Comparative safety and effectiveness of sitagliptin in patients with type 2 diabetes: retrospective population based cohort study

TO: Jose Mario Franco de Oliveira, Associate Professor of Medicine; Universidade Federal Fluminense, Rua Senador Vergueiro # 2 apt. 202. Rio de Janeiro, RJ, Brazil. ZIP CODE: 22230-001

1. Firstly, can an observational study be qualified enough for suggesting to the wide audience of readers from BMJ an apparently “Safety” take home message, when the patients in this study taking sitagliptin were followed-up for a mean of only 2.5 years(1), for a disease that not uncommonly lasts for several years, even decades?

....We agree that the long-term safety of the drug has not been established. However, it is important to remember that this drug has only been on the market for ~5 years. Our study adds to the safety profile of sitagliptin as no short-term adverse events were noted with sitagliptin. Currently, no study can answer the longer-term safety of these drugs; however, given the currently data available, we found no signals to suggest it was harmful.

2. Why is this very expensive anti-diabetic drug being under world-wide scrutiny, even by the FDA, because of heavy suspicions about its serious adverse effects?(2-5) Is it just because sitagliptin has proven benefits on hard endpoints, of the real world, that mostly matter to type 2 diabetics like cardiovascular diseases, amputations, and quality of life?

....We appreciate the comment. We believe all new drugs, not just sitagliptin, should be continually evaluated. Indeed, most major regulator bodies have implemented continuous evaluation programs (e.g. mini sentinel program in the United States) in real world patients to evaluate ongoing safety on new drugs.

3. Are triglycerides, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and blood pressure truly hard endpoints that decrease All-cause death and increase Quality of Life, or are they just surrogates markers of disease? If they are indeed hard endpoints, why did Olmesartan and Torcetrapib decreased blood pressure, microalbuminuria, and increased HDL-Cholesterol, respectively, at the costs of increasing mortality when compared to placebo in randomised clinical trials?

....We are unsure of the relevance of this comment to our article. We did not evaluate the impact of sitagliptin on the numerous surrogates identified by the reviewer. Our endpoints only included the hard clinical endpoints of hospitalization or death.

4. Does anybody still believe that type 2 diabetes mellitus is namely a hyperglycaemic disease? Because, if this is the case, All modern and large clinical trials should have provided consistent or at least measurable evidence for any clinical benefits of normalising blood glucose levels in these patients, and what was actually found was well the opposite: Significantly and important more harms with “Intensive” or “Aggressive”, glycaemic control on one of the most harmful type 2 diabetic treatment complications: Increased Hypoglycaemic episodes!(6,7)

....We cannot speak for everybody but we believe diabetes is a spectrum disorder. Although tight glycemic control has been shown to be beneficial in certain patient groups on microvascular endpoints, the evidence for macrovascular endpoints is scarce and notably harms have been observed. In our opinion, most patients and clinicians would be better served in managing blood pressure and cholesterol as a priority in patients with type 2 diabetes. However, that does not mean blood glucose can be ignored and treatments must be individualized and tailored to patients to achieve a reasonable A1c control to lower the risk of macrovascular disease.

5. If all of the above mentioned is true and are all about for the sake of science; should we all erase from our minds the reality of the Rosiglitazone saga?

....Obviously the experience with rosiglitazone is front and center in the diabetes communities. Importantly, a number of steps have been implemented since that time to protect patients including more post-marketing surveillance and the need for randomized controlled trials vs placebo. Indeed, the safety boards of the ongoing, very large, Tecos and Savour (amoung others) randomized trials have convened multiple times and each recommendation has been to continue the trials as planned. Thus, no significant safety concerns have been raised with these drugs in these highly controlled settings, which is encouraging. Perhaps if rosiglitazone had been tested against placebo, that experience would not have occurred.

Dr Dean Eurich on behalf of Drs Simpson, Asche, Senthilselvan, McAlister, and Mrs Minhas-Sandhu.