Diabetes mellitus type 2 medical therapy: Difference between revisions

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__NOTOC__
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{{Diabetes mellitus type 2}}
{{Diabetes mellitus type 2}}
{{Diabetes mellitus}}


{{CMG}}; '''Associate Editor(s)-In-Chief:''' [[Priyamvada Singh|Priyamvada Singh, M.B.B.S.]] [mailto:psingh13579@gmail.com]; {{CZ}}
{{CMG}}; {{AE}} {{MehdiP}}{{Anahita}} {{JA}}


==Medical Therapy==
==Overview==
Type 2 diabetes is usually first treated by increasing physical activity, decreasing [[carbohydrate]] intake, and [[weight loss|losing weight]]. These can restore insulin sensitivity even when the weight loss is modest, for example around 5&nbsp;kg (10 to 15&nbsp;lb), most especially when it is in abdominal fat deposits. It is sometimes possible to achieve long-term, satisfactory glucose control with these measures alone. However, the underlying tendency to insulin resistance is not lost, and so attention to diet, exercise, and weight loss must continue. The usual next step, if necessary, is treatment with oral [[antidiabetic drug]]s. Insulin production is initially only moderately impaired in type 2 diabetes, so oral medication (often used in various combinations) can be used to improve insulin production (e.g., sulfonylureas), to regulate inappropriate release of glucose by the liver and attenuate insulin resistance to some extent (e.g., [[metformin]]), and to substantially attenuate insulin resistance (e.g., [[thiazolidinedione]]s). According to one study, overweight patients treated with metformin compared with diet alone, had [[relative risk reduction]]s of 32% for any diabetes endpoint, 42% for diabetes related death and 36% for all cause mortality and stroke.<ref>{{cite journal |author= |title=Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group |journal=Lancet |volume=352 |issue=9131 |pages=854-65 |year=1998 |pmid=9742977}}</ref> Oral medication may eventually fail due to further impairment of beta cell insulin secretion. At this point, insulin therapy is necessary to maintain normal or near normal glucose levels.
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 a chronic, progressive disease that has no medically proven cure. There are two main goals of treatment of the disease:
==Pharmacologic therapy==
# reduction of mortality and concomitant morbidity (from assorted diabetic complications)
===Inpatients===
# preservation of quality of life
{{main|Diabetes Care in the Hospital Setting}}
The first goal can be achieved through close glycemic control (i.e., blood glucose levels); the reduction effect in diabetic complications has been well demonstrated in several extensive [[clinical trial]]s and is thus well established. The second goal is often addressed (in developed countries) by support and care from teams of diabetic health workers (physician, PA, nurse, dietitian or a certified diabetic educator). Endocrinologists, family practitioners, and general internists are the types of physicians most likely to treat people with diabetes.  Knowledgeable patient participation is vital and so patient education is a crucial aspect of this effort.  
===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>.


Type 2 is initially treated by adjustment in diet and exercise, and by  [[weight loss]], especially in obese patients. The amount of weight loss which improves the clinical picture is sometimes modest (2-5 kg or 4.4-11 lb); this is almost certainly due to currently poorly understood aspects of fat tissue chemical signaling (especially in visceral fat tissue in and around abdominal organs). In many cases, such initial efforts can substantially restore insulin sensitivity.  
*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]].


===Treatment Goals===
*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>
For most patients, [[clinical practice guideline]]s recommend a goal [[Glycosylated hemoglobin|Hba1c]] of 6.0%<ref name="pmid16373931">{{cite journal |author= |title=Standards of medical care in diabetes--2006 |journal=Diabetes Care |volume=29 Suppl 1 |issue= |pages=S4–42 |year=2006 |pmid=16373931 |doi=}}</ref> to 7.0%<ref name="pmidpending">Qaseem A, Vijan S, Snow V, Cross JT, Weiss KB, Owens DK, et al. Glycemic Control and Type 2 Diabetes Mellitus: The Optimal Hemoglobin A1c Targets. A Guidance Statement from the American College of Physicians. Ann Intern Med. 2007 Sep 18;147(6):417-422. [http://www.annals.org/cgi/content/full/147/6/417 Full text]</ref>.


