Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis
BMJ 2012; 344 doi: https://doi.org/10.1136/bmj.e1369 (Published 12 March 2012) Cite this as: BMJ 2012;344:e1369All rapid responses
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We were interested to read the meta-analysis of DPP-4 inhibitors for treatment of Type 2 diabetes.[1] It is encouraging to note that in return for increased pharmaceutical costs, DPP-4 inhibitors did not increase mortality or serious adverse events (versus placebo or active comparators) during short term studies, did not cause weight gain, and did lower HbA1C.
However, the clinical purpose of drug treatment for Type 2 diabetes is to prevent or delay serious adverse events and delay death. While this outcome has been demonstrated for metformin [2], it has not been demonstrated for DPP-4 inhibitors and many other widely utilized treatments. Some recent treatment strategies, including the guideline emphasis on lower capillary blood glucose and HbA1C targets, have led to increased harms, including mortality. [3]
Cost-effectiveness of DDP-4 inhibitors cannot be assessed until we know whether they are effective for the real goals of treatment. Pioglitazone, for example, significantly reduces HBA1c while achieving no positive impact on cardiovascular outcomes, but increasing the risk of heart failure. [4] Rosiglitazone also reduces HbA1c but increases heart failure and the risk of MI. [5,6] We are puzzled by the continued emphasis on lowering glycemic surrogate outcomes, despite the plethora of evidence that such surrogates do not reliably predict concomitant improvement in clinical outcomes. In fact, many interventions that reduce glycemic surrogate outcomes increase the risk of harms to people.
If a patient’s goal is simply to lower HbA1C, then a DPP-4 inhibitor appears comparable to other available drugs. If one’s goals include fewer adverse outcomes, reduced mortality, and a reduction in complications from diabetes, we see no advantage of these agents over less expensive pharmacologic options. Demonstration of clinical benefits from long term studies would change that conclusion.
In contrast, if the resources allocated to developing and promoting the use of such drugs were reoriented to prevention of Type 2 diabetes and its appropriate management by diet and exercise, there is good evidence to expect real and durable health benefits.
References
1. Karagiannis T et al. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369 doi: 10.1136/
bmj.e1369.
2. UK Prospective Diabetes Study group.Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective
Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65.
3. The Action to Control Cardiovascular Risk in Diabetes Study Group Effects of Intensive Glucose Lowering in Type 2 Diabetes. New Engl J Med 2008; 358:2545-2559.
4. Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2006, Issue 4. Art. No.: CD006060.
DOI: 10.1002/14651858.CD006060.pub2.
5. Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Rosiglitazone for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD006063.
DOI: 10.1002/14651858.CD006063.pub2.
6. Nissen SE et al. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. New Engl J Med 2007; 356:2457-2471.
Competing interests: No competing interests
We read with great interest the systematic review and meta-analysis recently published in BMJ by Karagiannis and collaborators. Although the study has methodological strengths worth citing, we disagree with some points related to the authors’ conclusions.
Considering the evaluation of the pre-specified primary endpoint (difference in HbA1c, figure 2), the results show that the DPP-4 inhibitors performance is far below that presented by the antidiabetics used as active comparators (metformin, sulfonylureas, pioglitazone and GLP-1 agonists). Even when the secondary endpoint was evaluated (risk ratio for achieving HbA1c < 7%, figure 3), the DPP-4 inhibitors showed at best similar efficacy to sulfonylureas, but remained less effective than metformin, pioglitazone and GLP-1 agonists. Therefore, we considered it inappropriate to say that the glycaemic efficacy of DPP-4 inhibitors is similar to that of sulfonylureas or pioglitazone.
We think that “What this study adds” is, literally: “As monotherapy or combined therapy, metformin, sulfonylureas, pioglitazone and GLP-1 agonists are superior to DPP-4 inhibitors in reducing HbA1c. Body weight benefits can be expected with DPP-4 inhibitors when these drugs are compared with sulfonylureas and pioglitazone, but not with metformin and GLP-1 agonists. Less hypoglycemia episodes can be expected with DPP-4 inhibitors when these drugs are compared with sulfonylureas, but not with metformin, pioglitazone and GLP-1 agonists.”
