||
The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L)<ref name="pmid1406860" />. If the fasting glucose is reported in mg/dl, multiple by 0.05551 (or divided by 18) to convert to mmol/L.<ref name="pmid9761809">{{cite journal |author=Kratz A, Lewandrowski KB |title=Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values |journal=N. Engl. J. Med. |volume=339|issue=15 |pages=1063–72 |year=1998 |pmid=9761809 |doi=}}</ref> | |||
Consider increasing by 3 units at a time<ref name="pmid30851006">{{cite journal| author=Russell-Jones D, Dauchy A, Delgado E, Dimitriadis G, Frandsen HA, Popescu L | display-authors=etal| title=Take Control: A randomized trial evaluating the efficacy and safety of self- versus physician-managed titration of insulin glargine 300 U/mL in patients with uncontrolled type 2 diabetes. | journal=Diabetes Obes Metab | year= 2019 | volume= 21 | issue= 7 | pages= 1615-1624 | pmid=30851006 | doi=10.1111/dom.13697 | pmc=6767413 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=30851006 }} </ref>. | |||
; Monitoring | |||
In both trails above, dosing was adjusted by monitoring fasting sugars<ref name="pmid1406860"/><ref name="pmid10068412"/>. In the second trial, the patient checked their "diurnal blood glucose level, measurements were taken before and 1.5 hours after breakfast, lunch and dinner; at 10 p.m.; and at 4 a.m." once a week for the first 3 months and then every other week<ref name="pmid10068412"/>. | |||
; Availability | |||
Novo Nordisk’s Novolin ReliOn N is less expensive at Walmart and CVS pharmacies<ref>Novo Nordisk has partnerships to provide low-cost human insulin. Available at https://www.novocare.com/diabetes-overview/let-us-help/human-insulin-options.html</ref>. | |||
===Combination therapy=== | ===Combination therapy=== | ||
Any agent can be added as second drug based on patient condition | *Any agent can be added as second drug based on patient condition. Nevertheless, the American Association of Clinical Endocrinologists recommends either [[incretin]] based [[therapy]] or [[SGLT2|sodium glucose transporter 2]] ([[SGLT2]]) inhibition agents.<ref name="pmid27088241">{{cite journal| author=Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z | display-authors=etal| title=Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. | journal=Ann Intern Med | year= 2016 | volume= 164 | issue= 11 | pages= 740-51 | pmid=27088241 | doi=10.7326/M15-2650 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27088241 }} [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=&cmd=prlinks&id=27679666 Review in: Evid Based Med. 2016 Dec;21(6):223] </ref><ref name="pmid10755495">{{cite journal| author=Fonseca V, Rosenstock J, Patwardhan R, Salzman A| title=Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. | journal=JAMA | year= 2000 | volume= 283 | issue= 13 | pages= 1695-702 | pmid=10755495 | doi=10.1001/jama.283.13.1695 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10755495 }} </ref> | ||
The following table summarize the available FDA approved glucose lowering agents that may help to individualize treatment for each patient. | *The following table summarize the available [[FDA]] approved [[glucose]] lowering agents that may help to individualize [[treatment]] for each patient. | ||
{| | {| style="border: 0px; font-size: 90%; margin: 3px;" align=center | ||
!Class | !align="center" style="background:#DCDCDC;"|Class | ||
!Drug | !align="center" style="background:#DCDCDC;"|Drug | ||
!Mechanism of action | !align="center" style="background:#DCDCDC;"|Mechanism of action | ||
!Primary physiologic action | !align="center" style="background:#DCDCDC;"|Primary physiologic action | ||
!Advantages | !align="center" style="background:#DCDCDC;"|Advantages | ||
!Disadvantages | !align="center" style="background:#DCDCDC;"|Disadvantages | ||
!Cost | !align="center" style="background:#DCDCDC;"|Cost | ||
|- | |- | ||
|[[Biguanides | |align="center" style="background:#DCDCDC;"|[[Biguanides]] | ||
|[[Metformin]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Metformin]] | ||
|Activates [[AMP-activated protein kinase|AMP-kinase]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[AMP-activated protein kinase|AMP-kinase]] | ||
|↓ Hepatic glucose | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |↓ Hepatic glucose | ||
production | production | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Extensive experience | * Extensive experience | ||
Line 42: | Line 138: | ||
* Relatively higher [[A1C]] efficacy | * Relatively higher [[A1C]] efficacy | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Gastrointestinal side effects ([[diarrhea]], [[abdominal cramping]], [[nausea]]) | * Gastrointestinal side effects ([[diarrhea]], [[abdominal cramping]], [[nausea]]) | ||
* [[Vitamin B12 deficiency]] | * [[Vitamin B12 deficiency]] | ||
* Contraindications: [[eGFR]] | * [[contraindication|Contraindications]]: [[eGFR]] ≤30 mL/min/1.73 m2, [[acidosis]], [[hypoxia]], [[dehydration]]. | ||
* [[Lactic acidosis]] risk (rare) | * [[Lactic acidosis]] risk (rare) | ||
|Low | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | ||
|- | |- | ||
|[[Sulfonylureas]] | |align="center" style="background:#DCDCDC;"|[[Sulfonylureas]] | ||
|2nd generation | |style="padding: 5px 5px; background: #F5F5F5;" align="left" |2nd generation | ||
* [[Glyburide]] | * [[Glyburide]] | ||
Line 59: | Line 155: | ||
* [[Glimepiride]] | * [[Glimepiride]] | ||
|Closes [[Potassium|K]]-[[ATP]] channels on [[beta cell]] [[Plasma membrane|plasma membranes]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Closes [[Potassium|K]]-[[ATP]] channels on [[beta cell]] [[Plasma membrane|plasma membranes]] | ||
|↑ [[Insulin]] secretion | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |↑ [[Insulin]] secretion | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Extensive experience | * Extensive experience | ||
Line 67: | Line 163: | ||
* Relatively higher [[A1C]] efficacy | * Relatively higher [[A1C]] efficacy | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Hypoglycemia]] | * [[Hypoglycemia]] | ||
* ↑ Weight | * ↑ Weight | ||