In older patients, [[clinical practice guideline]]s by the [[American Geriatrics Society]] states "for frail older adults, persons with life expectancy of less than 5 years, and others in whom the risks of intensive glycemic control appear to outweigh the benefits, a less stringent target such as 8% is appropriate".<ref name="pmid12694461">{{cite journal |author=Brown AF, Mangione CM, Saliba D, Sarkisian CA |title=Guidelines for improving the care of the older person with diabetes mellitus |journal=Journal of the American Geriatrics Society |volume=51 |issue=5 Suppl Guidelines |pages=S265–80 |year=2003 |pmid=12694461 |doi=10.1046/j.1532-5415.51.5s.1.x|url=http://www.americangeriatrics.org/products/positionpapers/JAGSfinal05.pdf}}</ref>
===Metformin===


===Self Monitoring of Blood Glucose===
* [[Metformin]] is effective, safe and inexpensive.
{{main|Blood glucose monitoring}}
*It may reduce risk of [[cardiovascular]] events and death.
It is unclear if self-monitoring of blood glucose improves outcomes among "reasonably well controlled non-insulin treated patients with type 2 diabetes".<ref name="pmid17591623">{{cite journal |author=Farmer A, Wade A, Goyder E, ''et al'' |title=Impact of self monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial |journal= |volume= |issue= |pages= |year=2007 |pmid=17591623 |doi=10.1136/bmj.39247.447431.BE}}</ref>
*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>  


===Dietary Management===
==== Contraindications ====
Modifying the diet is known to help control glucose intake, and in response, blood glucose levels.


One 2007 study will report that in a [[Paleolithic diet]], all 14 patients returned blood glucose levels to normal after the trial period of 12 weeks, and improved glucose tolerance (26% less blood glucose rise following a carbohydrate intake compared to 7% reduction for control group on a Mediterranean diet). This was the first Paleolithic diet study, and suggested that "it may be more efficient to avoid some of our modern foods than to count calories or carbohydrate".<ref>{{cite news |title=Original Human 'Stone Age' Diet Is Good For People With Diabetes, Study Finds |url=http://www.sciencedaily.com/releases/2007/06/070627225459.htm |date=June 28, 2007 |publisher=ScienceDaily.com}}</ref>
*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]].


Other evidence for modified diets treating and being beneficial include:
{| class="wikitable"
* A vegan diet.<ref>{{cite web |title=Diabetes: Can a Vegan Diet Reverse Diabetes? |url=http://www.pcrm.org/health/clinres/diabetes.html |author=Nicholson A| date=02/15/05 |publisher=Physicians Committee for Responsible Medicine}}</ref><ref>{{cite journal |author=Barnard ND, Cohen J, Jenkins DJ, ''et al'' |title=A low-fat vegan diet improves glycemic control and cardiovascular risk factors in a randomized clinical trial in individuals with type 2 diabetes |journal=Diabetes Care |volume=29 |issue=8 |pages=1777-83 |year=2006 |pmid=16873779 |doi=10.2337/dc06-0606 |url=http://care.diabetesjournals.org/cgi/content/full/29/8/1777}}<br/>'''Related news articles:'''
|+,[[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>.
*{{cite news |title=Low-fat vegan diet treats type 2 diabetes more effectively than a standard diabetes diet |url=http://www.news-medical.net/?id=19351 |date=8-Aug-2006 |publisher=News-Medical.Net}}</ref>
* Caloric restriction.<ref>{{cite journal |author=Nielsen JV, Joensson E |title=Low-carbohydrate diet in type 2 diabetes. Stable improvement of bodyweight and glycemic control during 22 months follow-up |journal=Nutrition & metabolism |volume=3 |issue= |pages=22 |year=2006 |pmid=16774674 |doi=10.1186/1743-7075-3-22 |url=http://www.nutritionandmetabolism.com/content/3/1/22}}</ref>
* Cinnamon and Nutmeg (spices commonly found in apple pie).<ref>{{cite journal |author=Khan A, Bryden NA, Polansky MM, Anderson RA |title=Insulin potentiating factor and chromium content of selected foods and spices |journal=Biological trace element research |volume=24 |issue=3 |pages=183-8 |year=1990 |pmid=1702671 |doi=}}<br/>'''Related news articles:'''
*{{cite news |title=Apple Pie Improves Blood Sugar Regulation and Insulin Sensitivity? -- Apple pie spices (typically cinnamon and nutmeg) were responsible for the beneficial effects. |url=http://www.diabetesincontrol.com/issue118/item8.shtml |date=August, 2001 |publisher=Diabetes In Control}}</ref>


