Hypoglycemia is the most common side effect and is more common with long-acting sulfonylureas. Patients recently discharged from hospital are at the highest risk for hypoglycemia. Patients should be cautioned about those settings in which hypoglycemia is most likely to occur. They are:. Other, infrequent side effects that can occur with all sulfonylureas include nausea, skin reactions, and abnormal liver function tests. Weight gain can also occur unless the diabetic diet and exercise program are followed.
Safety of oral antidiabetic agents in pregnancy
Chlorpropamide has two unique effects: it can cause an unpleasant flushing reaction after alcohol ingestion and it can cause hyponatremia low blood sodium , primarily by increasing the action of antidiuretic hormone. Clinical use — Sulfonylureas usually lower blood glucose concentrations by about 20 percent.
- Diabetes Mellitus.
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They are most likely to be effective in patients whose weight is normal or slightly increased. In contrast, insulin should be used in patients who are underweight, are losing weight, or are ketotic despite adequate caloric intake. The choice of sulfonylurea is primarily dependent upon cost and availability, because their efficacy is similar. However, given the relatively high incidence of hypoglycemia in patients taking glyburide or chlorpropamide, shorter acting drugs should probably be used in elderly patients.
Repaglinide — Repaglinide is a short-acting glucose-lowering drug recently approved by the Food and Drug Administration for therapy of type 2 diabetes alone or in combination with metformin. It is structurally different than sulfonylureas, but acts similarly by increasing insulin secretion. The clinical efficacy of repaglinide is similar to that of the sulfonylureas. The recommended starting dose is 0. The maximum dose is 4 mg before each meal; the dose should be skipped if the meal is missed. Hypoglycemia is the most common adverse effect. Natiglinide — Natiglinide Starlix is a very short-acting glucose lowering drug whose mode of action is similar to the sulfonylureas and is nearing approval by the FDA.
The first phase of insulin release is brisk, of short duration and occurs within minutes of ingesting food. The usual dose is mg before meals. It is effective only in the presence of insulin but, in contrast to sulfonylureas, it does not directly stimulate insulin secretion. Its major effect is to increase insulin action. How metformin increases insulin action is not known but it is known to affect many tissues.
One important effect appears to be suppression of glucose output from the liver. Clinical use — Metformin is most often used in patients with type 2 diabetes who are obese, because it promotes modest weight reduction or at least weight stabilization. This is in contrast to the increased appetite and weight gain often induced by insulin and sulfonylureas. Metformin typically lowers fasting blood glucose concentrations by approximately 20 percent, a response similar to that achieved with a sulfonylurea.
Omarigliptin:First global approval. Mol Endocrinol ; BMJ ;e Ann Pharmacother ; Scheen AJ.
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Cardiovascular effects of gliptins. Nat Rev Cardiol ; Diabetes Care ; Diabetes Metab Res Rev ; Diabetologia ; SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol ; Active sugar transport in health and disease.
Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci ; Biology of human sodium glucose transporters. Physiol Rev ; In addition, the Guidance for Industry update requires that excess cardiovascular risk associated with new antidiabetic drugs be ruled out [ 5 ].
We thus performed a sub-analysis according to year of study. Metformin, the first-line medication for treating type 2 diabetes, provided cardiovascular protection in previous studies [ 10 , 11 ]. However, there was no difference in all-cause or cardiovascular mortality and MI risk between metformin and placebo or other OADs in our study. In most recent RCTs focused on the efficacy and safety of individual newly developed drugs, metformin was usually included in the baseline medications.
Therefore, few metformin trials were included in our analysis. Events occurred in one of patients and two of patients, respectively [ 26 , 27 ]. Hence, the association between metformin use and higher ACS risk compared with SGLT2 inhibitors in our network meta-analysis should be interpreted with caution. There was no difference between metformin and sulfonylurea in all-cause or cardiovascular mortality, different to results reported in a recent systematic review. In our study, the direct comparison between metformin and sulfonylurea was based on the same two RCTs.
