Diabetes mellitus type 2 medical therapy: Difference between revisions
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==Overview== | ==Overview== | ||
The main goals of [[treatment]] are to eliminate [[hyperglycemic]] symptoms, control the long term complications and improve the patient's quality of life. | The main goals of [[treatment]] are to eliminate [[hyperglycemic]] [[Symptom|symptoms]], control the long term [[Complication (medicine)|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 [[Obesity|obese]] patients. [[Metformin]] is the first line pharmacologic [[therapy]] that is usually started once the [[diagnosis]] is confirmed unless [[Contraindication|contraindications]] exist. 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 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. 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]]. | |||
==Pharmacologic therapy== | ==Pharmacologic therapy== | ||
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{{main|Diabetes Care in the Hospital Setting}} | {{main|Diabetes Care in the Hospital Setting}} | ||
===Outpatients=== | ===Outpatients=== | ||
The most effective class of drugs for reducing death are probably [[SGLT2|sodium glucose transporter 2]] (SGLT2) inhibitors or [[GLP-1]] receptor agonists. | * Medical therapy starts with [[metformin]] [[monotherapy]] unless there is a [[contraindication]] for it. In the following conditions, treatment starts with dual [[therapy]]: | ||
**If [[HbA1C]] is greater than 9, start with dual oral [[Blood sugar|blood glucose]] lowering agent. | |||
**If [[HbA1C]] is greater than 10 or [[Blood sugar|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]]. | |||
===Metformin=== | ===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 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. | *[[Metformin]] is capable of decreasing the [[body weight]] but it's effect on [[Muscle|muscle mass]] is unclear. | ||
* 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.]] | * A systemic [[review]], observing 34,000 patients in total, concluded that [[Metformin]] is as safe as other [[Anti-diabetic drug|anti-diabetic]] treatments in [[Diabetes mellitus|diabetic]] patients with [[Congestive heart failure|heart failure.]] | ||
* 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. | * 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. | ||
* Metformin use in diabetic patients with [[sepsis]], [[tuberculosis]] and Chronic obstructive pulmonary disease [[Chronic obstructive pulmonary disease|(COPD]]) were associated with lower [[mortality rate]]. | *[[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]]. | ||
*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. | *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]]. | ||
==== Contraindications ==== | ==== 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]]). | * 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-[[N-Nitrosodimethylamine|nitrosodimethylamine]] ([[N-Nitrosodimethylamine|NDMA]]). | ||
* N-nitrosodimethylamine ([[N-Nitrosodimethylamine|NDMA]]) is a [[Carcinogen|carcinogenic]] agent when exposed in higher levels leads to cancer. | *[[N-Nitrosodimethylamine|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:]] | * The following are the pharma companies that the FDA recalls the [[Metformin extended release|extended-release metformin:]] | ||
** Lupin | ** Lupin | ||
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{| class="wikitable" | {| class="wikitable" | ||
|+ | |+[[Randomized controlled trial]] comparing initial doses for metformin. | ||
! style="text-align: center;" | Total duration was 14 weeks with at least 8 weeks on final dose. | ! style="text-align: center;" | Total duration was 14 weeks with at least 8 weeks on final dose. | ||
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| style="text-align: center;" | 29% | | style="text-align: center;" | 29% | ||
|- | |- | ||
| Diarrhea | |[[Diarrhea]] | ||
| style="text-align: center;" | 5% | | style="text-align: center;" | 5% | ||
| style="text-align: center;" | 8% | | style="text-align: center;" | 8% | ||
Line 75: | Line 74: | ||
| style="text-align: center;" | 14% | | style="text-align: center;" | 14% | ||
|- | |- | ||
| HbA1c change | |[[Glycosylated hemoglobin|HbA1c]] change | ||
| style="text-align: center;" | + 1.2 | | style="text-align: center;" | + 1.2 | ||
| style="text-align: center;" | + 0.3 | | style="text-align: center;" | + 0.3 | ||
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===Insulin=== | ===Insulin=== | ||
* The lack of inexpensive, generic insulin may lead to underuse of insulin | * The lack of inexpensive, generic [[insulin]] may lead to underuse of [[insulin]] and occurs for unusual reasons. | ||
