Diabetes Research

Open journal

ISSN 2379-6375

Current Perspectives for Oral Hypoglycemic Agents with Clinical Evidence of Larger Studies

Hiroshi Bando*

Hiroshi Bando, MD, PhD, FACP

Tokushima University, Medical Research, Nakashowa 1-61, Tokushima 770-0943, Japan; Tel. +81-90-3187-2485; ORCID: 0000-0002-6304-0224; E-mail: pianomed@bronze.ocn.ne.jp


Standard guideline for diabetes mellitus in 2021 was presented by American Diabetes Association (ADA).1 Recent topics for oral hypoglycemic agents (OHAs) will be introduced here with clinical evidence of larger studies. The episodes of hypoglycemia are risk factors for cardiovascular prognosis. A cohort study examining the prognosis of 74,610 patients for type 2 diabetes mellitus (T2DM) was reported.2 After follow-up of 7.1-years in median, the absolute 5-year risk of death was 6.6% for cardiovascular death, 1.1% for cancer deaths, and 13.1% for other deaths in hospitalized group (n=388) for severe hypoglycemia, respectively. In contrast, the group who was not hospitalized for severe hypoglycemia had cardiovascular deaths 4.7%, cancer deaths 1.4%, and other deaths 11.1%, which were lower than those who experienced hypoglycemia, respectively.

Dipeptidyl peptidase-4 inhibitors (DPP-4i) has been recently prevalent. A systematic review was reported on the efficacy of DPP-4i for cardiovascular disease, and 18 randomized controlled trials (RCTs) and meta-analyses were analyzed.3 As a result, no additional benefit to cardiovascular risk could be expected when DPP-4i was added to standard treatment. Some studies are found concerning DPP-4i and bullous pemphigoid (BP). For 138 RCTs, including 61514 DPP-4 inhibitor users and 59661 subjects were analyzed.4 Among them, only 6 studies reported BP. As a result of meta-analysis, an odds ratio (OR) of 4.44 was found to be significantly associated with this risk. Meta-analysis study was conducted for evaluating the risk of BP and skin-related adverse events (AEs). Totally, 46 randomized placebo-controlled trials (n=59332) were included.5 Among them, 3 studies revealed BP (n=38011), which included AEs. Comparison with control group, DPP4i group showed significantly higher-risk (OR 7.38). Moreover, DPP-4i therapy revealed increased overall risk of AEs (OR 1.22 p=0.03). To evaluate the relationship for BP, 5 studies for different kinds of DPP-4i were analyzed.6 From adjusted meta-analysis, significant association between them were observed as OR 2.13. The OR was 5.08 in vildagliptin, 2.87 in linagliptin, while OR 1.29 (not significant p=0.31) in sitagliptin. By subgroup analysis, the OR in male was 2.35 and 1.88 in female. Consequently, the adjusted analysis can support a significant association of DPP-4i use and BP.

Comparative study was performed between sodium/glucose cotransporter-2 inhibitors (SGLT2i) and DPP-4i. A retrospective cohort study for cardiovascular risk was reported using large databases in Canada and UK.7 Subjects included matched 209,867 cases each for users of SGLT2i and DPP-4i. The primary outcome was major adverse cardiovascular events (MACE) and secondary outcomes were individual MACE, heart failure, and mortality of all causes. SGLT2i group for 0.9-years showed lower hazard ratio (HR) as MACE 0.76, myocardial infarction 0.82, cardiovascular death 0.60, heart failure 0.43, all-cause mortality 0.60, ischemic stroke 0.85. Similar beneficial effect for MACE were found with canagliflozin (0.79), dapagliflozin (0.73), and empagliflozin (0.77). Thus, the short-term use of SGLT2i can reduce the cardiovascular risks, compared with DPP-4i.

