dipeptidyl-peptidase IV inhibitors

Importance: Type 2 diabetes involves progressive loss of insulin secretion from pancreatic β cells in the setting of insulin resistance and manifests clinically as hyperglycemia. Type 2 diabetes accounts for 90% to 95% of all cases of diabetes globally, with estimates ranging from 589 million to 828 million people worldwide. In the US, type 2 diabetes affects approximately 1 in 6 adults.

Observations: Risk factors for type 2 diabetes include older age, family history, overweight or obesity, physical inactivity, gestational diabetes, Hispanic ethnicity, and American Indian or Alaska Native, Asian, or Black race. Diabetes is diagnosed if fasting plasma glucose is greater than or equal to 126 mg/dL, hemoglobin A1C is greater than or equal to 6.5%, or 2-hour glucose during 75-g oral glucose tolerance testing is greater than or equal to 200 mg/dL. Approximately one-third of adults with type 2 diabetes have cardiovascular disease and 10.1% have severe vision difficulty or blindness. The prevalence of type 2 diabetes is 39.2% among patients with kidney failure. Although weight management is an important component of treatment for type 2 diabetes, no specific diet has been proven to be most effective for improving health outcomes. Physical activity can reduce hemoglobin A1C by 0.4% to 1.0% and improve cardiovascular risk factors (ie, hypertension and dyslipidemia). Randomized clinical trials have reported absolute reductions in microvascular disease (3.5%), such as retinopathy and nephropathy, myocardial infarction (3.3%-6.2%), and mortality (2.7%-4.9%), with intensive glucose-lowering strategies (hemoglobin A1C <7%) vs conventional treatment 2 decades after trial completion. First-line medications for type 2 diabetes include metformin and, in patients with cardiovascular or kidney comorbidities or at high cardiovascular risk, glucagon-like peptide-1 receptor agonists (GLP-1RAs) or sodium-glucose cotransporter 2 inhibitors (SGLT2is). Common add-on medications include dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1RAs, dipeptidyl peptidase-4 inhibitors, sulfonylureas, and thiazolidinediones. Approximately one-third of patients with type 2 diabetes require treatment with insulin during their lifetime. Several randomized clinical trials have demonstrated benefits of specific SGLT2i and GLP-1RA medications compared with placebo for atherosclerotic cardiovascular disease (12%-26% risk reduction), heart failure (18%-25% risk reduction), and kidney disease (24%-39% risk reduction) over 2 to 5 years. Most trial participants with type 2 diabetes were taking metformin. High-potency GLP-1RA and dual GIP/GLP-1RA medications result in weight loss of greater than 5% in most individuals with type 2 diabetes, and weight loss may exceed 10%.

Conclusions: Type 2 diabetes affects up to 14% of the global population and is associated with preventable long-term complications, such as cardiovascular disease, kidney failure, vision loss, and increased mortality. In addition to lifestyle modifications including diet, exercise, and weight management, metformin is generally first-line therapy for attainment of hemoglobin A1C targets. For individuals with type 2 diabetes and cardiovascular or kidney disease or at high cardiovascular risk, guidelines recommend early treatment with SGLT2i and/or GLP-1RA medications.

Author/s:

Rita R Kalyani, Joshua J Neumiller, Nisa M Maruthur, Deborah J Wexler

Management of Outpatients With Diabetes at High Risk of Hypoglycemia

Erin Blanchette — Tue, 26 Mar 2024 16:29:29 +0000

Date Added:

March 26, 2024

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

March 14, 2024

URL:

Management of Outpatients With Diabetes at High Risk of Hypoglycemia

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2024.1137

Keywords

diabetes

Diabetes and Endocrinology

Endocrinology

insulin

PMID (1):

38483370

MeSH

diabetes mellitus

diabetes mellitus, type 2

dipeptidyl-peptidase IV inhibitors

diabetes mellitus, type 1

blood glucose

Hypoglycemia

Insulins

Guidance for management of diabetes in patients at risk of hypoglycemia. James W. Mold, MD, MPH

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More than 30 million people in the US have diabetes, approximately 5% with type 1 and approximately 95% with type 2. About 5 million individuals in the US with type 2 diabetes use insulin and 7 million take sulfonylureas; both of these medications have a greater association with hypoglycemia than metformin, glucagon-like peptide 1 receptor agonists, dipeptidyl peptidase 4 inhibitors, or sodium-glucose cotransporter 2 inhibitors. Each month, 70% of people with type 1 diabetes experience some degree of hypoglycemia.1 Level 1 hypoglycemia is defined as blood glucose of 54 to 70 mg/dL; level 2 is less than 54 mg/dL; and severe hypoglycemia (level 3) occurs when low blood glucose levels cause neurologic or physical symptoms that require help from others. Furthermore, recurrent severe hypoglycemia increases risk of future dementia.2 Hypoglycemia occurs more often in people with lower education, lower income, and food insecurity.3 This synopsis focuses on outpatient management of diabetes with high risk of hypoglycemia; the guideline also addresses prevention of hypoglycemia in hospitalized patients.4

Author/s:

Celeste C Thomas, Karishma Chopra, Andrew M Davis

Using Insulin to Treat Poorly Controlled Type 2 Diabetes in 2020

John Bayhi — Tue, 26 May 2020 20:43:16 +0000

Date Added:

May 26, 2020

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

May 22, 2020

Volume:

Online ahead of print

URL:

Using Insulin to Treat Poorly Controlled Type 2 Diabetes in 2020

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2020.1303

Keywords

PMID (1):

32442246

MeSH

Sodium-Glucose Transporter 2 Inhibitors

hypoglycemic agents

insulin

glycated hemoglobin a

dipeptidyl-peptidase IV inhibitors

Metformin

diabetes mellitus, type 2

Glucagon-Like Peptide-1 Receptor

Thiazolidinediones

A potentially useful decision algorithm for management of patients with Type 2 diabetes, which includes early consideration of use of basal insulin in patients with A1c > 9%. James W. Mold, MD, MPH

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No abstract available

Author/s:

Hirsch, IB, Gaudiani, LM

Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes

Jeffrey Wilson — Mon, 22 Oct 2018 15:42:39 +0000

Date Added:

November 1, 2018

Journal/Publication:

JAMA

Publisher:

American Medical Association

Publication Date:

April 17, 2018

Issue:

Volume:

319

Pages:

1580-1591

URL:

Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes

Type:

Meta-analyses, Reviews, and Guidelines

Format:

Article

DOI (1):

10.1001/jama.2018.3024

Keywords

SGLT-2 inhibitors

GLP-1 agonists

hypertension

PMID (1):

29677303

MeSH

dipeptidyl-peptidase IV inhibitors

diabetes mellitus, type 2

glucagon-like peptide 1

sodium-glucose transport proteins

While both SGLT-2 inhibitors and GLP-1 agonists reduced both cardiovascular and all-cause mortality compared to controls, their impact was very small (1% or less in both/all cases), probably not enough to be a reason to choose these medications over others, particularly if you are recommending more effective risk reduction strategies like smoking cessation, physical activity, BP reduction, and statins.

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IMPORTANCE:

The comparative clinical efficacy of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors for treatment of type 2 diabetes is unknown.

OBJECTIVE:

To compare the efficacies of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors on mortality and cardiovascular end points using network meta-analysis.

DATA SOURCES:

MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, and published meta-analyses from inception through October 11, 2017.

STUDY SELECTION:

Randomized clinical trials enrolling participants with type 2 diabetes and a follow-up of at least 12 weeks were included, for which SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors were compared with either each other or placebo or no treatment.

DATA EXTRACTION AND SYNTHESIS:

Data were screened by 1 investigator and extracted in duplicate by 2 investigators. A Bayesian hierarchical network meta-analysis was performed.

MAIN OUTCOMES AND MEASURES:

The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke; safety end points: adverse events and hypoglycemia.

RESULTS:

This network meta-analysis of 236 trials randomizing 176 310 participants found SGLT-2 inhibitors (absolute risk difference [RD], -1.0%; hazard ratio [HR], 0.80 [95% credible interval {CrI}, 0.71 to 0.89]) and GLP-1 agonists (absolute RD, -0.6%; HR, 0.88 [95% CrI, 0.81 to 0.94]) were associated with significantly lower all-cause mortality than the control groups. SGLT-2 inhibitors (absolute RD, -0.9%; HR, 0.78 [95% CrI, 0.68 to 0.90]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.86 [95% CrI, 0.77 to 0.96]) were associated with lower mortality than were DPP-4 inhibitors. DPP-4 inhibitors were not significantly associated with lower all-cause mortality (absolute RD, 0.1%; HR, 1.02 [95% CrI, 0.94 to 1.11]) than were the control groups. SGLT-2 inhibitors (absolute RD, -0.8%; HR, 0.79 [95% CrI, 0.69 to 0.91]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.85 [95% CrI, 0.77 to 0.94]) were significantly associated with lower CV mortality than were the control groups. SGLT-2 inhibitors were significantly associated with lower rates of HF events (absolute RD, -1.1%; HR, 0.62 [95% CrI, 0.54 to 0.72]) and MI (absolute RD, -0.6%; HR, 0.86 [95% CrI, 0.77 to 0.97]) than were the control groups. GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal than were SGLT-2 inhibitors (absolute RD, 5.8%; HR, 1.80 [95% CrI, 1.44 to 2.25]) and DPP-4 inhibitors (absolute RD, 3.1%; HR, 1.93 [95% CrI, 1.59 to 2.35]).

CONCLUSIONS AND RELEVANCE:

In this network meta-analysis, the use of SGLT-2 inhibitors or GLP-1 agonists was associated with lower mortality than DPP-4 inhibitors or placebo or no treatment. Use of DPP-4 inhibitors was not associated with lower mortality than placebo or no treatment.

Author/s:

Zheng, Sean L., Roddick, Alistair J., Aghar-Jaffar, Rochan, Shun-Shin, Matthew J., Francis, Darrel, Oliver, Nick, Meeran, Karim