|Low | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | ||
|- | |- | ||
|[[Meglitinide|Meglitinides]] | |align="center" style="background:#DCDCDC;"|[[Meglitinide|Meglitinides]] | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Repaglinide]] | * [[Repaglinide]] | ||
* [[Nateglinide]] | * [[Nateglinide]] | ||
|Closes [[Potassium|K]]-[[ATP]] channels on [[beta cell]] [[Plasma membrane|plasma membranes]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Closes [[Potassium|K]]-[[ATP]] channels on [[beta cell]] [[Plasma membrane|plasma membranes]] | ||
|↑ [[Insulin]] secretion | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |↑ [[Insulin]] secretion | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↓ [[Postprandial]] glucose excursions | * ↓ [[Postprandial]] glucose excursions | ||
* Dosing flexibility | * Dosing flexibility | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Hypoglycemia]] | * [[Hypoglycemia]] | ||
Line 91: | Line 187: | ||
* Frequent dosing schedule | * Frequent dosing schedule | ||
|Moderate | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Moderate | ||
|- | |- | ||
|[[Thiazolidinedione | |align="center" style="background:#DCDCDC;"|[[Thiazolidinedione]] | ||
(TZDs) | ([[TZD|TZDs]]) | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Pioglitazone]]<sup>‡</sup> | * [[Pioglitazone]]<sup>‡</sup> | ||
* [[Rosiglitazone]]<sup>§</sup> | * [[Rosiglitazone]]<sup>§</sup> | ||
|Activates the nuclear transcription factor [[PPARG|PPAR-gama]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates the nuclear transcription factor [[PPARG|PPAR-gama]] | ||
|↑ Insulin sensitivity | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |↑ Insulin sensitivity | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare hypoglycemia | * Rare [[hypoglycemia]] | ||
* Relatively higher A1C efficacy | * Relatively higher [[A1C]] efficacy | ||
* Durability | * Durability | ||
* ↓ Triglycerides (pioglitazone) | * ↓ [[Triglyceride|Triglycerides]] ([[pioglitazone]]) | ||
* ↓ CVD events (PROactive, pioglitazone) | * ↓ [[CVD]] events (PROactive, [[pioglitazone]]) | ||
* ↓ Risk of stroke and MI in patients without diabetes and with insulin resistance and history of recent [[stroke]] or [[TIA]] | * ↓ Risk of [[stroke]] and [[MI]] in patients without [[diabetes]] and with [[insulin resistance]] and history of recent [[stroke]] or [[TIA]] | ||
| | *[[Pioglitazone]] use is associated with higher chance of [[pneumonia]]<ref name="SinghKhunti20202">{{cite journal|last1=Singh|first1=Awadhesh Kumar|last2=Khunti|first2=Kamlesh|title=Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review|journal=Diabetes Research and Clinical Practice|volume=165|year=2020|pages=108266|issn=01688227|doi=10.1016/j.diabres.2020.108266}}</ref> | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* ↑ Weight | * ↑ Weight | ||
* [[Edema]]/[[heart failure]] | * [[Edema]]/[[heart failure]] | ||
* Bone fractures | * [[bone fracture|Bone fractures]] | ||
* ↑ [[LDL-C]] ([[rosiglitazone]]) | * ↑ [[LDL-C]] ([[rosiglitazone]]) | ||
|Low | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | ||
|- | |- | ||
|α-Glucosidase | |align="center" style="background:#DCDCDC;"|α-Glucosidase | ||
inhibitors | inhibitors | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Acarbose]] | * [[Acarbose]] | ||
* [[Miglitol]] | * [[Miglitol]] | ||
|Inhibits intestinal | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Inhibits intestinal | ||
α-glucosidase | α-glucosidase | ||
|Slows intestinal carbohydrate | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Slows intestinal carbohydrate | ||
digestion/absorption | digestion/absorption | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare hypoglycemia | * Rare hypoglycemia | ||
* ↓ Postprandial glucose excursions | * ↓ Postprandial [[glucose]] excursions | ||
* ↓ CVD events in prediabetes | * ↓ [[CVD]] events in [[prediabetes]] | ||
* | * Nonsystemic | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Generally modest A1C efficacy | * Generally modest A1C efficacy | ||
* Gastrointestinal side effects ([[flatulence]], [[diarrhea]]) | * Gastrointestinal [[side effect|side effects]] ([[flatulence]], [[diarrhea]]) | ||
* Frequent dosing schedule | * Frequent dosing schedule | ||
|Low to | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low to | ||
moderate | moderate | ||
|- | |- | ||
|[[Dipeptidyl peptidase-4 inhibitor|DPP-4]] | |align="center" style="background:#DCDCDC;"|[[Dipeptidyl peptidase-4 inhibitor|DPP-4]] | ||
[[Dipeptidyl peptidase-4 inhibitor|inhibitors]] | [[Dipeptidyl peptidase-4 inhibitor|inhibitors]] | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Sitagliptin]] | * [[Sitagliptin]] | ||
Line 163: | Line 260: | ||
* [[Alogliptin]] | * [[Alogliptin]] | ||
|Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↑ [[Insulin]] secretion (glucose dependent) | * ↑ [[Insulin]] secretion ([[glucose]] dependent) | ||
* ↓ [[Glucagon]] secretion (glucose dependent) | * ↓ [[Glucagon]] secretion ([[glucose]] dependent) | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
* Well tolerated | * Well tolerated | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Angioedema]]/[[urticaria]] and other immune-mediated dermatological effects | * [[Angioedema]]/[[urticaria]] and other immune-mediated dermatological effects | ||
Line 178: | Line 275: | ||
* ↑ [[Heart failure]] hospitalizations ([[saxagliptin]], [[alogliptin]]) | * ↑ [[Heart failure]] hospitalizations ([[saxagliptin]], [[alogliptin]]) | ||
|High | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|Bile acid sequestrants | |align="center" style="background:#DCDCDC;"|[[Bile acid sequestrants]] | ||
|[[Colesevelam]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Colesevelam]] | ||
|Binds bile acids in intestinal tract, | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Binds bile acids in intestinal tract, | ||
increasing hepatic bile acid production | increasing hepatic [[bile acid]] production | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↓ Hepatic glucose production | * ↓ Hepatic [[glucose]] production | ||