* The insulin analogues may not provide a meaningful advantage | * The [[insulin]] [[Analog (chemistry)|analogues]] may not provide a meaningful advantage. | ||
* Although Insulin increases the body weight, some data suggest that it is capable of increasing the muscle mass. | * Although [[Insulin]] increases the [[body weight]], some data suggest that it is capable of increasing the [[muscle]] mass. | ||
* A [[meta-analysis]] of [[randomized controlled trial]]s 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<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 | * A [[meta-analysis]] of [[randomized controlled trial]]s by the [[Cochrane Collaboration]] found "only a minor clinical benefit of treatment with long-acting [[insulin]] [[Analog (chemistry)|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 [[Insulin Glargine|glargine]] and have found that although long acting [[Insulin|insulins]] were less effective, they were associated with less [[hypoglycemia]]. | ||
* Premixed combinations of insulin, human or analogue, have similar reductions in [[HbA1c]] | * Premixed combinations of [[insulin]], human or [[Analog (chemistry)|analogue]], have similar reductions in [[HbA1c]]. 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==== | ====Bedtime insulin==== | ||
Initially, adding bedtime insulin to patients | |||
* Initially, adding bedtime [[insulin]] to patients failed oral [[Medication|medications]] is more effective ''and'' with less [[weight gain]] than using multiple dose [[insulin]]. Nightly | |||
* [[Insulin]] combines better with [[metformin]] that with [[sulfonylurea]]s. | |||
* The initial dose of nightly [[insulin]] (measured in IU/d) should be equal to the fasting [[Blood sugar|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. | |||
===Combination therapy=== | ===Combination therapy=== | ||
The following table summarize the available FDA approved glucose lowering agents that may help to individualize treatment for each patient | * Any agent can be added as second drug based on patient condition. Although, the American Association of Clinical Endocrinologists recommends either [[incretin]] based [[therapy]] or [[SGLT2|sodium glucose transporter 2]] ([[SGLT2]]) inhibition agents. | ||
{| style="border: 0px; font-size: 90%; margin: 3px;" align=center | |||
!align="center" style="background:#DCDCDC;"|Class | * The following table summarize the available [[Food and Drug Administration|FDA]] approved [[glucose]] lowering agents that may help to individualize [[treatment]] for each patient : | ||
!align="center" style="background:#DCDCDC;"|Drug | |||
!align="center" style="background:#DCDCDC;"|Mechanism of action | {| style="border: 0px; font-size: 90%; margin: 3px;" align="center" | ||
!align="center" style="background:#DCDCDC;"|Primary physiologic action | ! align="center" style="background:#DCDCDC;" |Class | ||
!align="center" style="background:#DCDCDC;"|Advantages | ! align="center" style="background:#DCDCDC;" |Drug | ||
!align="center" style="background:#DCDCDC;"|Disadvantages | ! align="center" style="background:#DCDCDC;" |Mechanism of action | ||
!align="center" style="background:#DCDCDC;"|Cost | ! 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]] | | align="center" style="background:#DCDCDC;" |[[Biguanides]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Metformin]] | | 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" |Activates [[AMP-activated protein kinase|AMP-kinase]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |↓ Hepatic glucose | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |↓ Hepatic glucose | ||
production | production | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Extensive experience | * Extensive experience | ||
Line 123: | Line 127: | ||
* Relatively higher [[A1C]] efficacy | * Relatively higher [[A1C]] efficacy | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Gastrointestinal side effects ([[diarrhea]], [[abdominal cramping]], [[nausea]]) | *[[Gastrointestinal tract|Gastrointestinal]] side effects ([[diarrhea]], [[abdominal cramping]], [[nausea]]) | ||
* [[Vitamin B12 deficiency]] | *[[Vitamin B12 deficiency]] | ||
* Contraindications: [[eGFR]] ≤30 mL/min/1.73 m2, [[acidosis]], [[hypoxia]], [[dehydration]]. | *[[Contraindication|Contraindications]]: [[eGFR]] ≤30 mL/min/1.73 m2, [[acidosis]], [[hypoxia]], [[dehydration]]. | ||
* [[Lactic acidosis]] risk (rare) | *[[Lactic acidosis]] risk (rare) | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[Sulfonylureas]] | | align="center" style="background:#DCDCDC;" |[[Sulfonylureas]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" |2nd generation | | style="padding: 5px 5px; background: #F5F5F5;" align="left" |2nd generation | ||
* [[ | *[[Glyburide]] | ||
* [[Glimepiride]] | *[[Glipizide]] | ||