Semaglutide has been a topic for oral agent of GLP-1a. Systematic review for the effect of semaglutide was conducted in 11 RCTs with 9890 cases.8 The results showed that hemoglobin A1C (HbA1c) decreased 0.89% and body weight decreased 2.99 kg, respectively. Semaglutide showed superiority of decreased HbA1c/weight as -0.35%/-1.48 kg, compared with sitagliptin, empagliflozin and liraglutide. Furthermore, semaglutide decreased allcause mortality (OR 0.58) and cardiovascular mortality (OR 0.55), and showed the neutral efficacy for stroke, myocardial infarction, diabetic retinopathy and hypoglycemia. Seven cardiovascular outcome trials (CVOTs) were conducted including 56004 patients using network meta-analysis (NMA).9 Semaglutide showed reduced OR of cardiovascular death statistically than exenatide 0.47, dulaglutide 0.46, albiglutide 0.45, lixisenatide 0.43. In contrast, significant differences were not detected for reducing death from any case, stroke and MI events. Consequently, GLP-1RAs revealed significant benefits for cardiovascular safety.

Regarding SGLT2i, several recent reports are found. The cardiovascular efficacy of ertugliflozin was evaluated for the study of VERTIS CV. T2DM cases (n=8246) received ertugliflozin or placebo, and a major adverse cardiovascular event (MACE) was analyzed for 3.5-years.10 OR were 0.97 for MACE, 0.88 for death or hospitalization for heart failure (HHF). Hazard ratio (HR) for death from cardiovascular causes was 0.92, and death from renal causes was 0.81. Thus, ertugliflozin was proved to be non-inferior to placebo for MACE. In order to assess the renal and cardiovascular outcomes of T2DM for SGLT2i agents, analysis of systematic literature search was conducted.11 The data were from 46969 T2DM cases including 31116 cases of cardiovascular disease. The results showed reduction risk of MACE (HR 0.90), HHF/cardiovascular death (HR 0.78), renal outcomes (HR 0.62). Consequently, SGLT2i showed reduced risk of MACE, HHF and renal outcomes, associated with beneficial effects of HHF risk that is consistent findings across the trials.

Chronic kidney disease (CKD) patients have elevated risk of adverse cardiovascular and renal outcomes. Clinical efficacy of dapagliflozin was studied for CKD patients as dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPACKD) trial.12 Randomly assigned 4304 cases with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 and urinary Alb/Cre ratio (200-5000) were investigated and provided dapagliflozin or placebo. The primary outcome included a sustained eGFR decline, end-stage kidney disease (ESKD) or death from kidney or cardiovascular causes. HRs were primary outcome event 0.61, sustained eGFR decline 0.56 and death for various cause 0.69. The results were similar for patients with/without T2DM. Consequently, safer profile of dapagliflozin was confirmed. The study was apparently effective and then discontinued early, for 2.4-years in median.

SGLT2i may reduce the risk of HHF. For 3730 patients with heart failure with class II, III, IV and <40% of ejection fraction, double-blind trial was conducted by providing empagliflozin 10 mg a day or control as EMPEROR-Reduced Trial.13 Primary outcome was HHF or cardiovascular death. During 16-months, primary outcome event was observed in 19.4% in empagliflozin group, and 24.7% in control group (HR 0.75). The total number of HHF was lower in empagliflozin group (HR 0.70). Annual decline of eGFR was slower in empagliflozin group (-0.55 vs. -2.28 ml/ min/1.73 m2 /year, p<0.001). Consequently, patients in the empagliflozin group showed lower risk of cardiovascular death or HHF, irrespective of the presence or absence of diabetes.><0.001). Consequently, patients in the empagliflozin group showed lower risk of cardiovascular death or HHF, irrespective of the presence or absence of diabetes.

Concerning the relationship between SGLT2i and lower extremity amputation outcomes, 12 RCTs and 18 observational studies were investigated.14 Meta-analysis of 7 RCTs has brought absence of significant association as RR 1.28. From sub-group analysis, canagliflozin showed significantly increased risk in metaanalysis (RR 1.59) (2 RCTs), while dapagliflozin or empagliflozin did not show a significantly increased risk (2 RCTs each). Generally, no consistent evidence of increased risk was not found. Another study of adverse limb event was performed from 6 reports.15 They include canagliflozin (CANVAS, CREDENCE), empagliflozin (EMPA-REG OUTCOME), ertugliflozin (VERTIS CV) and dapagliflozin (DECLARE-TIMI 58, DAPA-HF trials). Out of 51713 cases, 858 had amputation operations. The amputation ratio was 2.0/1.3% in SGLT-2i/control group, as pooled risk ratio of 1.24. From this analysis, SGLT-2i is not statistically associated with increased risks of amputation operations.