* ↑ [[Incretin]] levels | * ↑ [[Incretin]] levels | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
* ↓ [[LDL-C]] | * ↓ [[LDL-C]] | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modest [[A1C]] efficacy | * Modest [[A1C]] efficacy | ||
Line 200: | Line 297: | ||
* ↑ [[Triglyceride|Triglycerides]] | * ↑ [[Triglyceride|Triglycerides]] | ||
* May ↓ absorption of other medications | * May ↓ absorption of other [[medication|medications]] | ||
|High | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|[[Dopamine agonists|Dopamine-2]] | |align="center" style="background:#DCDCDC;"|[[Dopamine agonists|Dopamine-2]] | ||
[[Dopamine agonists|agonists]] | [[Dopamine agonists|agonists]] | ||
|[[Bromocriptine]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Bromocriptine]] | ||
(quick release)§ | (quick release)<sup>§</sup> | ||
|Activates dopaminergic receptors | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates dopaminergic receptors | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modulates [[hypothalamic]] regulation of metabolism | * Modulates [[hypothalamic]] regulation of metabolism | ||
* ↑ Insulin sensitivity | * ↑ [[Insulin]] sensitivity | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
* ↓ [[Cardiovascular disease|CVD]] events | * ↓ [[Cardiovascular disease|CVD]] events | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modest [[A1C]] efficacy | * Modest [[A1C]] efficacy | ||
Line 228: | Line 325: | ||
* [[Rhinitis]] | * [[Rhinitis]] | ||
|High | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|[[SGLT2]] | |align="center" style="background:#DCDCDC;"|[[SGLT2]] | ||
inhibitors | inhibitors | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Canagliflozin]] | * [[Canagliflozin]] | ||
* [[Dapagliflozin]]‡ | * [[Dapagliflozin]]<sup>‡</sup> | ||
* [[Empagliflozin]] | * [[Empagliflozin]] | ||
|Inhibits [[SGLT2]] in the proximal [[nephron]] | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Inhibits [[SGLT2]] in the proximal [[nephron]] | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Blocks glucose reabsorption by the kidney,increasing [[glucosuria]] | * Blocks glucose reabsorption by the kidney,increasing [[glucosuria]] | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
* ↓ Weight | * ↓ Weight | ||
* ↓ Blood pressure | * ↓ [[Blood pressure]] | ||
* | *↓ The chance of [[kidney]] disease progression, including the [[macroalbuminuria]]. They are also capable of lowering the risk of worsening estimated [[glomerular filtration rate]], [[end-stage kidney disease]], or death due to [[renal failure]].<ref name="ZelnikerWiviott2019">{{cite journal|last1=Zelniker|first1=Thomas A.|last2=Wiviott|first2=Stephen D.|last3=Raz|first3=Itamar|last4=Im|first4=KyungAh|last5=Goodrich|first5=Erica L.|last6=Furtado|first6=Remo H.M.|last7=Bonaca|first7=Marc P.|last8=Mosenzon|first8=Ofri|last9=Kato|first9=Eri T.|last10=Cahn|first10=Avivit|last11=Bhatt|first11=Deepak L.|last12=Leiter|first12=Lawrence A.|last13=McGuire|first13=Darren K.|last14=Wilding|first14=John P.H.|last15=Sabatine|first15=Marc S.|title=Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus|journal=Circulation|volume=139|issue=17|year=2019|pages=2022–2031|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.118.038868}}</ref> | ||
| | * Research shows that SGLT-2 inhibitors and GLP-1 receptor [[agonist]]s reduce [[cardiovascular]] and [[renal]] outcomes among [[patients]] with [[diabetes]] type 2.<ref name="PalmerTendal2021">{{cite journal|last1=Palmer|first1=Suetonia C|last2=Tendal|first2=Britta|last3=Mustafa|first3=Reem A|last4=Vandvik|first4=Per Olav|last5=Li|first5=Sheyu|last6=Hao|first6=Qiukui|last7=Tunnicliffe|first7=David|last8=Ruospo|first8=Marinella|last9=Natale|first9=Patrizia|last10=Saglimbene|first10=Valeria|last11=Nicolucci|first11=Antonio|last12=Johnson|first12=David W|last13=Tonelli|first13=Marcello|last14=Rossi|first14=Maria Chiara|last15=Badve|first15=Sunil V|last16=Cho|first16=Yeoungjee|last17=Nadeau-Fredette|first17=Annie-Claire|last18=Burke|first18=Michael|last19=Faruque|first19=Labib I|last20=Lloyd|first20=Anita|last21=Ahmad|first21=Nasreen|last22=Liu|first22=Yuanchen|last23=Tiv|first23=Sophanny|last24=Millard|first24=Tanya|last25=Gagliardi|first25=Lucia|last26=Kolanu|first26=Nithin|last27=Barmanray|first27=Rahul D|last28=McMorrow|first28=Rita|last29=Raygoza Cortez|first29=Ana Karina|last30=White|first30=Heath|last31=Chen|first31=Xiangyang|last32=Zhou|first32=Xu|last33=Liu|first33=Jiali|last34=Rodríguez|first34=Andrea Flores|last35=González-Colmenero|first35=Alejandro Díaz|last36=Wang|first36=Yang|last37=Li|first37=Ling|last38=Sutanto|first38=Surya|last39=Solis|first39=Ricardo Cesar|last40=Díaz González-Colmenero|first40=Fernando|last41=Rodriguez-Gutierrez|first41=René|last42=Walsh|first42=Michael|last43=Guyatt|first43=Gordon|last44=Strippoli|first44=Giovanni F M|title=Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials|journal=BMJ|year=2021|pages=m4573|issn=1756-1833|doi=10.1136/bmj.m4573}}</ref> | ||
* [[Genitourinary]] infections | |||
* Empagliflozin is associated with lower [[Cardiovascular disease|CVD]] event rate and mortality in patients with [[Cardiovascular disease|CVD]].<ref name="pmid28606340">{{cite journal| author=Paneni F, Lüscher TF| title=Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes. | journal=Am J Cardiol | year= 2017 | volume= 120 | issue= 1S | pages= S17-S27 | pmid=28606340 | doi=10.1016/j.amjcard.2017.05.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28606340 }} </ref> It is also related to reduction of [[left ventricle]] mass after 6 months treatment.<ref name="VermaMazer2019">{{cite journal|last1=Verma|first1=Subodh|last2=Mazer|first2=C. David|last3=Yan|first3=Andrew T.|last4=Mason|first4=Tamique|last5=Garg|first5=Vinay|last6=Teoh|first6=Hwee|last7=Zuo|first7=Fei|last8=Quan|first8=Adrian|last9=Farkouh|first9=Michael E.|last10=Fitchett|first10=David H.|last11=Goodman|first11=Shaun G.|last12=Goldenberg|first12=Ronald M.|last13=Al-Omran|first13=Mohammed|last14=Gilbert|first14=Richard E.|last15=Bhatt|first15=Deepak L.|last16=Leiter|first16=Lawrence A.|last17=Jüni|first17=Peter|last18=Zinman|first18=Bernard|last19=Connelly|first19=Kim A.|title=Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease|journal=Circulation|volume=140|issue=21|year=2019|pages=1693–1702|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.119.042375}}</ref> | |||