The main concern regarding this type of interpretation bias is that authors stress in the abstract and abstract box the findings of secondary endpoints and consider the DPP-4 inhibitors similar to sulfonylureas regarding glycaemic control. This misinterpretation could lead to overprescribing this class of drugs, which are more expensive and have limited data concerning long term safety.
Competing interests: No competing interests
The use of DPP-4 inhibitors is certainly on the rise, thanks to aggressive marketing of its benefits ie once daily dosing, weight neutrality and no risk of hypoglycaemia. This meta-analysis reassures DPP-4 users about its benefits and short and medium term safety. This group of drugs are effective alternatives for patients with type 2 diabetes for whom weight gain is a demotivating factor or who are troubled by hypogycaemic episodes. Also, this helps to postpone the use of insulin in patients who are intolerant to metformin or in whom metformin is contraindicated as most of the DPP-4s are licenced for use in low eGFR. Cost to the health care system is an issue, but it is too complex to calculate meaningfully in management of chronic diseases.
Competing interests: No competing interests
I would like to appreciate the sincere effort and work done by the authors through this systemic reviews and metanalysis. What is very interesting and different to find here and assuring for us in this particular review is that gliptins were not associated with any significant increase in nasopharyngitis, urinary tract infections and headache found with sitagliptin and vildagliptin in earlier three metanalysis done by Amori RE etal (2007), Richter B etal(2008) and Monami M et al(2010)respectively. This might add confidence for those physician who frequently use gliptins in their type 2 diabetic patient either as a second line or third line drug after metformin or metformin and SU combination failure. Glycemic control with gliptins may look slightly inferior to metformin and SUs but weight neutrality and almost nil hypoglycemia makes this group of drugs non-inferior to SUs in balance. Considering current practice algorithm gliptins or GLP-1 analogue seems to be most promising second line drug after metformin failure. Currently we look at this molecule to be a cardiac friendly or at least CV neutral untill ongoing trial results comes out and says different stories altogether. Thanks...
Competing interests: No competing interests
Thanks to the author’s for such an excellent study.
This study still ascertains that Metformin is still the preferred monotheraphy. Metformin has been prescribed for diabetic patients for more than 50 years Hence long term studies and data with Metformin are completely available .Metformin has minimal GI side effects .In most of the patients if started slowly or modified release Metformin is given GI side effects are minimal .Though caution is entertained with Creatinine >130 and eGFr less than 45 , apart from few case reports there are no established studies to prove that metformin taken orally in patients with low eGFr is associated with lactic acidosis .
The study shows say that there was nausea, vomiting with metformin but would be interesting to know the GI side effects and relationship to the dosage of metformin, rather than just metformin started on a low dose
New medications are not always the best , but certainly in terms of DPP4 currently they are second line medication of choice with no weight gain , no hypoglycaemia and minimal side effects in diabetic patients though long term study has not been established and one of the serious side effects cautioned currently with sitagliptin is pancreatitis
Data shows DPP-4 as less effective in controlling HBa1c ,compared to sulphonyl urea However with studies showing increase cardiovascular events with aggressive Hba1c control (ACCORD Trial ) DPP4 are still a matter of choice and the risks of aggressive glycaemic control associated with hypoglycaemia and weight gain, must be weighed against the benefits in each patient with Type 2 diabetes .If someone wants a Legacy Effect obviously control should be aimed more intensively with education , diet and more than just DPP4 inhibitors
It will be also interesting to know whether there have been any significant adverse events in long term study in animal models as we had cancer scare with Glargine a while ago and rosiglitazone was associated with cardiovascular events in humans.