===Exercise===
! style="text-align: center;" | Total duration was 14 weeks with at least 8 weeks on final dose.
In September 2007, a joint [[randomized controlled trial]] by the University of Calgary and the University of Ottawa found that "Either aerobic or resistance training alone improves glycemic control in type 2 diabetes, but the improvements are greatest with combined aerobic and resistance training than either alone."<ref name="pmid17876019">{{cite journal |author=Sigal RJ, Kenny GP, Boulé NG, ''et al'' |title=Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial |journal=Ann. Intern. Med. |volume=147 |issue=6 |pages=357–69 |year=2007 |pmid=17876019 |doi=|url=http://www.annals.org/cgi/content/full/147/6/357}} [http://www.annals.org/cgi/content/summary/147/6/357 Non-technical summary]</ref><ref>{{cite web |url=http://www.time.com/time/health/article/0,8599,1662683,00.html?xid=newsletter-weekly |title=Study: The Best Exercise for Diabetes|publisher=Time Inc|
! style="text-align: center;" | Placebo
author=Song S|format= |work=}}</ref> The combined program reduced the [[Glycosylated hemoglobin|HbA1c]] by 0.5 percentage point.
! 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  }}
|}


===Antidiabetic Drugs===
===Insulin===
[[Image:Metformin 500mg Tablets.jpg|200px|thumb|Metformin 500mg tablets]]
{{main|anti-diabetic drug}}
The most important drug now used in Type 2 Diabetes is the [[Biguanide]] [[metformin]] which works primarily by reducing liver release of blood glucose from glycogen stores as well as some increase in uptake of glucose by the body's tissues. Both historically and currently commonly used are the [[Sulfonylurea]] group, of which several members (including [[glibenclamide]] and [[gliclazide]]) are widely used; these increase glucose stimulated [[secretagogue|insulin secretion]] by the pancreas.


Newer drug classes include:
* 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>.
* [[Thiazolidinedione]]s ([[TZD]]s) ([[rosiglitazone]], [[pioglitazone]], and [[troglitazone]]) (withdrawn from the US market)
* 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>.
* [[Alpha-glucosidase inhibitor|α-glucosidase inhibitors]] ([[acarbose]] and [[miglitol]])
* 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>
* [[Meglitinide]]s which stimulate insulin release ([[nateglinide]], [[repaglinide]], and their analogs)
* 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>
* Peptide analogs which work in a variety of ways:
* 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>.
** Incretin mimetics act as insulin secretagogue among other effects. These includes the Glucagon-like peptide (GLP) analog [[exenatide]]
** [[Dipeptidyl peptidase-4 inhibitors|Dipeptidyl peptidase-4 (DPP-4) inhibitors]] increase [[Incretin]] levels ( [[sitagliptin]])
** Amylin agonist analog, which slows gastric emptying and suppresses glucagon ([[pramlintide]])