* [[Dapagliflozin]] has minor effect on [[diastolic]] cardiac function of [[diabetes mellitus|diabetic]] patients. Nevertheless, it is able to lower the risk of major adverse cardiovascular events in a diabetic patients with previous [[MI]]. <ref name="FurtadoBonaca2019">{{cite journal|last1=Furtado|first1=Remo H.M.|last2=Bonaca|first2=Marc P.|last3=Raz|first3=Itamar|last4=Zelniker|first4=Thomas A.|last5=Mosenzon|first5=Ofri|last6=Cahn|first6=Avivit|last7=Kuder|first7=Julia|last8=Murphy|first8=Sabina A.|last9=Bhatt|first9=Deepak L.|last10=Leiter|first10=Lawrence A.|last11=McGuire|first11=Darren K.|last12=Wilding|first12=John P.H.|last13=Ruff|first13=Christian T.|last14=Nicolau|first14=Jose C.|last15=Gause-Nilsson|first15=Ingrid A.M.|last16=Fredriksson|first16=Martin|last17=Langkilde|first17=Anna Maria|last18=Sabatine|first18=Marc S.|last19=Wiviott|first19=Stephen D.|title=Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction|journal=Circulation|volume=139|issue=22|year=2019|pages=2516–2527|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.119.039996}}</ref><ref name="EickhoffOlsen2020">{{cite journal|last1=Eickhoff|first1=Mie K.|last2=Olsen|first2=Flemming J.|last3=Frimodt-Møller|first3=Marie|last4=Diaz|first4=Lars J.|last5=Faber|first5=Jens|last6=Jensen|first6=Magnus T.|last7=Rossing|first7=Peter|last8=Persson|first8=Frederik|title=Effect of dapagliflozin on cardiac function in people with type 2 diabetes and albuminuria – A double blind randomized placebo-controlled crossover trial|journal=Journal of Diabetes and its Complications|volume=34|issue=7|year=2020|pages=107590|issn=10568727|doi=10.1016/j.jdiacomp.2020.107590}}</ref> | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* [[Genitourinary]] infections<sup>†</sup> | |||
* [[Polyuria]] | * [[Polyuria]] | ||
Line 262: | Line 363: | ||
* [[DKA]], [[urinary tract infections]] leading to urosepsis, [[pyelonephritis]] | * [[DKA]], [[urinary tract infections]] leading to urosepsis, [[pyelonephritis]] | ||
|High | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|[[GLP-1]] receptor | |align="center" style="background:#DCDCDC;"|[[GLP-1]] receptor agonists | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
agonists | |||
| | |||
* [[Exenatide]] | * [[Exenatide]] | ||
Line 279: | Line 378: | ||
* [[Dulaglutide]] | * [[Dulaglutide]] | ||
|Activates GLP-1 receptors | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates GLP-1 receptors | ||
|↑ Insulin secretion | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↑ [[Insulin]] secretion (glucose dependent) | |||
(glucose dependent) | * ↓ [[Glucagon]] secretion (glucose dependent) | ||
* Slows gastric emptying | |||
* ↑ [[Satiety]] | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* Rare [[hypoglycemia]] | |||
* ↓ Weight | |||
* ↓ [[Postprandial]] [[glucose]] excursions | |||
* ↓ Some cardiovascular [[risk factor|risk factors]] | |||
* ↓ The chance of [[kidney]] disease progression, including the [[macroalbuminuria]]<ref name="ZelnikerWiviott2019">{{cite journal|last1=Zelniker|first1=Thomas A.|last2=Wiviott|first2=Stephen D.|last3=Raz|first3=Itamar|last4=Im|first4=KyungAh|last5=Goodrich|first5=Erica L.|last6=Furtado|first6=Remo H.M.|last7=Bonaca|first7=Marc P.|last8=Mosenzon|first8=Ofri|last9=Kato|first9=Eri T.|last10=Cahn|first10=Avivit|last11=Bhatt|first11=Deepak L.|last12=Leiter|first12=Lawrence A.|last13=McGuire|first13=Darren K.|last14=Wilding|first14=John P.H.|last15=Sabatine|first15=Marc S.|title=Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus|journal=Circulation|volume=139|issue=17|year=2019|pages=2022–2031|issn=0009-7322|doi=10.1161/CIRCULATIONAHA.118.038868}}</ref> | |||
* [[Liraglutide]] associated with lower [[Cardiovascular disease|CVD]] event rate and mortality in patients with [[CVD]].<ref name="pmid28606340">{{cite journal| author=Paneni F, Lüscher TF| title=Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes. | journal=Am J Cardiol | year= 2017 | volume= 120 | issue= 1S | pages= S17-S27 | pmid=28606340 | doi=10.1016/j.amjcard.2017.05.015 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=28606340 }} </ref> | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* Gastrointestinal [[side effect|side effects]] ([[nausea]]/[[vomiting]]/[[diarrhea]]) | |||
* ↑ [[Tachycardia|Heart rate]] | |||
* [[Acute pancreatitis]] | |||
* C-cell [[hyperplasia]]/[[Medullary thyroid cancer|medullary thyroid tumors]] in animals | |||
| | |||
* Injectable | |||
* Training requirements | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | |||
|High | |||
|- | |- | ||
|Amylin mimetics | |align="center" style="background:#DCDCDC;"|[[Amylin]] mimetics | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Pramlintide]]<sup>§</sup> | ||
|Activates amylin receptors | |style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[amylin]] receptors | ||
|↓ Glucagon secretion | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↓ [[Glucagon]] secretion | |||
* Slows gastric emptying | |||
* ↑ [[Satiety]] | |||
|Postprandial glucose excursions | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Postprandial [[glucose]] excursions | |||
* ↓ Weight | |||
|Modest A1C efficacy | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modest [[A1C]] efficacy | |||
* Gastrointestinal [[side effect|side effects]] ([[Nausea and vomiting|nausea/vomiting]]) | |||
* [[Hypoglycemia]] unless [[insulin]] dose is simultaneously reduced | |||
* Injectable | |||
* Frequent dosing schedule | |||
* Training requirements | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | |||
| | |||
|- | |- | ||
|Insulins | | rowspan="5" align="center" style="background:#DCDCDC;"|[[Insulin|Insulins]] | ||
|Rapid-acting analogs | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rapid-acting analogs | |||
