- Three types of hypoglycemic agents (DPP- 4Is, GLP-1RAs, SGLT-2Is) for patients with type 2 diabetes: effectiveness and safety evaluation network meta-analysis
In view of the development of hypoglycemic agents in recent years and the growth in the number of people with type 2 diabetes mellitus(T2DM), latest information is needed for clinicians and patients to make more reliable decisions. The objective of this systematic review database is to compare and summarize the effects of the current three new types of hypoglycemic agents: dipeptidyl peptidase-4 inhibitors (DPP-4Is), glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-dependent glucose transporter 2 inhibition SGLT-2Is on outcomes of effectiveness, safety and economy.
We searched the PubMed, Embase and Cochrane Library databases for original English-language articles, and collected unpublished studies’ data from clinicaltrial.org and other sources,we also manually search reference list of review literatures and grey literatures. We included all randomized controlled trials (RCTs) that any one of the three new types of hypoglycemic drugs (DPP-4Is, GLP-1RAs or SGLT-2Is) was applied in at least one comparative group in the RCT, alone or combined with other drugs. The searching process is now updated to March 2019, and will be updated every 1-2 years.
The numbers of RCTs we found completed and have reported outcomes were as follow: DPP-4Is 414, GLP-1RAs 338, SGLT-2Is 307. The total number of these literatures were 1059. After removing the duplicate literatures between the three types of hypoglycemic drugs, the total number of studies included in this systematic review database is now 930.
The most common control group is placebo in this literature warehouse now. Other hypoglycemic drugs are also be compared as control, including: Biguanide, Sulfonylureas, Thiazolidinedione, Alpha-glucosidase inhibitor, insulin preparations, etc. Meanwhile, there are also comparisons between or within the three new types of hypoglycemic drugs.
Till today, the existing results of original researches on the effectiveness and safety of three type of hypoglycemic drugs are diverse, and related systematic reviews are still incomplete. For example, study had shown that SGLT-2Is improve cardiovascular function in T2DM patients with coronary artery disease or chronic kidney dysfunction compared to DPP-4Is; DPP-4Is(sitagliptin)may exert a less potent effect on HbA1C, FPG, PPG, and weight reduction than GLP-1 receptor agonists in obese or overweight patients; There are also differences between different drugs in one single type. Observing the effects of hypoglycemic drugs requires studies with large samples and long term observation. Therefore, better evidences are needed to provide a compelling reason for their use in different situations and different population subgroups.
A network evidence set of the three types of new hypoglycemic drugs can be constructed based on all the RCTs in this constantly updated database. With the help of real-world research partners, in-depth discussion on the differences of the three types of new hypoglycemic drugs in a single outcome (effectiveness, safety and economy) and multiple comprehensive outcomes can be conducted by network meta-analysis and IPD meta-analysis. After evaluating the quality of these above evidences, further summaries and recommendations can be made combining with the benefit-risk relationship based on different decision-making scenarios and expert opinions.
We hope that more comprehensive and multi-dimensional evidences of the comparison of the three types of new hypoglycemic drugs will be obtained through this evidence-based evaluation research. These evidences will provide more reliable basis for clinicians when making decisions, provide reference for guideline makers and regulatory decision-making departments. It will enhance the accuracy and confidence when we make decisions, and actually bring the greatest health benefits to patients with T2DM, which also provide a reference for the evaluation of other drugs.
- Authors of Report
- Methodology description
- During literature search, all the names of the three types of new hypoglycemic drugs, as well as all the listed drugs and searchable products in these three categories were covered. These interventions are showed as follow.
DPP-4Is：Sitagliptin, Vildagliptin, Linagliptin, Saxagliptin, Alogliptin, Gemigliptin, Anagliptin, Teneligliptin, Trelagliptin, Retagliptin, Melogliptin, Evogliptin, Carmegliptin, Omarigliptin, Dutogliptin, Diabeglipt, Elant, Glucal, Teneglucon Veriglip, Glipten, PF-734200, Suganon, LC-150444, DA-1229, Januvia, Janumet, Juvisync, Galvus, Eucreas, GalvusMet, Onglyza, KombiglyzeXR, Qtern, Nesina, Oseni, Kazano, Vipidia, Vipdoment, Trajenta, Gemiglo, Beskoa, Tenelia；
GLP-1RAs：Liraglutide, Exenatide, Albiglutide, Taspoglutide, Lixisenatide, Dulaglutide, Semaglutide, Byetta, Bydureon, Victoza, Lyxumia, Adlyxin, Tanzeum, Eperzan, Trulicity, AVE-0010, Ozempic；
SGLT-2Is：Dapagliflozin, Canagliflozin, Empagliflozin, Luseogliflozin, Ipragliflozin, Ertugliflozin, Sotagliflozin, Tofogliflozin, Rongliflozin, Janagliflozin, Bexagliflozin, Remogliflozin, Forxiga, Invokana, Jardiance, Glyxambi, JNJ-28431754, TA-7284, BI-10773, SAR-439954, LX-4211, EGT-0001442, ASP-1941。
We searched the following databases for primary studies for the periods in parentheses: MEDLINE(1966 to March 2019), Embase(1974 to March 2019), and Cochrane Library(1995 to March 2019). We developed a search strategy based on the purposes of this research and the analysis of MeSH terms. The articles which were selected out from above mentioned databases were exported and gathered into an EndNote library(EndNote version X9). We used the duplication check feature in EndNote to scan for duplicate articles, and deleted duplicates more precisely by two reviewers during screening. Then two reviewers screened these articles by their titles and abstracts independently, classified those which meet the criterion, and excluded those which do not.