However, the results were not significant in either the pairwise or the network meta-analysis.
In the RECORD trial the basis of the withdrawal of the previous restriction of rosiglitazone , overall cardiovascular morbidity and mortality in the rosiglitazone group were not different from those in the metformin and sulfonylurea groups [ 31 ]. Several studies of pioglitazone reported that it did not increase the risk of cardiovascular complications [ 32 — 35 ].
The potential discrepancy in cardiovascular risk between rosiglitazone and pioglitazone might stem from their distinct effects on the lipid profile. In a meta-analysis, pioglitazone decreased triglycerides and increased high-density lipoprotein cholesterol [ 36 ]. Therefore, we performed a sub-analysis excluding rosiglitazone data, but could not demonstrate a difference.
DPP4 inhibitors decrease serum glucose levels with fewer hypoglycemia events and less weight gain [ 37 ], which may be cardio-protective. However, the comparison between DPP4 inhibitors and placebo in the present study did not show any difference in all-cause and cardiovascular mortality, consistent with previous RCTs and meta-analyses. Three prior large RCTs suggested that DPP4 inhibitors do not improve cardiovascular endpoints compared with placebo, except for the risk of hospitalization for heart failure [ 38 — 40 ]. However, DPP4 inhibitors were associated with a reduction in ACS compared with sulfonylureas in our pairwise meta-analysis.
This result is plausible considering the aforementioned differing mechanisms of action and side effects of the two drugs. Our study has certain limitations. First, we aimed to compare the difference between the classes of OADs, not individual drugs. However, individual drugs within the same class could differ. Onset time and affected organs could differ among sulfonylureas [ 41 , 42 ]. In a recent network meta-analysis, gliclazide and glimepiride were associated with a lower risk of all-cause and cardiovascular mortality, compared with glibenclamide [ 43 ].
Second, we did not distinguish between doses of individual drugs owing to high levels of inconsistency when the analysis was stratified by dosage. With additional studies a more robust conclusion could be reached.
Third, we did not consider rescue or background medications owing to their diverse use. Additionally, we could not consider the influence of other drugs like antihypertensive drugs or statins because most RCTs have not provided information on these drugs. Thus, the effect of add-on medication, or of drug-to-drug interactions, was not evaluated.
Oral antidiabetic drugs
Fourth, we did not consider causality between OADs and individual death events because many trials did not report that. Our analyses utilized a systematic and comprehensive approach. The data quality in almost all included RCTs including unpublished reports was relatively high. Robustness was confirmed via sensitivity and subgroup analyses.
Furthermore, we compared the effect of each OAD class with placebo and with other OAD classes through conventional and network meta-analyses. The currently available data provide evidence of a cardiovascular benefit with SGLT2 inhibitor use in patients with type 2 diabetes.
However, additional results from ongoing studies are pivotal. This research was supported by grant no. Funding acquisition: SWO. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field. Abstract In the Guidance for Industry from the Food and Drug Administration in , excess cardiovascular risk should be ruled out in trials of all new antidiabetic drugs; however, relatively few studies have focused on cardiovascular safety with antidiabetic drug use.
Introduction Diabetes, given the burden of associated morbidity and mortality [ 1 ], particularly related to cardiovascular disease CVD , is one of the most challenging diseases globally. Data extraction and risk of bias assessment One author used a standardized form to extract data from each included study; a second verified data accuracy and completeness. Role of the funding source The funder played no role in the study design; data collection, analysis, or interpretation; or writing of the report.
Download: PPT. All-cause mortality The analysis of all-cause mortality risk included data from 73 RCTs reporting 3, 3.
Fig 2. Network of oral antidiabetic drugs comparison of all-cause mortality for the network meta-analysis. Fig 3. Network and pairwise meta-analyses for all-cause mortality of oral antidiabetic drugs.