** [[Insulin Lispro|Lispro]] | |||
** [[Insulin aspart|Aspart]] | |||
** [[Insulin Glulisine|Glulisine]] | |||
** Inhaled [[insulin]] | |||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates insulin receptors | |||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* ↑ [[Glucose]] disposal | |||
* ↓ Hepatic [[glucose]] production | |||
* Suppresses [[ketogenesis]] | |||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* Nearly universal response | |||
* Theoretically unlimited efficacy | |||
* ↓ Microvascular risk | |||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* [[Hypoglycemia]] | |||
* [[Weight gain]] | |||
* Training requirements | |||
* Patient and provider reluctance | |||
* Injectable (except inhaled [[insulin]]) | |||
* Pulmonary toxicity (inhaled [[insulin]]) | |||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | |||
|- | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* Short-acting | |||
** [[Regular insulin|Human Regular]] | |||
|- | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* Intermediate-acting | |||
- | ** [[NPH insulin|Human NPH]] | ||
|- | |||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | |||
* Basal insulin analogs | |||
** [[Insulin Glargine|Glargine]] | |||
** [[Insulin Detemir|Detemir]] | |||
** [[Insulin degludec|Degludec]] | |||
| | |- | ||
| | |style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Premixed insulin products | |||
** NPH/Regular 70/30 | |||
** 70/30 aspart mix | |||
** 75/25 lispro mix | |||
** 50/50 lispro mix | |||
|} | |} | ||
<sup>‡</sup> Initial concerns regarding [[bladder cancer]] risk are decreasing after subsequent study. | |||
<sup>§</sup> Not licensed in Europe for [[type 2 diabetes]]. | |||
<sup>†</sup> One study demonstrates factors like previous genital infection history, concurrent [[Estrogen|estrogen therapy]] and younger age as [[Risk factor|risk factors]] that augment the chance of this [[Adverse effect (medicine)|side effect]]. This study also reports [[Chronic renal failure|chronic kidney disease]] and baseline [[Dipeptidyl peptidase-4 inhibitor|DPP4 inhibitor]] therapy as factors that lower the risk of genital infection development.<ref name="NakhlehZloczower2020">{{cite journal|last1=Nakhleh|first1=Afif|last2=Zloczower|first2=Moshe|last3=Gabay|first3=Linoy|last4=Shehadeh|first4=Naim|title=Effects of sodium glucose co-transporter 2 inhibitors on genital infections in female patients with type 2 diabetes mellitus– Real world data analysis|journal=Journal of Diabetes and its Complications|volume=34|issue=7|year=2020|pages=107587|issn=10568727|doi=10.1016/j.jdiacomp.2020.107587}}</ref> | |||
==References== | ==References== | ||
{{Reflist|2}} | {{Reflist|2}} | ||
[[Category:Endocrinology]] | [[Category:Endocrinology]] | ||
Latest revision as of 14:27, 11 April 2023
Diabetes mellitus type 2 Microchapters |
Differentiating Diabetes Mellitus Type 2 from other Diseases |
Diagnosis |
Treatment |
Medical therapy |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]Anahita Deylamsalehi, M.D.[3] Javaria Anwer M.D.[4]
Overview
The main goals of treatment are to eliminate hyperglycemic symptoms, control the long term complications and improve the patient's quality of life. Diabetes mellitus type 2 is initially treated by life style modification and weight loss, especially in obese patients. Metformin is the first line pharmacologic therapy that is usually started once the diagnosis is confirmed unless contraindications exist. Nevertheless, in patients presented with high HbA1C/fasting blood sugar levels or if glycemic goals are not achieved, a second agent must be added to metformin. A wide range of options are available to add as combination therapy based on the patient's condition and comorbidities.
Pharmacologic therapy
Inpatients
Outpatients
A network meta-analysis summarizes the risks and benefits of available medications for diabetes mellitus type 2[1].
- Medical therapy starts with metformin monotherapy unless there is a contraindication for it. In the following conditions, treatment starts with dual therapy:[2][3][4][5][6][7]
- If HbA1C is greater than 9, start with dual oral blood glucose lowering agent.
- If HbA1C is greater than 10 or blood glucose is more than 300 mg/dl or patient is markedly symptomatic, consider combination therapy with insulin.
- The most effective class of drugs for reducing death are probably sodium glucose transporter 2 (SGLT2) inhibitors or GLP-1 receptor agonists.[8]
Metformin
- Metformin is effective, safe and inexpensive.
- It may reduce risk of cardiovascular events and death.
- Patients should be advised to stop the medication in cases of nausea, vomiting or dehydration.
- Metformin is capable of decreasing the body weight but it's effect on muscle mass is unclear.[9]
- A systemic review, observing 34,000 patients in total concluded that Metformin is as safe as other anti-diabetic treatments in diabetic patients with heart failure.[10]
- Some studies demonstrated lower risk of mortality in diabetic patients with concurrent COPD or Asthma who were taking Metformin compared to non-users.[11]
- Metformin use in diabetic patients with sepsis, tuberculosis and Chronic obstructive pulmonary disease (COPD) were associated with lower mortality rate.[12][13]
- One of the possible effects of Metformin is gut microbiota alteration, which results in Tauroursodeoxycholic acid (TUDCA) and Glycoursodeoxycholic Acid (GUDCA) elevation. Since both TUDCA and GUDCA act as intestinal farnesoid X receptor (FXR) antagonists, they can be effective in hyperglycemia treatment.[14]
Contraindications
- As of June 2020, The US Food and Drug Administration (FDA) recalls extended-release metformin which is made by few pharma companies due to detection of high levels of N-Nitrosodimethylamine (NDMA).[15][16]
- N-Nitrosodimethylamine (NDMA) is a carcinogenic agent when exposed in higher levels leads to cancer.
- The following are the pharma companies that the FDA recalls the extended-release metformin:
- Lupin
- Apotex Corp
- Actavis
- Time-Cap Labs, Inc
- Amneal
- Contraindications to metformin include, heart failure, liver failure, GFR ≤30 and metabolic acidosis.