====Selecting an Antidiabetic Drug====
====Bedtime insulin====
=====Oral Drugs=====
For [[Diabetes mellitus type 2]]:
A systematic review of randomized controlled trials found that [[metformin]] and second-generation sulfonylureas are the preferred choices for most.<ref>Bolen S et al. Systematic Review: [http://www.annals.org/cgi/content/full/0000605-200709180-00178v1 Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus]. Ann Intern Med 2007;147:6
</ref> Failure of response after a time is not unknown with most of these agents: the initial choice of anti-diabetic drug has been compared in a [[randomized controlled trial]] which found "cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide".<ref name="pmid17145742">
{{cite journal |author=Kahn SE, Haffner SM, Heise MA, ''et al'' |title=Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy |journal=N. Engl. J. Med. |volume=355 |issue=23 |pages=2427-43 |year=2006 |pmid=17145742 |doi=10.1056/NEJMoa066224}}
</ref> Of these, rosiglitazone had more weight gain and edema.<ref name="pmid17145742"/> Rosiglitazone may increase risk of death from cardiovascular causes.<ref name="nejm-rosiglitazone">
{{cite web |url=http://content.nejm.org/cgi/content/full/NEJMoa072761 |title=NEJM -- Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes}}
</ref> Pioglitazone and rosiglitazone may increase the risk of fractures.<ref name="fda-actos>
{{cite web |url=http://www.fda.gov/medwatch/safety/2007/safety07.htm#actos |title=MedWatch - 2007 Safety Information Alerts (Actos (pioglitazone))}}
</ref><ref name="fda-rosiglitazone">{{cite web |url=http://www.fda.gov/medwatch/safety/2007/safety07.htm#rosiglitazone |title=MedWatch - 2007 Safety Information Alerts (Rosiglitazone)}}
</ref>


For patients who also have heart failure, [[metformin]] may be the best drug.<ref name="pmid17761999">{{cite journal |author=Eurich DT, McAlister FA, Blackburn DF, ''et al'' |title=Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review |journal=BMJ |volume=335 |issue=7618 |pages=497 |year=2007 |pmid=17761999 |doi=10.1136/bmj.39314.620174.80}}</ref>
*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>  


=====Insulin Preparations=====
* 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>.
=====Starting Insulin=====
If [[antidiabetic drug]]s fail (or stop helping), [[insulin]] therapy may be necessary -- usually in addition to oral medication therapy -- to maintain normal glucose levels.


Typical total daily dosage of insulin is 0.6 U/kg.<ref name="pmid10068412"/> More complicated estimations to guide initial dosage of insulin are:<ref name="pmid2951066">{{cite journal |author=Holman RR, Turner RC |title=A practical guide to basal and prandial insulin therapy |journal=Diabet. Med. |volume=2 |issue=1 |pages=45–53 |year=1985 |pmid=2951066 |doi=}}</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>.
* For men, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(14.3xheight [m])–height [m])
* For women, [(fasting plasma glucose [mmol/liter]–5)x2] x (weight [kg]÷(13.2xheight [m])–height [m])


The initial insulin regimen can be chosen based on the patient's blood glucose profile.<ref name="pmid16847295">{{cite journal |author=Mooradian AD, Bernbaum M, Albert SG |title=Narrative review: a rational approach to starting insulin therapy |journal=Ann. Intern. Med. |volume=145 |issue=2 |pages=125-34 |year=2006 |pmid=16847295 |doi=|url=http://www.annals.org/cgi/content/full/145/2/125}}</ref> Initially, adding nightly insulin to patients failing oral medications may be best.<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=}}</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> The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L). If the fasting glucose is reported in mg/dl, multiple by 0.05551 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>
; 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>


When nightly insulin is insufficient, choices include:
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>.
* Premixed insulin with a fixed ratio of short and intermediate acting insulin; this tends to be more effective than long acting insulin, but is associated with more hypoglycemia.<ref name="pmid17890232">{{cite journal |author=Holman RR, Thorne KI, Farmer AJ, ''et al'' |title=Addition of Biphasic, Prandial, or Basal Insulin to Oral Therapy in Type 2 Diabetes |journal=N. Engl. J. Med. |volume=357 |issue= |pages= |year=2007 |pmid=17890232 |doi=10.1056/NEJMoa075392}}</ref><ref name="pmid15677776">{{cite journal |author=Raskin P, Allen E, Hollander P, ''et al'' |title=Initiating insulin therapy in type 2 Diabetes: a comparison of biphasic and basal insulin analogs |journal=Diabetes Care |volume=28 |issue=2 |pages=260-5 |year=2005 |pmid=15677776 |doi=|url=http://care.diabetesjournals.org/cgi/content/full/28/2/260}}</ref><ref name="pmid15823767">{{cite journal |author=Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH |title=Combined therapy with insulin lispro Mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy |journal=Clinical therapeutics |volume=26 |issue=12 |pages=2034-44 |year=2004 |pmid=15823767 |doi=10.1016/j.clinthera.2004.12.015}}</ref>. Initial total daily dosage of biphasic insulin can be 10 units if the fasting plasma glucose values are less than 180 mg/dl or 12 units when the fasting plasma glucose is above 180 mg/dl".<ref name="pmid15677776"/> A guide to titrating fixed ratio insulin is available (http://www.annals.org/cgi/content/full/145/2/125/T4).<ref name="pmid16847295"/>


