Published the Study Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes

Journal of the American Medical Association 2016; 316 (3): 313-324. doi: 10.1001 / jama.2016.9400


The watchwords are: control, stem it. But the fight against diabetes becomes successful if between the several possible therapeutic strategies, the choice falls on the most appropriate and patient-friendly.

New, important evidence in the fight against type 2 diabetes emerge from far-reaching survey set to be milestone in the study of this disease and whose data were just released by the Journal of the American Medical Association (JAMA) on 19th July.



A disease, a veritable pandemic of 21st century, affecting over 380 million people around the world and within two decades estimated affecting 600 million people.

Only in Italy, more than 4 million patients are suffering from diabetes and considering the impact of events (especially cardiovascular, kidney and eye) on quality of life and on the consequent use of health resources, it is estimated an annual cost of illness amounting to 20 billion euro.



Today they are available to the physician several possibilities of pharmacological intervention.

The new International study, monumental for data, workload and research area, has been designed to meet stringent and delicate questions raised by contemporary clinical needs: in short, what the optimal treatment pathway? What benefits for the single patient and for the health service?

Italian contribution has been fundamental for the execution of the research that has involved researchers from several centers around the world from Australia to Canada, from Greece to New Zealand.

Among the principal ideators and authors of the study, appear in fact experts from the Center for Outcomes Research and Clinical Epidemiology (CORESEARCH) of Pescara and from the University of Bari.

Antonio Nicolucci, epidemiologist and CORESEARCH Director, is the author of numerous national and international studies. The italian researcher was among the initiators of the study, a meta-analysis that evaluated over 300 single studies on the therapeutic efficacy on diabetologic drugs.

The title of the study “Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes (Comparison of clinical and adverse outcomes due to hypoglycemic agents in patients with type 2 diabetes)” makes explicit the nature of in-depth analysis of a topic so clinically and socially relevant.

“It is well documented as an effective and timely treatment can substantially reduce the negative consequences of diabetes” says Dr Nicolucci. “Today there are many treatment options, with new classes of drugs (DPP-4 inhibitors, GLP-1 analogs, SGLT-2 inhibitors), available over those used for a long time.”


That’s the context, so rich and complex, that inspired the need for a new survey: “These drug classes differ in mechanism of action, safety and cost, and have similar efficacy,” says the expert. “National and international guidelines recommend starting treatment with a single oral medication in most patients. Where a single drug was no longer enough to keep diabetes controlled, it is recommended the addition of a second drug and, if necessary, of more additional drugs. The insulin therapy is usually reserved for cases of longer duration of the disease, not controlled by oral drugs (or injective, as in the case of the GLP-1 analogs)”.



Despite the availability of multiple therapeutic opportunities, there is a lack of evidence due to the scarcity of studies that directly consider head-to-head comparison of individual drugs or their combinations.

The new study appeared in JAMA consistently contributes to provide useful addresses in the clinical and therapeutic management of the disease: what is the best single agent? In case of monotherapy not more efficacious, what is the best combination of two drugs? Finally, a combination of three drugs is it preferable when two are not enough?

“The study”, recalls Nicolucci, “is a network meta-analysis conducted with innovative and highly sophisticated statistical techniques. By combining data from over 300 studies on the topic performed to date, has determined a rank of all medications regarding their ability to reduce cardiovascular events, mortality and blood glucose. Moreover, precious informations were obtained about the duration of efficacy of the treatment and the typical related side effects such as weight gain or hypoglycemia and other adverse events.”



In effects, as before mentioned, there are no clear evidence on the superiority of one treatment over another in reducing diabetes complications or risk of death. This complicates the choice of initial therapeutical regimen and can lead to substantial issues during the journey to be undertaken to combat the disease.

“The lack of conclusive evidence is mainly due to the short duration of many studies,” said the epidemiologist. “However, the comparisons made possible with our study confirm the metformin as the first choice monotherapy drug, with a high efficacy and safety profile. Interestingly, we have observed that in patients for whom metformin is found to be not tolerated or contraindicated, SGLT-2 inhibitors may represent a viable alternative. This thanks to the advantage of a greater duration of their efficacy (with clear benefits on the prolongation of the time required for the possible addition of a second drug) togeteher with a good tolerability and safety profile “.

The study then offers relevant perspectives in the clinical benefits assessment of combination therapy with two different molecules.

“No combination of 2 drugs has showed superiority as compared with other differently composed combination in the efficacy on blood glucose levels. In terms of safety, the combination of metformin with a SGLT-2 inhibitor is associated with lower risk of hypoglycemia, while the combination of metformin with a GLP-1 analogue determines the best effect on body weight, “says Antonio Nicolucci.

So, important implications could arise from these evidences for a diabetic patient-tailored choice of treatment when to be contemplated is a 2-drugs combination.

That’s not all: it is often necessary, and is widespread, the use of a combination of three drugs. In this case also the new network metanalysis offers insights of absolute practical interest. “Although the association of metformin, sulfonylureas and insulin have a more pronounced and lasting effect in reducing blood glucose, it is associated with a higher risk of hypoglycemia and weight gain”, underlines Dr. Nicolucci. Therefore, the study has analyzed the validity of additional therapeutic alternatives with the use of three drugs. It was found that “the combination metformin + sulfonylurea + GLP1 agonists has produced the best effect on body weight, while the combination metformin + sulfonylurea + dell’SGLT-2 inhibitors has been better in terms of riskof  hypoglycemia”, as indicated by Nicolucci.

In analogy to the results regarding the associations with two antidiabetic drugs, even in the case of a 3-drugs combination appears clear and advantgeous the opportunity for efficacy and safety profiles of more “tailored” treatment regimens.


The study provides an important reference point in addressing therapeutic decisions as a guide for a rational choice of the therapeutical approach on the basis of the individual characterisitcs of the diabetic patient.

The rational use of available drugs has important consequences for several reasons:

  1. The choice for individual patient of a regimen with best efficacy/safety profile helps in achieving the goals of care and minimize the risk of long-term complications.
  2. Lowering the risk of hypoglycemia or weight gain has an important effect on the acceptance of therapy and on the quality of life of people with diabetes, ensuring their adherence to the treatment over the long time.
  3. A similar approach could have positive impact in terms of economic burden, if one only wants consider that over 50% of the direct costs for diabetes are linked to hospitalizations for complications.

The study is also important because it emphasizes the need for large studies of adequate duration to directly compare the different therapeutic strategies and to assess their impact on the long-term complications.



Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, Maggo J, Gray V, De Berardis G, Ruospo M, Natale P, Saglimbene V, Badve SV, Cho Y, Nadeau-Fredette AC, Burke M, Faruque L, Lloyd A, Ahmad N, Liu Y, Tiv S, Wiebe N, Strippoli GF. Comparison of Clinical Outcomes and Adverse Events Associated With Glucose-Lowering Drugs in Patients With Type 2 Diabetes: A Meta-analysis. JAMA. 2016;316:313-24.