Then detailed data, including study design, treatments for the comparison groups, baseline characteristics, outcome indicators and adverse events, was extracted from each study by using standardized protocols and pooled into ADDIS(Aggregate Data Drug Information System). The overall outcomes covered in our database can be classified into three clusters: effectiveness outcomes, safety outcomes, and economy outcomes. The specific outcomes are showed as follow.
1. Effectiveness outcomes: Blood glucose related indicators (glycated hemoglobin, fasting serum glucose, 2 hours postprandial serum glucose, fasting C peptide, HOMA-β, HOMA-IR, etc.); Blood lipid related indicators (low density lipoprotein cholesterol, high-density lipoprotein cholesterol, total cholesterol, triglyceride, etc.); Other indicators (estimated glomerular filtration rate, body weight, body mass index, waist circumference, waist-to-hip ratio, systolic blood pressure, diastolic blood pressure, heart rate, etc.). 2. Safety outcomes: All cause motality; Adverse gastrointestinal events (nausea, vomiting, diarrhea, constipation, indigestion, gastroenteritis, decrease of appetite, appendicitis, cholelithiasis, etc.); Respiratory diseases (respiratory failure, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, bronchitis, pneumonia, etc.); Endocrine decompensation (hyperglycemia, hypoglycemia, hyperthyroidism, etc.); Cardiovascular diseases (major adverse cardiovascular events, stroke, angina, arrhythmia, myocardial Infarction, aortic aneurysm, coronary atherosclerosis, atrioventricular block, cardiac arrest, hypertension, etc.); Liver and renal dysfunction (cirrhosis, kidney stones, acute renal failure, hepatic encephalopathy, liver steatosis, liver failure, etc.); Infectious diseases (septicemia, abdominal abscess, urinary tract infection, cellulitis, flu, etc.); Nervous system dysfunction (dizziness, headache, neurasthenia, migraine, etc.); Tumors (digestive system tumors, bladder benign tumor, thyroid cancer, brain tumor, breast cancer, etc.); Mental disorders (anxiety, depression, cognitive impairment, paresthesia, etc.); Musculoskeletal diseases (arthritis, arthralgia, back pain, fractures, muscle weakness, etc.); Diabetic complications (diabetic foot, diabetic ketoacidosis, diabetic retinopathy, diabetic nephropathy, etc.) and other adverse events.
3. Economy outcomes: drug cost, quality-adjusted life years (QALYs), drug incremental cost effectiveness ratio (ICER), life expectancy, etc.
Population baseline characteristics were also collected, include: gender, age, ethnicity, duration of type 2 diabetes, whether they have cardiovascular and cerebrovascular diseases, whether they have a family history of type 2 diabetes, and other related baseline indicators (glycated hemoglobin, fasting serum glucose, 2 hours postprandial serum glucose, body weight, body mass index, waist circumference, waist-to-hip ratio, etc.).
Network meta-analysis can be performed base on this database. All of comprehensive information was included in this database, which is essential for further statistical analysis. Studies that focus on a single outcome have certain limitations. So in the future, we will use this database to explore the benefit-risk of these drugs with multiple outcomes. The models we are interested in are multi-criteria decision analysis (MCDA) model and its derivative model stochastic multicriteria acceptability analysis (SMAA). When we conduct benefit/risk analysis, we will make good use of indirect comparative studies through network meta-analysis.
- The data was entered retrospectively by uploading Excel worksheets. Uploaded data includes study characteristics, risk of bias assessments, outcome and adverse events data.
DPP- 4Is= dipeptidyl peptidase-4 inhibitors
GLP-1RAs= glucagon-like peptide-1 receptor agonists
SGLT-2Is= sodium-dependent glucose transporters 2 inhibitors
T2DM= type 2 diabetes mellitus
BMI = body mass index;
BP = blood pressure;
CVD = cardiovascular diseases;
DBP = diastolic blood pressure;
DM = diabetes mellitus;
FPG = fasting plasma glucose;
PPG= postprandial plasma glucose;
g/day = grams per day;
g/dl = grams per deciliter;
GFR = glomerular filtration rate;
HbA1c = hemoglobin A1c;
HOMA-β= Homeostasis model assessment- β
HOMA-IR= Homeostasis model assessment- insulin resistance
kg = kilogram;
kg/m2 = kilograms per meter squared;
LDL = low density lipoprotein;
met = metformin;
mg = milligram;
mg/d = milligrams per day;
mg/dL = milligrams per deciliter;
mm Hg = millimeters of mercury;
mmol/l = millimoles per liter;
SBP = systolic blood pressure;
RCT = randomized controlled trial;
TG = triglycerides;
TC= total cholesterol
- Funding Source
- The National Natural Science Foundation of China(no.71673003); National Natural Science Foundation of China(no.81302508); National Natural Science Foundation of China(no.72074011)