Total duration was 14 weeks with at least 8 weeks on final dose. | Placebo | 500 mg once daily | 1000 mg
(500 mg twice daily) |
1500 mg
(500 mg thrice daily) |
2000 mg
(1000 mg twice daily) |
2500 mg
(1000 am, 500 lunch, 1000 at supper daily |
---|---|---|---|---|---|---|
Any GI ADR | 13% | 16% | 29% | 24% | 23% | 29% |
Diarrhea | 5% | 8% | 21% | 12% | 19% | 14% |
HbA1c change | + 1.2 | + 0.3 | + 0.1 | - 0.5 | - 0.8 | - 0.04 |
Source: Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL (1997). "Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial". Am J Med. 103 (6): 491–7. doi:10.1016/s0002-9343(97)00254-4. PMID 9428832. |
Insulin
- The lack of inexpensive, generic insulin may lead to underuse of insulin[18] and occurs for unusual reasons[19].
- The insulin analogues may not provide a meaningful advantage[20][21][22].
- Although Insulin increases the body weight, some data suggest that it is capable of increasing the muscle mass.[23]
- A meta-analysis of randomized controlled trials by the Cochrane Collaboration found "only a minor clinical benefit of treatment with long-acting insulin analogues for patients with diabetes mellitus type 2" compared to human insulin[22] More recent randomized controlled trials have found no differences with glargine[24] and have found that although long acting insulins were less effective, they were associated with less hypoglycemia.[25]
- Premixed combinations of insulin, human or analogue, have similar reductions in HbA1c[26]. A cohort study likewise found similar rates of hypoglycemia[21].
Bedtime insulin
- Initially, a randomized controlled trial found that adding bedtime insulin to patients failed oral medications is more effective and with less weight gain than using multiple dose insulin.[27] Nightly insulin combines better with metformin that with sulfonylureas.[28]
- More recently, the Cochrane Collaboration concluded: "hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with insulin detemir instead of NPH insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted"[29].
- Kaiser Permanente, in a large cohort study, found no benefit from long-acting insulin analogues compared to human NPH insulin[21].
- Dosing
The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L)[27]. If the fasting glucose is reported in mg/dl, multiple by 0.05551 (or divided by 18) to convert to mmol/L.[30]
Consider increasing by 3 units at a time[31].
- Monitoring
In both trails above, dosing was adjusted by monitoring fasting sugars[27][28]. In the second trial, the patient checked their "diurnal blood glucose level, measurements were taken before and 1.5 hours after breakfast, lunch and dinner; at 10 p.m.; and at 4 a.m." once a week for the first 3 months and then every other week[28].
- Availability
Novo Nordisk’s Novolin ReliOn N is less expensive at Walmart and CVS pharmacies[32].
Combination therapy
- Any agent can be added as second drug based on patient condition. Nevertheless, the American Association of Clinical Endocrinologists recommends either incretin based therapy or sodium glucose transporter 2 (SGLT2) inhibition agents.[6][33]
- The following table summarize the available FDA approved glucose lowering agents that may help to individualize treatment for each patient.
Class | Drug | Mechanism of action | Primary physiologic action | Advantages | Disadvantages | Cost |
---|---|---|---|---|---|---|
Biguanides | Metformin | Activates AMP-kinase | ↓ Hepatic glucose
production |
|
|
Low |
Sulfonylureas | 2nd generation | Closes K-ATP channels on beta cell plasma membranes | ↑ Insulin secretion |
|
|
Low |
Meglitinides | Closes K-ATP channels on beta cell plasma membranes | ↑ Insulin secretion |
|
|
Moderate | |
Thiazolidinedione
(TZDs) |
Activates the nuclear transcription factor PPAR-gama | ↑ Insulin sensitivity |
|
|
Low | |
α-Glucosidase
inhibitors |
Inhibits intestinal
α-glucosidase |
Slows intestinal carbohydrate
digestion/absorption |
|
|
Low to
moderate | |
DPP-4 | Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations |
|
|
High | ||
Bile acid sequestrants | Colesevelam | Binds bile acids in intestinal tract,
increasing hepatic bile acid production |
|
|
|
High |
Dopamine-2 | Bromocriptine
(quick release)§ |
Activates dopaminergic receptors |
|
|
|
High |
SGLT2
inhibitors |
Inhibits SGLT2 in the proximal nephron |
|
|
|
High | |
GLP-1 receptor agonists |
|
Activates GLP-1 receptors |
|
|
|
High |
Amylin mimetics | Pramlintide§ | Activates amylin receptors |
|
|
|
High |
Insulins |
|
Activates insulin receptors |
|
|
|
High |
| ||||||
| ||||||
| ||||||
|
‡ Initial concerns regarding bladder cancer risk are decreasing after subsequent study.
§ Not licensed in Europe for type 2 diabetes.
† One study demonstrates factors like previous genital infection history, concurrent estrogen therapy and younger age as risk factors that augment the chance of this side effect. This study also reports chronic kidney disease and baseline DPP4 inhibitor therapy as factors that lower the risk of genital infection development.[41]
References
- ↑ Shi Q, Nong K, Vandvik PO, Guyatt GH, Schnell O, Rydén L; et al. (2023). "Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials". BMJ. 381: e074068. doi:10.1136/bmj-2022-074068. PMC 10077111 Check
|pmc=
value (help). PMID 37024129 Check|pmid=
value (help). - ↑ Qaseem A, Hopkins RH, Sweet DE, Starkey M, Shekelle P (2013). "Screening, monitoring, and treatment of stage 1 to 3 chronic kidney disease: A clinical practice guideline from the American College of Physicians". Ann. Intern. Med. 159 (12): 835–47. doi:10.7326/0003-4819-159-12-201312170-00726. PMID 24145991.
- ↑ "Standards of Medical Care in Diabetes-2017: Summary of Revisions". Diabetes Care. 40 (Suppl 1): S4–S5. 2017. doi:10.2337/dc17-S003. PMID 27979887.
- ↑ Colagiuri S, Cull CA, Holman RR (2002). "Are lower fasting plasma glucose levels at diagnosis of type 2 diabetes associated with improved outcomes?: U.K. prospective diabetes study 61". Diabetes Care. 25 (8): 1410–7. PMID 12145243.
- ↑ Davidson MB (1992). "Successful treatment of markedly symptomatic patients with type II diabetes mellitus using high doses of sulfonylurea agents". West. J. Med. 157 (2): 199–200. PMC 1011263. PMID 1441492.
- ↑ 6.0 6.1 Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, Chu Y, Iyoha E, Segal JB, Bolen S (2016). "Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis". Ann. Intern. Med. 164 (11): 740–51. doi:10.7326/M15-2650. PMID 27088241.
- ↑ Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, Natale P, Saglimbene V, Badve SV, Cho Y, Nadeau-Fredette AC, Burke M, Faruque L, Lloyd A, Ahmad N, Liu Y, Tiv S, Wiebe N, Strippoli GF (2016). "Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis". JAMA. 316 (3): 313–24. doi:10.1001/jama.2016.9400. PMID 27434443.