Patients with metabolic syndrome and insulin resistance form the main population of Type 2 diabetes where using DPP4 inhibitors with metformin is a major choice currently while it has no effect on body weight
After the rosiglitazone relationship to cardiovascular deaths pioglitazone is very minimally prescribed in primary care hence in terms of second line therapy the choice lies mostly towards a DPP4 inhibitor
Glucagon like peptide 1 analogues resulted in weight loss of 1.4 kg and 4.8 kg compared to placebo and insulin, though the cost price for prescribing exenatide annually in UK will be 820 pounds / year and liraglutide will be around 950 pounds / year compared to sitagliptin of around 400 pounds / year and metformin to 50 pounds/ year and hence cost effect proves inferior to the achieved goals in GLP 1 analogues
Competing interests: No competing interests
Thanks to the authors for this editorial on DPP-4 inhibitor.Though US-FDA has approved this group of drugs in patients with type-2 diabetes mellitus, but exact position of this drugs in treatment of type-2 diabetes mellitus is still undefined.One thing i want to mention strongly against it is that the cost of the therapy,when we added this group of drugs to therapy with metformin or sulfonylureas, the cost of therapy increases several folds.Another point, the exact long term effects of this drugs are still unknown. Weight reducing capacity and HbA1c reducing capacity is still negligeble as compared to cost of therapy specially in developing country like india.But trials revealed that this kind of drugs are quite safe.Because of its short term safety profile, its use is quite high specially in private sectors as compared to its efficacy level.
so to conclude we should balance and individualise the therapy according to patients socioeconomic background.
Competing interests: No competing interests
Thanks for having a detailed study on DPP-IV inhibitors. DPP-IV had grown as a promising target in type -2 diabetes. The long term efficacy of the drugs belonging to this class is still questionable.
It is learned that it is better to have a combination therapy using DPP-IV inhibitors with metformin to achieve a better glycaemic control. US FDA has approved the use of sitagliptin in combination with metformin marketed as JANUMET. The information regarding the efficacy of the combination in current clinical setting is inadequete.
There are post marketing reports of acute pancreatitis including the severe forms, hemorrhagic or necrotizing pancreatitis in patients using sitagliptin. The effect of these drugs on renal system is not clear.Studies are awaited on DPP-IV inhibitors to establish its place among the current therapeutic targets for the treatment of type-2 DM.
Competing interests: No competing interests
Failure of clinicians to implement time tested interventions with diet, exercise and medications with biguanides, sulphonylureas and insulin regimes aggressively and effectively is the major barrier for good diabetic care. Since hearing a talk on incretins in 2004, I have not yet found any reason to add any form of gliptins to my armament of drugs to manage T2 DM to date. When my colleague asked my opinion on a very close relative of mine with BMI of 22 whose control on maximal OHA was failing 5 years ago to suggest between basal insulin vs a Gliptin, the basal insulin started has done a good job so far. My take from this article is that Gliptins have a possible role is where obesity is complicating T2DM control. Mathew Jose, Kochi
Competing interests: No competing interests
Re: Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis
We appreciate Drs Scheffel and Shan interest and rapid response to our systematic review "Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis"1. Our meta-analysis provides evidence that DPP-4 inhibitors are indeed inferior to metformin and GLP-1 agonists regarding the primary endpoint of change in HbA1c. However, we do not agree with Drs Scheffel and Shan interpretation regarding the results of the comparison against pioglitazone or sulfonylureas. Against pioglitazone results were not statistically significant (weighted mean difference 0.09, 95% confidence interval 0.07 to 0.24). Sulfonylureas were marginally more effective than DPP-4 inhibitors (0.07, 0.03 to 0.11), and this difference is not clinically meaningful according to existing regulatory guidelines for effect size in trials in diabetes2. Thus, based on these results for the primary endpoint we believe that our conclusions and “what this study adds” comments are indeed justified when claiming that DPP-4 inhibitors have similar glycaemic efficacy to sulfonylureas or pioglitazone. Finally, we have also expressed our concerns regarding lack of long-term safety data and increased cost, which should indeed be taken into account by treating healthcare professionals.
References
1. Karagiannis T, Paschos P, Paletas K, Matthews DR, Tsapas A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 2012;344:e1369
2. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati...
Competing interests: DRM has been a member of an advisory board for vildagliptin (Novartis) and has received consulting fees from Novartis, Novo Nordisk, GlaxoSmithKline, Merck, Eli Lilly, Boehringer Ingelheim, AstraZeneca, Johnson and Johnson, and Janssen Global Services; AT has been a member of an advisory board for liraglutide (Novo Nordisk), has received lecture fees and a research grant from Novartis, and has received support with an educational grant from Novo Nordisk.