|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 | *[[Glimepiride]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | 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 | * Extensive experience | ||
* ↓ [[Microvascular disease|Microvascular]] risk | * ↓ [[Microvascular disease|Microvascular]] risk | ||
* Relatively higher [[A1C]] efficacy | * Relatively higher [[A1C]] efficacy | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Hypoglycemia]] | *[[Hypoglycemia]] | ||
* ↑ Weight | * ↑ Weight | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[Meglitinide|Meglitinides]] | | align="center" style="background:#DCDCDC;" |[[Meglitinide|Meglitinides]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Repaglinide]] | *[[Repaglinide]] | ||
* [[Nateglinide]] | *[[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" |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="center" |↑ [[Insulin]] secretion | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | 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" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Hypoglycemia]] | *[[Hypoglycemia]] | ||
* ↑ Weight | * ↑ Weight | ||
* Frequent dosing schedule | * Frequent dosing schedule | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Moderate | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Moderate | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[Thiazolidinedione]] | | align="center" style="background:#DCDCDC;" |[[Thiazolidinedione]] | ||
(TZDs) | [[Thiazolidinedione|(TZDs)]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Pioglitazone]]<sup>‡</sup> | *[[Pioglitazone]]<sup>‡</sup> | ||
* [[Rosiglitazone]]<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" |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="center" |↑ [[Insulin resistance|Insulin sensitivity]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
* Relatively higher A1C efficacy | * Relatively higher [[Glycosylated hemoglobin|A1C]] efficacy | ||
* Durability | * Durability | ||
* ↓ [[Triglyceride|Triglycerides]] (pioglitazone) | * ↓ [[Triglyceride|Triglycerides]] ([[pioglitazone]]) | ||
* ↓ CVD events (PROactive, pioglitazone) | * ↓ [[Cardiovascular disease|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 mellitus|diabetes]] and with [[insulin resistance]] and history of recent [[stroke]] or [[TIA]] | ||
*[[Pioglitazone]] use is associated with higher chance of [[pneumonia]] | *[[Pioglitazone]] use is associated with higher chance of [[pneumonia]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↑ Weight | * ↑ Weight | ||
* [[Edema]]/[[heart failure]] | *[[Edema]]/[[heart failure]] | ||
* Bone fractures | * Bone [[Bone fracture|fractures]] | ||
* ↑ [[LDL-C]] ([[rosiglitazone]]) | * ↑ [[LDL-C]] ([[rosiglitazone]]) | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|α-Glucosidase | | align="center" style="background:#DCDCDC;" |α-Glucosidase | ||
inhibitors | inhibitors | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Acarbose]] | *[[Acarbose]] | ||
* [[Miglitol]] | *[[Miglitol]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Inhibits intestinal | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Inhibits intestinal | ||
α-glucosidase | α-glucosidase | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |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" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare hypoglycemia | * Rare [[hypoglycemia]] | ||
* ↓ Postprandial glucose excursions | * ↓ Postprandial [[glucose]] excursions | ||
* ↓ CVD events in prediabetes | * ↓ [[Cardiovascular disease|CVD]] events in [[prediabetes]] | ||
* Nonsystemic | * Nonsystemic | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Generally modest A1C efficacy | * Generally modest [[Glycosylated hemoglobin|A1C]] efficacy | ||
* Gastrointestinal side effects ([[flatulence]], [[diarrhea]]) | *[[Gastrointestinal tract|Gastrointestinal]] [[Adverse effect (medicine)|side effects]] ([[flatulence]], [[diarrhea]]) | ||
* Frequent dosing schedule | * Frequent dosing schedule | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low to | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Low to | ||
moderate | moderate | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[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" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Sitagliptin]] | *[[Sitagliptin]] | ||
* [[Saxagliptin]] | *[[Saxagliptin]] | ||
* [[Linagliptin]] | *[[Linagliptin]] | ||
* [[Alogliptin]] | *[[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="center" |Inhibits [[Dipeptidyl peptidase-4 inhibitor|DPP-4]] activity, increasing postprandial [[incretin]] ([[Glucagon-like peptide-1|GLP-1]], GIP) concentrations | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | 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" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