* Long acting insulins such as [[insulin glargine]] and [[insulin detemir]]. 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".<ref name="pmid17443605">{{cite journal |author=Horvath K, Jeitler K, Berghold A, Ebrahim Sh, Gratzer T, Plank J, Kaiser T, Pieber T, Siebenhofer A |title=Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus |journal=Cochrane database of systematic reviews (Online) |volume= |issue=2 |pages=CD005613 |year=2007 |pmid=17443605}}</ref> More recently, a [[randomized controlled trial]] found that although long acting insulins were less effective, they were associated with less hypoglycemia.<ref name="pmid17890232"/>
; 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"/>.


===Alternative Medicines===
; Availability
[[Carnitine]] has been shown to increase insulin sensitivity and glucose storage in humans. <ref name="AMC study">{{cite journal | title=L-Carnitine Improves Glucose Disposal in Type 2 Diabetic Patients| journal=Journal of the American College of Nutrition| author=Geltrude Mingrone, Aldo V. Greco, Esmeralda Capristo, Giuseppe Benedetti, Annalisa Giancaterini, Andrea De Gaetano, and Giovanni Gasbarrini |year=1999 |volume=18 |issue=1 |pages=77-82 |url=http://www.jacn.org/cgi/content/full/18/1/77}}</ref>. It is important to note that this was with a constant blood infusion, not an oral dose, and that the clinical significance of this result is unclear.
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>.


[[Taurine]] has also shown significant improvement in [[insulin sensitivity]] and [[hyperlipidemia]] in rats.<ref name="Japanese rats">{{cite journal | title=Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes |authors=Yutaka Nakaya, Asako Minami, Nagakatsu Harada, Sadaichi Sakamoto, Yasuharu Niwa and Masaharu Ohnaka |date January 2000 |journal=American Journal of Clinical Nutrition |volume= 71 |issue= 1 |pages=54-58 |url=http://www.ajcn.org/cgi/content/full/71/1/54}}</ref>
===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 [[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>


Neither of these have shown permanent positive effects, nor a complete restoration to pre-diabetes conditions, only improvement. Their clinical importance in humans remains unclear.
*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
!align="center" style="background:#DCDCDC;"|Class
!align="center" style="background:#DCDCDC;"|Drug
!align="center" style="background:#DCDCDC;"|Mechanism of action
!align="center" style="background:#DCDCDC;"|Primary physiologic action
!align="center" style="background:#DCDCDC;"|Advantages
!align="center" style="background:#DCDCDC;"|Disadvantages
!align="center" style="background:#DCDCDC;"|Cost
|-
|align="center" style="background:#DCDCDC;"|[[Biguanides]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Metformin]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[AMP-activated protein kinase|AMP-kinase]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |↓ Hepatic glucose
production
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Extensive experience


===Antihypertensive Agents===
* Rare [[hypoglycemia]]
{{main|Antihypertensive}}


The goal blood pressure is 130/80 which is lower than in non-diabetic patients.<ref name="pmid12748199">{{cite journal |author=Chobanian AV, Bakris GL, Black HR, ''et al'' |title=The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report |journal=JAMA |volume=289 |issue=19 |pages=2560-72 |year=2003 |pmid=12748199 |doi=10.1001/jama.289.19.2560}}</ref>
* ↓ [[Cardiovascular disease|CVD]] events