- ↑ GitHub Contributors. Hypertonic Saline for Bronchiolitis: a living systematic review. GitHub. Available at http://openmetaanalysis.github.io/Diabetes-mellitus-type-2-mortality-prevention-with-pharmacotherapy/. Accessed June 11, 2018.
- ↑ Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D (2019). "Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship". Diabetes Metab Syndr Obes. 12: 1057–1072. doi:10.2147/DMSO.S186600. PMC 6630094 Check
|pmc=
value (help). PMID 31372016. - ↑ Eurich, Dean T.; Weir, Daniala L.; Majumdar, Sumit R.; Tsuyuki, Ross T.; Johnson, Jeffrey A.; Tjosvold, Lisa; Vanderloo, Saskia E.; McAlister, Finlay A. (2013). "Comparative Safety and Effectiveness of Metformin in Patients With Diabetes Mellitus and Heart Failure". Circulation: Heart Failure. 6 (3): 395–402. doi:10.1161/CIRCHEARTFAILURE.112.000162. ISSN 1941-3289.
- ↑ Mendy A, Gopal R, Alcorn JF, Forno E (2019). "Reduced mortality from lower respiratory tract disease in adult diabetic patients treated with metformin". Respirology. 24 (7): 646–651. doi:10.1111/resp.13486. PMC 6579707 Check
|pmc=
value (help). PMID 30761687. - ↑ Liang, Huoyan; Ding, Xianfei; Li, Lifeng; Wang, Tian; Kan, Quancheng; Wang, Lexin; Sun, Tongwen (2019). "Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies". Critical Care. 23 (1). doi:10.1186/s13054-019-2346-4. ISSN 1364-8535.
- ↑ Singh, Awadhesh Kumar; Khunti, Kamlesh (2020). "Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review". Diabetes Research and Clinical Practice. 165: 108266. doi:10.1016/j.diabres.2020.108266. ISSN 0168-8227.
- ↑ Wu, Yingjie; Zhou, An; Tang, Li; Lei, Yuanyuan; Tang, Bo; Zhang, Linjing (2020). "Bile Acids: Key Regulators and Novel Treatment Targets for Type 2 Diabetes". Journal of Diabetes Research. 2020: 1–11. doi:10.1155/2020/6138438. ISSN 2314-6745.
- ↑ Sulkin TV, Bosman D, Krentz AJ (1997). "Contraindications to metformin therapy in patients with NIDDM". Diabetes Care. 20 (6): 925–8. doi:10.2337/diacare.20.6.925. PMID 9167101.
- ↑ Holstein A, Stumvoll M (2005). "Contraindications can damage your health--is metformin a case in point?". Diabetologia. 48 (12): 2454–9. doi:10.1007/s00125-005-0026-1. PMID 16283245.
- ↑ Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL (1997). "Efficacy of metformin in type II diabetes: results of a double-blind, placebo-controlled, dose-response trial". Am J Med. 103 (6): 491–7. doi:10.1016/s0002-9343(97)00254-4. PMID 9428832.
- ↑ Herkert D, Vijayakumar P, Luo J, Schwartz JI, Rabin TL, DeFilippo E; et al. (2018). "Cost-Related Insulin Underuse Among Patients With Diabetes". JAMA Intern Med. doi:10.1001/jamainternmed.2018.5008. PMID 30508012.
- ↑ Greene JA, Riggs KR (2015). "Why is there no generic insulin? Historical origins of a modern problem". N Engl J Med. 372 (12): 1171–5. doi:10.1056/NEJMms1411398. PMID 25785977.
- ↑ Luo J, Khan NF, Manetti T, Rose J, Kaloghlian A, Gadhe B; et al. (2019). "Implementation of a Health Plan Program for Switching From Analogue to Human Insulin and Glycemic Control Among Medicare Beneficiaries With Type 2 Diabetes". JAMA. 321 (4): 374–384. doi:10.1001/jama.2018.21364. PMID 30694321.
- ↑ 21.0 21.1 21.2 Lipska KJ, Parker MM, Moffet HH, Huang ES, Karter AJ (2018). "Association of Initiation of Basal Insulin Analogs vs Neutral Protamine Hagedorn Insulin With Hypoglycemia-Related Emergency Department Visits or Hospital Admissions and With Glycemic Control in Patients With Type 2 Diabetes". JAMA. 320 (1): 53–62. doi:10.1001/jama.2018.7993. PMC 6134432. PMID 29936529.
- ↑ 22.0 22.1 Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer TW, Plank J; et al. (2007). "Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus". Cochrane Database Syst Rev (2): CD005613. doi:10.1002/14651858.CD005613.pub3. PMID 17443605. Review in: ACP J Club. 2007 Sep-Oct;147(2):46
- ↑ Mesinovic J, Zengin A, De Courten B, Ebeling PR, Scott D (2019). "Sarcopenia and type 2 diabetes mellitus: a bidirectional relationship". Diabetes Metab Syndr Obes. 12: 1057–1072. doi:10.2147/DMSO.S186600. PMC 6630094 Check
|pmc=
value (help). PMID 31372016. - ↑ Esposito K; et al. (2008). "Addition of neutral protamine lispro insulin or insulin glargine to oral type 2 diabetes regimens for patients with suboptimal glycemic control: a randomized trial". Ann Intern Med. 149: 531–9. PMID 18936501.
- ↑ Holman RR; et al. (2007). "Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes". N Engl J Med. 357: 1716–30. doi:10.1056/NEJMoa075392. PMID 17890232.
- ↑ Qayyum R, Bolen S, Maruthur N, Feldman L, Wilson LM, Marinopoulos SS; et al. (2008). "Systematic review: comparative effectiveness and safety of premixed insulin analogues in type 2 diabetes". Ann Intern Med. 149 (8): 549–59. PMC 4762020. PMID 18794553.
- ↑ 27.0 27.1 27.2 Yki-Järvinen H, Kauppila M, Kujansuu E; et al. (1992). "Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus". N. Engl. J. Med. 327 (20): 1426–33. PMID 1406860.
- ↑ 28.0 28.1 28.2 Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M (1999). "Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. A randomized, controlled trial". Ann. Intern. Med. 130 (5): 389–96. PMID 10068412.