* Well tolerated | * Well tolerated | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Angioedema]]/[[urticaria]] and other immune-mediated dermatological effects | *[[Angioedema]]/[[urticaria]] and other immune-mediated dermatological effects | ||
* [[Acute pancreatitis]] | *[[Acute pancreatitis]] | ||
* ↑ [[Heart failure]] hospitalizations ([[saxagliptin]], [[alogliptin]]) | * ↑ [[Heart failure]] hospitalizations ([[saxagliptin]], [[alogliptin]]) | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|Bile acid sequestrants | | align="center" style="background:#DCDCDC;" |[[Bile acid sequestrant|Bile acid sequestrants]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Colesevelam]] | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Colesevelam]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Binds bile acids in intestinal tract, | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Binds [[Bile acid|bile acids]] in intestinal tract, | ||
increasing hepatic bile acid production | increasing hepatic [[bile acid]] production | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | 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" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
* ↓ [[LDL-C]] | * ↓ [[LDL-C]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modest [[A1C]] efficacy | * Modest [[A1C]] efficacy | ||
* [[Constipation]] | *[[Constipation]] | ||
* ↑ [[Triglyceride|Triglycerides]] | * ↑ [[Triglyceride|Triglycerides]] | ||
* May ↓ absorption of other medications | * May ↓ absorption of other [[Medication|medications]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[Dopamine agonists|Dopamine-2]] | | align="center" style="background:#DCDCDC;" |[[Dopamine agonists|Dopamine-2]] | ||
[[Dopamine agonists|agonists]] | [[Dopamine agonists|agonists]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Bromocriptine]] | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |[[Bromocriptine]] | ||
(quick release)<sup>§</sup> | (quick release)<sup>§</sup> | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates dopaminergic receptors | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[dopaminergic]] receptors | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modulates [[hypothalamic]] regulation of metabolism | * Modulates [[hypothalamic]] regulation of metabolism | ||
* ↑ Insulin sensitivity | * ↑ [[Insulin resistance|Insulin sensitivity]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | 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" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modest [[A1C]] efficacy | * Modest [[A1C]] efficacy | ||
* [[Dizziness]]/[[syncope]] | *[[Dizziness]]/[[syncope]] | ||
* [[Nausea]] | *[[Nausea]] | ||
* [[Fatigue]] | *[[Fatigue]] | ||
* [[Rhinitis]] | *[[Rhinitis]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[SGLT2]] | | align="center" style="background:#DCDCDC;" |[[SGLT2]] | ||
inhibitors | inhibitors | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Canagliflozin]] | *[[Canagliflozin]] | ||
* [[Dapagliflozin]]<sup>‡</sup> | *[[Dapagliflozin]]<sup>‡</sup> | ||
* [[Empagliflozin]] | *[[Empagliflozin]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |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" | | | 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" | | | 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]]. | *↓ 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]]. | ||
* Empagliflozin is associated with lower [[Cardiovascular disease|CVD]] event rate and mortality in patients with [[Cardiovascular disease|CVD]]. | *[[Empagliflozin]] is associated with lower [[Cardiovascular disease|CVD]] event rate and mortality in patients with [[Cardiovascular disease|CVD]]. It is also related to reduction of [[left ventricle]] mass after 6 months [[treatment]]. | ||
* 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]]. | *[[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]]. | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Genitourinary]] infections<sup>†</sup> | *[[Genitourinary]] infections<sup>†</sup> | ||
* [[Polyuria]] | *[[Polyuria]] | ||
* [[Volume depletion]], [[hypotension]], [[dizziness]] | *[[Volume depletion]], [[hypotension]], [[dizziness]] | ||
* ↑ [[LDL-C]] | * ↑ [[LDL-C]] | ||
Line 347: | Line 352: | ||
* ↑ [[Creatinine]] (transient) | * ↑ [[Creatinine]] (transient) | ||
* [[DKA]], [[urinary tract infections]] leading to urosepsis, [[pyelonephritis]] | *[[DKA]], [[urinary tract infections]] leading to urosepsis, [[pyelonephritis]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[GLP-1]] receptor agonists | | align="center" style="background:#DCDCDC;" |[[GLP-1]] receptor [[Agonist|agonists]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Exenatide]] | *[[Exenatide]] | ||