===ACE Inhibitors===
* Relatively higher [[A1C]] efficacy
The HOPE study suggests that diabetics should be treated with [[ACE inhibitors]] (specifically [[ramipril]] 10 mg/d) if they have one of the following <ref name="pmid10639539">{{cite journal |author=Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G |title=Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators |journal=N. Engl. J. Med. |volume=342 |issue=3 |pages=145-53 |year=2000 |pmid=10639539 |doi=}}</ref>:
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Hypertension]]
* Gastrointestinal side effects ([[diarrhea]], [[abdominal cramping]], [[nausea]])
* [[Hypercholesterolemia]] or reduced low high-density lipoprotein cholesterol levels
* Cigarette smoking
* [[Microalbuminuria]]
After treatment with [[ramipril]] for 5 years the [[number needed to treat]] was 50 patients to prevent one cardiovascular death. Other [[ACE inhibitors]] may not be as effective.<ref name="pmid15262665">{{cite journal |author=Pilote L, Abrahamowicz M, Rodrigues E, Eisenberg MJ, Rahme E |title=Mortality rates in elderly patients who take different angiotensin-converting enzyme inhibitors after acute myocardial infarction: a class effect? |journal=Ann. Intern. Med. |volume=141 |issue=2 |pages=102-12 |year=2004 |pmid=15262665 |doi=}}</ref>


===Hypolipidemic Agents===
* [[Vitamin B12 deficiency]]
{{main|Hypercholesterolemia#Diabetic_patients}}
 
* [[contraindication|Contraindications]]: [[eGFR]] ≤30 mL/min/1.73 m2, [[acidosis]], [[hypoxia]], [[dehydration]].
 
* [[Lactic acidosis]] risk (rare)
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low
|-
|align="center" style="background:#DCDCDC;"|[[Sulfonylureas]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |2nd generation
* [[Glyburide]]
 
* [[Glipizide]]
 
* [[Glimepiride]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Closes [[Potassium|K]]-[[ATP]] channels on [[beta cell]] [[Plasma membrane|plasma membranes]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |↑ [[Insulin]] secretion
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Extensive experience
 
* ↓ [[Microvascular disease|Microvascular]] risk
 
* Relatively higher [[A1C]] efficacy
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Hypoglycemia]]
 
* ↑ Weight
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low
|-
|align="center" style="background:#DCDCDC;"|[[Meglitinide|Meglitinides]]
 
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Repaglinide]]
 
* [[Nateglinide]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Closes [[Potassium|K]]-[[ATP]] channels on [[beta cell]] [[Plasma membrane|plasma membranes]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |↑ [[Insulin]] secretion
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* ↓ [[Postprandial]] glucose excursions
 
* Dosing flexibility
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Hypoglycemia]]
 
* ↑ Weight
 
* Frequent dosing schedule
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Moderate
|-
|align="center" style="background:#DCDCDC;"|[[Thiazolidinedione]]
([[TZD|TZDs]])
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Pioglitazone]]<sup>‡</sup>
 
* [[Rosiglitazone]]<sup>§</sup>
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates the nuclear transcription factor [[PPARG|PPAR-gama]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |↑ Insulin sensitivity
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Rare [[hypoglycemia]]
 
* Relatively higher [[A1C]] efficacy
 
* Durability
 
* ↓ [[Triglyceride|Triglycerides]] ([[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]]
*[[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
 
* [[Edema]]/[[heart failure]]
 
* [[bone fracture|Bone fractures]]
 
* ↑ [[LDL-C]] ([[rosiglitazone]])
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low
|-
|align="center" style="background:#DCDCDC;"|α-Glucosidase
inhibitors
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Acarbose]]
* [[Miglitol]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Inhibits intestinal
 
α-glucosidase
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Slows intestinal carbohydrate
 
digestion/absorption
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Rare hypoglycemia
 
* ↓ Postprandial [[glucose]] excursions
 
* ↓ [[CVD]] events in [[prediabetes]]
 
* Nonsystemic
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Generally modest A1C efficacy
 
* Gastrointestinal [[side effect|side effects]] ([[flatulence]], [[diarrhea]])
 
* Frequent dosing schedule
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low to
 
moderate
|-
|align="center" style="background:#DCDCDC;"|[[Dipeptidyl peptidase-4 inhibitor|DPP-4]]
 
[[Dipeptidyl peptidase-4 inhibitor|inhibitors]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Sitagliptin]]
 
* [[Saxagliptin]]
 
* [[Linagliptin]]
 
* [[Alogliptin]]
|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)
 