- ↑ Semlitsch T, Engler J, Siebenhofer A, Jeitler K, Berghold A, Horvath K (2020). "(Ultra-)long-acting insulin analogues versus NPH insulin (human isophane insulin) for adults with type 2 diabetes mellitus". Cochrane Database Syst Rev. 11: CD005613. doi:10.1002/14651858.CD005613.pub4. PMC 8095010 Check
|pmc=
value (help). PMID 33166419 Check|pmid=
value (help). - ↑ Kratz A, Lewandrowski KB (1998). "Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Normal reference laboratory values". N. Engl. J. Med. 339 (15): 1063–72. PMID 9761809.
- ↑ Russell-Jones D, Dauchy A, Delgado E, Dimitriadis G, Frandsen HA, Popescu L; et al. (2019). "Take Control: A randomized trial evaluating the efficacy and safety of self- versus physician-managed titration of insulin glargine 300 U/mL in patients with uncontrolled type 2 diabetes". Diabetes Obes Metab. 21 (7): 1615–1624. doi:10.1111/dom.13697. PMC 6767413 Check
|pmc=
value (help). PMID 30851006. - ↑ Novo Nordisk has partnerships to provide low-cost human insulin. Available at https://www.novocare.com/diabetes-overview/let-us-help/human-insulin-options.html
- ↑ Fonseca V, Rosenstock J, Patwardhan R, Salzman A (2000). "Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial". JAMA. 283 (13): 1695–702. doi:10.1001/jama.283.13.1695. PMID 10755495.
- ↑ Singh, Awadhesh Kumar; Khunti, Kamlesh (2020). "Assessment of risk, severity, mortality, glycemic control and antidiabetic agents in patients with diabetes and COVID-19: A narrative review". Diabetes Research and Clinical Practice. 165: 108266. doi:10.1016/j.diabres.2020.108266. ISSN 0168-8227.
- ↑ 35.0 35.1 Zelniker, Thomas A.; Wiviott, Stephen D.; Raz, Itamar; Im, KyungAh; Goodrich, Erica L.; Furtado, Remo H.M.; Bonaca, Marc P.; Mosenzon, Ofri; Kato, Eri T.; Cahn, Avivit; Bhatt, Deepak L.; Leiter, Lawrence A.; McGuire, Darren K.; Wilding, John P.H.; Sabatine, Marc S. (2019). "Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus". Circulation. 139 (17): 2022–2031. doi:10.1161/CIRCULATIONAHA.118.038868. ISSN 0009-7322.
- ↑ Palmer, Suetonia C; Tendal, Britta; Mustafa, Reem A; Vandvik, Per Olav; Li, Sheyu; Hao, Qiukui; Tunnicliffe, David; Ruospo, Marinella; Natale, Patrizia; Saglimbene, Valeria; Nicolucci, Antonio; Johnson, David W; Tonelli, Marcello; Rossi, Maria Chiara; Badve, Sunil V; Cho, Yeoungjee; Nadeau-Fredette, Annie-Claire; Burke, Michael; Faruque, Labib I; Lloyd, Anita; Ahmad, Nasreen; Liu, Yuanchen; Tiv, Sophanny; Millard, Tanya; Gagliardi, Lucia; Kolanu, Nithin; Barmanray, Rahul D; McMorrow, Rita; Raygoza Cortez, Ana Karina; White, Heath; Chen, Xiangyang; Zhou, Xu; Liu, Jiali; Rodríguez, Andrea Flores; González-Colmenero, Alejandro Díaz; Wang, Yang; Li, Ling; Sutanto, Surya; Solis, Ricardo Cesar; Díaz González-Colmenero, Fernando; Rodriguez-Gutierrez, René; Walsh, Michael; Guyatt, Gordon; Strippoli, Giovanni F M (2021). "Sodium-glucose cotransporter protein-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials". BMJ: m4573. doi:10.1136/bmj.m4573. ISSN 1756-1833.
- ↑ 37.0 37.1 Paneni F, Lüscher TF (2017). "Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results Across Drug Classes". Am J Cardiol. 120 (1S): S17–S27. doi:10.1016/j.amjcard.2017.05.015. PMID 28606340.
- ↑ Verma, Subodh; Mazer, C. David; Yan, Andrew T.; Mason, Tamique; Garg, Vinay; Teoh, Hwee; Zuo, Fei; Quan, Adrian; Farkouh, Michael E.; Fitchett, David H.; Goodman, Shaun G.; Goldenberg, Ronald M.; Al-Omran, Mohammed; Gilbert, Richard E.; Bhatt, Deepak L.; Leiter, Lawrence A.; Jüni, Peter; Zinman, Bernard; Connelly, Kim A. (2019). "Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease". Circulation. 140 (21): 1693–1702. doi:10.1161/CIRCULATIONAHA.119.042375. ISSN 0009-7322.
- ↑ Furtado, Remo H.M.; Bonaca, Marc P.; Raz, Itamar; Zelniker, Thomas A.; Mosenzon, Ofri; Cahn, Avivit; Kuder, Julia; Murphy, Sabina A.; Bhatt, Deepak L.; Leiter, Lawrence A.; McGuire, Darren K.; Wilding, John P.H.; Ruff, Christian T.; Nicolau, Jose C.; Gause-Nilsson, Ingrid A.M.; Fredriksson, Martin; Langkilde, Anna Maria; Sabatine, Marc S.; Wiviott, Stephen D. (2019). "Dapagliflozin and Cardiovascular Outcomes in Patients With Type 2 Diabetes Mellitus and Previous Myocardial Infarction". Circulation. 139 (22): 2516–2527. doi:10.1161/CIRCULATIONAHA.119.039996. ISSN 0009-7322.
- ↑ Eickhoff, Mie K.; Olsen, Flemming J.; Frimodt-Møller, Marie; Diaz, Lars J.; Faber, Jens; Jensen, Magnus T.; Rossing, Peter; Persson, Frederik (2020). "Effect of dapagliflozin on cardiac function in people with type 2 diabetes and albuminuria – A double blind randomized placebo-controlled crossover trial". Journal of Diabetes and its Complications. 34 (7): 107590. doi:10.1016/j.jdiacomp.2020.107590. ISSN 1056-8727.
- ↑ Nakhleh, Afif; Zloczower, Moshe; Gabay, Linoy; Shehadeh, Naim (2020). "Effects of sodium glucose co-transporter 2 inhibitors on genital infections in female patients with type 2 diabetes mellitus– Real world data analysis". Journal of Diabetes and its Complications. 34 (7): 107587. doi:10.1016/j.jdiacomp.2020.107587. ISSN 1056-8727.