* Exenatide extended release | * Exenatide extended release | ||
* [[Liraglutide]] | *[[Liraglutide]] | ||
* [[Albiglutide]] | *[[Albiglutide]] | ||
* [[Lixisenatide]] | *[[Lixisenatide]] | ||
* [[Dulaglutide]] | *[[Dulaglutide]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates GLP-1 receptors | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[Glucagon-like peptide-1|GLP-1]] receptors | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↑ [[Insulin]] secretion (glucose dependent) | * ↑ [[Insulin]] secretion ([[glucose]] dependent) | ||
* ↓ [[Glucagon]] secretion (glucose dependent) | * ↓ [[Glucagon]] secretion ([[glucose]] dependent) | ||
* Slows gastric emptying | * Slows gastric emptying | ||
* ↑ Satiety | * ↑ [[Satiety]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rare [[hypoglycemia]] | * Rare [[hypoglycemia]] | ||
Line 379: | Line 384: | ||
* ↓ [[Postprandial]] glucose excursions | * ↓ [[Postprandial]] glucose excursions | ||
* ↓ Some cardiovascular risk factors | * ↓ Some cardiovascular [[Risk factor|risk factors]] | ||
* ↓ The chance of [[kidney]] | * ↓ The chance of [[kidney|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> | *[[Liraglutide]] associated with lower [[Cardiovascular disease|CVD]] event rate and [[Mortality rate|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> | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Gastrointestinal side effects ([[nausea]]/[[vomiting]]/[[diarrhea]]) | * Gastrointestinal [[Adverse effect (medicine)|side effects]] ([[nausea]]/[[vomiting]]/[[diarrhea]]) | ||
* ↑ [[Tachycardia|Heart rate]] | * ↑ [[Tachycardia|Heart rate]] | ||
* [[Acute pancreatitis]] | *[[Acute pancreatitis]] | ||
* C-cell hyperplasia/[[Medullary thyroid cancer|medullary thyroid tumors]] in animals | * C-cell [[hyperplasia]]/[[Medullary thyroid cancer|medullary thyroid tumors]] in animals | ||
* Injectable | * Injectable | ||
* Training requirements | * Training requirements | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|align="center" style="background:#DCDCDC;"|[[Amylin]] mimetics | | 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" |[[Pramlintide]]<sup>§</sup> | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[amylin]] receptors | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[amylin]] receptors | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↓ [[Glucagon]] secretion | * ↓ [[Glucagon]] secretion | ||
* Slows gastric emptying | * Slows gastric emptying | ||
* ↑ Satiety | *[[Satiety|↑ Satiety]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Postprandial glucose excursions | * Postprandial glucose excursions | ||
* ↓ Weight | * ↓ Weight | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Modest A1C efficacy | * Modest [[Glycosylated hemoglobin|A1C]] efficacy | ||
* Gastrointestinal side effects ([[Nausea and vomiting|nausea/vomiting]]) | *[[Gastrointestinal tract|Gastrointestinal]] [[Adverse effect (medicine)|side effects]] ([[Nausea and vomiting|nausea/vomiting]]) | ||
* [[Hypoglycemia]] unless insulin dose is simultaneously reduced | *[[Hypoglycemia]] unless [[insulin]] dose is simultaneously reduced | ||
* Injectable | * Injectable | ||
Line 423: | Line 428: | ||
* Training requirements | * Training requirements | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | | style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
| rowspan="5" align="center" style="background:#DCDCDC;"|[[Insulin|Insulins]] | | rowspan="5" align="center" style="background:#DCDCDC;" |[[Insulin|Insulins]] | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Rapid-acting analogs | * Rapid-acting [[Analog (chemistry)|analogs]] | ||
** [[Insulin Lispro|Lispro]] | **[[Insulin Lispro|Lispro]] | ||
** [[Insulin aspart|Aspart]] | **[[Insulin aspart|Aspart]] | ||
** [[Insulin Glulisine|Glulisine]] | **[[Insulin Glulisine|Glulisine]] | ||
** Inhaled insulin | ** Inhaled [[insulin]] | ||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates insulin receptors | | rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="center" |Activates [[insulin]] receptors | ||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* ↑ Glucose disposal | * ↑ [[Glucose]] disposal | ||
* ↓ Hepatic glucose production | * ↓ Hepatic [[glucose]] production | ||
* Suppresses [[ketogenesis]] | * Suppresses [[ketogenesis]] | ||
Line 448: | Line 453: | ||
* Theoretically unlimited efficacy | * Theoretically unlimited efficacy | ||
* ↓ Microvascular risk | * ↓ Microvascular risk | ||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* [[Hypoglycemia]] | *[[Hypoglycemia]] | ||
* [[Weight gain]] | *[[Weight gain]] | ||