* ↓ [[Glucagon]] secretion ([[glucose]] dependent)
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Rare [[hypoglycemia]]
 
* Well tolerated
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Angioedema]]/[[urticaria]] and other immune-mediated dermatological effects
 
* [[Acute pancreatitis]]
 
* ↑ [[Heart failure]] hospitalizations ([[saxagliptin]], [[alogliptin]])
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High
|-
|align="center" style="background:#DCDCDC;"|[[Bile acid sequestrants]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Colesevelam]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Binds bile acids in intestinal tract,
 
increasing hepatic [[bile acid]] production
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* ↓ Hepatic [[glucose]] production
 
* ↑ [[Incretin]] levels
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Rare [[hypoglycemia]]
 
* ↓ [[LDL-C]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Modest [[A1C]] efficacy
 
* [[Constipation]]
 
* ↑ [[Triglyceride|Triglycerides]]
 
* May ↓ absorption of other [[medication|medications]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High
|-
|align="center" style="background:#DCDCDC;"|[[Dopamine agonists|Dopamine-2]]
 
[[Dopamine agonists|agonists]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Bromocriptine]]
 
(quick release)<sup>§</sup>
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates dopaminergic receptors
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Modulates [[hypothalamic]] regulation of metabolism
 
* ↑ [[Insulin]] sensitivity
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Rare [[hypoglycemia]]
 
* ↓ [[Cardiovascular disease|CVD]] events
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Modest [[A1C]] efficacy
 
* [[Dizziness]]/[[syncope]]
 
* [[Nausea]]
 
* [[Fatigue]]
 
* [[Rhinitis]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High
|-
|align="center" style="background:#DCDCDC;"|[[SGLT2]]
 
inhibitors
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Canagliflozin]]
 
* [[Dapagliflozin]]<sup>‡</sup>
 
* [[Empagliflozin]]
|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]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Rare [[hypoglycemia]]
 
* ↓ Weight
 
* ↓ [[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>
 
* 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]]
 
* [[Volume depletion]], [[hypotension]], [[dizziness]]
 
* ↑ [[LDL-C]]
 
* ↑ [[Creatinine]] (transient)
 
* [[DKA]], [[urinary tract infections]] leading to urosepsis, [[pyelonephritis]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High
|-
|align="center" style="background:#DCDCDC;"|[[GLP-1]] receptor agonists
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* [[Exenatide]]
 
* Exenatide extended release
 
* [[Liraglutide]]
 
* [[Albiglutide]]
 
* [[Lixisenatide]]
 
* [[Dulaglutide]]
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates GLP-1 receptors
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* ↑ [[Insulin]] secretion (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
|-
|align="center" style="background:#DCDCDC;"|[[Amylin]] mimetics
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Pramlintide]]<sup>§</sup>
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[amylin]] receptors
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* ↓ [[Glucagon]] secretion
 
* Slows gastric emptying
 
* ↑ [[Satiety]]
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |
* Postprandial [[glucose]] excursions
 
* ↓ Weight
|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
|-
| rowspan="5" align="center" style="background:#DCDCDC;"|[[Insulin|Insulins]]
|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}}
{{WH}}
 
{{WS}}
[[Category:Disease]]
[[Category:Medicine]]
[[Category:Endocrinology]]
[[Category:Endocrinology]]
[[Category:Autoimmune diseases]]
[[Category:Mature chapter]]
[[Category:Diabetes]]
[[Category:Aging-associated diseases]]
[[Category:Medical conditions related to obesity]]
[[Category:Emergency medicine]]
[[Category:Primary care]]
[[Category:Intensive care medicine]]
[[Category:Needs overview]]

Latest revision as of 14:27, 11 April 2023

Diabetes mellitus main page

Diabetes mellitus type 2 Microchapters

Home

Patient information

Overview

Historical Perspective

Pathophysiology

Causes

Differentiating Diabetes Mellitus Type 2 from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

Chest X Ray

CT

MRI

Echocardiography or Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical therapy

Life Style Modification
Pharmacotherapy
Glycemic Control

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

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

Main article: Diabetes Care in the Hospital Setting

Outpatients

A network meta-analysis summarizes the risks and benefits of available medications for diabetes mellitus type 2[1].