In summary, recent meaningful reports were introduced. The information will be hopefully useful for future research and practice for diabetes mellitus.

1. American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of medical care in diabetesd 2021. Diabetes Care. 2021; 44(Suppl.1): S111-S124. doi: 10.2337/dc21-S009

2. Zaccardi F, Ling S, Lawson C, Davies MJ, Khunti K. Severe hypoglycaemia and absolute risk of cause-specific mortality in individuals with type 2 diabetes: A UK primary care observational study. Diabetologia. 2020; 63(10): 2129-2139. doi: 10.1007/s00125- 020-05223-3

3. Taylor OM, Lam C. The Effect of dipeptidyl peptidase-4 inhibitors on macrovascular and microvascular complications of diabetes mellitus: A systematic review. Curr Ther Res Clin Exp. 2020; 93: 100596. doi: 10.1016/j.curtheres.2020.100596

4. Silverii GA, Dicembrini I, Nreu B, Montereggi C, Mannucci E, Monami M. Bullous pemphigoid and dipeptidyl peptidase-4 inhibitors: A meta-analysis of randomized controlled trials. Endocrine. 2020; 69(3): 504-507. doi: 10.1007/s12020-020-02272-x

5. Yang W, Cai X, Zhang S, Han X, Ji L. Dipeptidyl peptidase-4 inhibitor treatment and the risk of bullous pemphigoid and skinrelated adverse events: A systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2021; 37(3): e3391. doi: 10.1002/dmrr.3391

6. Phan K, Charlton O, Smith SD. Dipeptidyl peptidase-4 inhibitors and bullous pemphigoid: A systematic review and adjusted meta-analysis. Australas J Dermatol. 2020; 61(1): e15-e21. doi: 10.1111/ajd.13100

7. Filion KB, Lix LM, Yu OH, Dell’Aniello S, Douros A, Shah BR, et al. Canadian Network for Observational Drug Effect Studies (CNODES) Investigators. Sodium glucose cotransporter 2 inhibitors and risk of major adverse cardiovascular events: Multidatabase retrospective cohort study. BMJ. 2020; 370: m3342. doi: 10.1136/bmj.m3342

8. Avgerinos I, Michailidis T, Liakos A, Karagiannis T, Matthews DR, Tsapas A, et al. Oral semaglutide for type 2 diabetes: A systematic review and meta-analysis. Diabetes Obes Metab. 2020; 22(3): 335-345. doi: 10.1111/dom.13899

9. Alfayez OM, Almohammed OA, Alkhezi OS, Almutairi AR, Al Yami MS. Indirect comparison of glucagon like peptide-1 receptor agonists regarding cardiovascular safety and mortality in patients with type 2 diabetes mellitus: Network meta-analysis. Cardiovasc Diabetol. 2020; 19(1): 96. doi: 10.1186/s12933-020-01070-z

10. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, et al. VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020; 383(15): 1425-1435. doi: 10.1056/NEJMoa2004967

11. McGuireDK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: A meta-analysis. JAMA Cardiol. 2021; 6(2): 148-158. doi: 10.1001/jamacardio.2020.4511

12. Heerspink HJL, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. DAPA-CKD trial committees and investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med. 2020; 383(15): 1436-1446. doi: 10.1056/NEJMoa2024816

13. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. EMPEROR-reduced trial investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020; 383(15): 1413-1424. doi: 10.1056/NEJMoa2022190

14. Heyward J, Mansour O, Olson L, Singh S, Alexander GC. Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis. PLoS One. 2020; 15(6): e0234065. doi: 10.1371/journal.pone.0234065

15. Huang CY, Lee JK. Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: A trial-level meta-analysis including 51 713 individuals. Diabetes Obes Metab. 2020; 22(12): 2348- 2355. doi: 10.1111/dom.14159


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