* Training requirements | * Training requirements | ||
Line 458: | Line 463: | ||
* Patient and provider reluctance | * Patient and provider reluctance | ||
* Injectable (except inhaled insulin) | * Injectable (except inhaled [[insulin]]) | ||
* Pulmonary toxicity (inhaled insulin) | *[[Pulmonary toxicity]] (inhaled [[insulin]]) | ||
| rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | | rowspan="5" style="padding: 5px 5px; background: #F5F5F5;" align="center" |High | ||
|- | |- | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Short-acting | * Short-acting | ||
** [[Regular insulin|Human Regular]] | **[[Regular insulin|Human Regular]] | ||
|- | |- | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Intermediate-acting | * Intermediate-acting | ||
** [[NPH insulin|Human NPH]] | **[[NPH insulin|Human NPH]] | ||
|- | |- | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Basal insulin analogs | * Basal [[insulin]] [[Analog (chemistry)|analogs]] | ||
**[[Insulin Glargine|Glargine]] | |||
** [[Insulin Glargine|Glargine]] | |||
** [[Insulin Detemir|Detemir]] | **[[Insulin Detemir|Detemir]] | ||
** [[Insulin degludec|Degludec]] | **[[Insulin degludec|Degludec]] | ||
|- | |- | ||
|style="padding: 5px 5px; background: #F5F5F5;" align="left" | | | style="padding: 5px 5px; background: #F5F5F5;" align="left" | | ||
* Premixed insulin products | * Premixed [[insulin]] products | ||
** NPH/Regular 70/30 | ** NPH/Regular 70/30 | ||
Line 496: | Line 500: | ||
<sup>‡</sup> Initial concerns regarding [[bladder cancer]] risk are decreasing after subsequent study. | <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> Not licensed in Europe for [[Diabetes mellitus type 2|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 | <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. | ||
==References== | ==References== | ||
Line 504: | Line 508: | ||
[[Category:Endocrinology]] | [[Category:Endocrinology]] | ||
<references /> |
Revision as of 12:16, 11 August 2020
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]
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. 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
- Medical therapy starts with metformin monotherapy unless there is a contraindication for it. In the following conditions, treatment starts with dual therapy:
- 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.
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.
- 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.
- Some studies demonstrated lower risk of mortality in diabetic patients with concurrent COPD or Asthma who were taking Metformin compared to non-users.
- Metformin use in diabetic patients with sepsis, tuberculosis and Chronic obstructive pulmonary disease (COPD) were associated with lower mortality rate.
- 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.
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).
- 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 and occurs for unusual reasons.
- The insulin analogues may not provide a meaningful advantage.
- Although Insulin increases the body weight, some data suggest that it is capable of increasing the muscle mass.
- 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[1] More recent randomized controlled trials have found no differences with glargine and have found that although long acting insulins were less effective, they were associated with less hypoglycemia.
- Premixed combinations of insulin, human or analogue, have similar reductions in HbA1c. A cohort study likewise found similar rates of hypoglycemia[2].
Bedtime insulin
- Initially, adding bedtime insulin to patients failed oral medications is more effective and with less weight gain than using multiple dose insulin. Nightly
- Insulin combines better with metformin that with sulfonylureas.
- The initial dose of nightly insulin (measured in IU/d) should be equal to the fasting blood glucose level (measured in mmol/L)[3]. If the fasting glucose is reported in mg/dl, multiple by 0.05551 (or divided by 18) to convert to mmol/L.
Combination therapy
- Any agent can be added as second drug based on patient condition. Although, the American Association of Clinical Endocrinologists recommends either incretin based therapy or sodium glucose transporter 2 (SGLT2) inhibition agents.
- 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 | 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.
References
- ↑ Horvath K; et al. (2007). "Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus". Cochrane database of systematic reviews (Online): CD005613. PMID 17443605.
- ↑ 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.
- ↑
- ↑ 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.
- ↑ 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.