Metformin

Contraindications

,Randomized controlled trial comparing initial doses for metformin[17].
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

Bedtime insulin

For Diabetes mellitus type 2:

  • 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

  • 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

  • Extensive experience
  • Relatively higher A1C efficacy
 Low
Sulfonylureas 2nd generation Closes K-ATP channels on beta cell plasma membranes ↑ Insulin secretion
  • Extensive experience
  • Relatively higher A1C efficacy
  • ↑ Weight
 Low
Meglitinides Closes K-ATP channels on beta cell plasma membranes ↑ Insulin secretion
  • Dosing flexibility
  • ↑ Weight
  • Frequent dosing schedule
 Moderate
Thiazolidinedione

(TZDs)

Activates the nuclear transcription factor PPAR-gama ↑ Insulin sensitivity
  • Relatively higher A1C efficacy
  • Durability
  • ↑ Weight
 Low
α-Glucosidase

inhibitors

Inhibits intestinal

α-glucosidase

Slows intestinal carbohydrate

digestion/absorption

  • Rare hypoglycemia
  • ↓ Postprandial glucose excursions
  • Nonsystemic
  • Generally modest A1C efficacy
  • Frequent dosing schedule
 Low to

moderate

DPP-4

inhibitors

Inhibits DPP-4 activity, increasing postprandial incretin (GLP-1, GIP) concentrations
  • Well tolerated
 High
Bile acid sequestrants Colesevelam Binds bile acids in intestinal tract,

increasing hepatic bile acid production

  • Modest A1C efficacy
 High
Dopamine-2

agonists

Bromocriptine

(quick release)§

Activates dopaminergic receptors
  • Modest A1C efficacy
 High
SGLT2

inhibitors

Inhibits SGLT2 in the proximal nephron
  • Blocks glucose reabsorption by the kidney,increasing glucosuria
  • ↓ Weight
  • Empagliflozin is associated with lower CVD event rate and mortality in patients with CVD.[37] It is also related to reduction of left ventricle mass after 6 months treatment.[38]
  • Dapagliflozin has minor effect on diastolic cardiac function of diabetic patients. Nevertheless, it is able to lower the risk of major adverse cardiovascular events in a diabetic patients with previous MI. [39][40]
 High
GLP-1 receptor agonists
  • Exenatide extended release
 Activates GLP-1 receptors
  • ↑ Insulin secretion (glucose dependent)
  • ↓ Glucagon secretion (glucose dependent)
  • Slows gastric emptying
  • ↓ Weight
  • Injectable
  • Training requirements
 High
Amylin mimetics Pramlintide§ Activates amylin receptors
  • Slows gastric emptying
  • ↓ Weight
  • Modest A1C efficacy
  • Injectable
  • Frequent dosing schedule
  • Training requirements
 High
Insulins
  • Rapid-acting analogs
 Activates insulin receptors
  • Nearly universal response
  • Theoretically unlimited efficacy
  • ↓ Microvascular risk
  • Training requirements
  • Patient and provider reluctance
  • Injectable (except inhaled insulin)
  • Pulmonary toxicity (inhaled insulin)
 High
  • Short-acting
  • Intermediate-acting
  • Basal insulin analogs
  • Premixed insulin products
    • NPH/Regular 70/30
    • 70/30 aspart mix
    • 75/25 lispro mix
    • 50/50 lispro mix

‡ 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

  1. ↑ 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).
  2. ↑ 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.
  3. ↑ "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.
  4. ↑ 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.
  5. ↑ 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. ↑ 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.
  7. ↑ 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ 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.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ 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.
  19. ↑ 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.
  20. ↑ 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. ↑ 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. ↑ 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
  23. ↑ 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.
  24. ↑ 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.
  25. ↑ 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.
  26. ↑ 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. ↑ 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. ↑ 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.
  29. ↑ 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).
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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
  33. ↑ 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.
  34. ↑ 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. ↑ 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.
  36. ↑ 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. ↑ 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.
  38. ↑ 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.
  39. ↑ 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.
  40. ↑ 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.
  41. ↑ 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.
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