Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysisBMJ 2017; 357 doi: https://doi.org/10.1136/bmj.j2499 (Published 08 June 2017) Cite this as: BMJ 2017;357:j2499
All rapid responses
Regulation of carbohydrate intake may be better than treatment of hyperglycaemia in patients with type 2 diabetes mellitus
Rajkumar Rajendram [1-3]
Ahmed Al Ibrahim 
1. Department of Medicine, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
2. Medication Use and Process Evaluation Subcommittee of the Medication Safety Program, Central Region, Ministry of National Guard Health Affairs, Saudi Arabia
3. Department of Nutrition and Dietetics, School of Biomedical and Life Sciences, King’s College London, UK
Mortality from diabetes is primarily due to cardiovascular disease. However, before the United States Food and Drug Administration industry required data on cardiovascular outcomes (CVO) to license new hypoglycaemic agents in 2008; few studies had examined the relationship between glucose lowering drugs and cardiovascular (CV) risk. This paradigm shift encouraged the use of hypoglycaemic agents with mortality benefits.
It was therefore extremely disappointing that the meta-analysis of 189 studies of incretin-based treatment on all cause mortality in patients with type 2 diabetes reported by Liu et al. found that there was no difference between incretin drugs and control. Indeed, Glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 (DPP-4) inhibitors have joined a long list of hypoglycaemic agents that do not improve cardiovascular outcomes or reduce mortality. This failure to identify hypoglycaemic medications that improve patient-relevant outcomes demands yet another paradigm shift in the management of type 2 diabetes.
Rather than attempting to control hyperglycaemia it may be more appropriate to prevent the development of hyperglycaemia. This may be achieved by regulation of carbohydrate intake. Cohort studies have suggested that whilst a carnivorous low-carbohydrate diet is associated with higher all-cause mortality; a vegetarian low-carbohydrate diet improves cardiovascular disease and reduces mortality.
Although further research is required to confirm these data; such lifestyle modifications are extremely difficult to achieve and maintain. Regardless, reducing morbidity and mortality from diabetes mellitus is critical to public health so a novel approach to the management is urgently required to improve outcomes.
1. Khan SS, Butler J, Gheorghiade M. Management of comorbid diabetes mellitus and worsening heart failure. JAMA2014;311:2379-80.
2. Liu J, Li L, Deng K, Xu C, Busse JW, Vandvik PO, Li S, Guyatt GH, Sun X. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ. 2017;357:j2499.
3. Fung TT, van Dam RM, Hankinson SE, Stampfer M, Willett WC, Hu FB. Low-carbohydrate diets and all-cause and cause-specific mortality: two cohort studies. Ann Intern Med. 2010;153:289-98.
4. Norris SL, Engelgau MM, Venkat Narayan KM. Effectiveness of self-management training in type 2 diabetes: a systematic review of randomized controlled trials. Diabetes Care 2001;24:561--87.
Competing interests: No competing interests
Re: Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis
Comparative effect sizes among large multinational trials of DPP-4 inhibitors and GLP-1 agonists from less developed and more developed countries.
C. Khouri, M. Roustit, R. Boussageon, J.-L. Cracowski, F. Gueyffier
We read with great interest the meta-analysis published by Liu and colleagues in the last issue of the BMJ, in which the authors suggest possible benefit on mortality with GLP-1 agonist but not with DPP-4 inhibitors (1). In this meta-analysis, six large, multinational cardio-vascular outcomes trials, including more than 55,000 patients from various countries around the world, represented more than 90% of the weight of the overall effect (2–7). We recently pointed out regional differences in treatment effect for some of these large trials (8). Panagiotou et al. in 2013 showed that treatment effect from trials conducted in less developed countries showed more favourable effects than trials from more developed countries (9). As a consequence we were wondering whether the results published by Liu et al. were comparable between less vs more developed countries.
To explore geographical variations of effects, we calculated the Ratio of Hazard Ratio (RHR) among each of the six major trials, and the summary of the RHR across DPP-4 inhibitors and GLP-1 analogues. We used the classification proposed by Panagiotou et al., the more developed being countries North America, Canada and Western Europe and less developed countries Latin America, Africa, Asia and Eastern Europe. When European countries were not sub-divided in Eastern and Western Europe analysis we excluded them from the main analysis. We calculated the summary of hazard ratio in each country group by fixed effect model and by DerSimonian-Laird random effect model in case of substantial heterogeneity (I2>50%) (10). Then we calculated for each trial the relative hazard ratio by dividing the summary hazard ratio from more developed countries by the summary hazard ratio from less developed countries. A relative hazard ratio >1 means that the treatment effect is more favorable in less developed countries than in more developed countries. Finally, we calculated the summary relative hazard ratio among DPP-4 inhibitors and GLP-1 analogues and across all trials. We conducted sensitivity analysis including Europe sub-group in more developed countries (available on demand). Analyses were conducted using R statistical software (version 3.2.3) and forest plot was drawn using MetaXL version 5.3 (EpiGear International, Sunrise Beach, Queensland, Australia). The results are presented in Figure 1 (available on demand).
Overall, GLP-1 agonists showed a 1.24-fold larger effect size in less developed countries than in more favorable countries, and this was homogenous among the three trials. In the subgroup meta-analysis conducted by Liu et al. (Figure 5) GLP-1 agonists achieved a reduction of odds ratio of cardio-vascular event of 1.13-fold therefore the difference observed in our analysis is of substantial importance. Regarding DPP-4 inhibitors, there was no significant difference between low and high income countries. However, in one trial (EXAMINE) the results were significantly more favorable in less developed countries than in more developed countries. Interestingly, this trial also provided the more favorable effect on cardio-vascular events among DPP-4 inhibitors (1).
In conclusion these results suggest that the higher the effect size, the larger the difference between low vs high income countries can be observed. This is consistent with the study by Panagiotou et al., and as this was observed in large-scale, international trials, we hypothesize that fraud or methodological bias are unlikely. Possible explanation of these differences could be due to genuine difference in included population according to region (e.g. baseline cardio-vascular risk) or differences in standard of care). To go further individual, patient-level data meta-analysis would allow understanding these differences in treatment effect.
1. Liu J, Li L, Deng K, Xu C, Busse JW, Vandvik PO, et al. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ. 2017 Jun 8;j2499.
2. Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2016 Sep 15;0(0):null.
3. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 juillet;375(4):311–22.
4. Pfeffer MA, Claggett B, Diaz R, Dickstein K, Gerstein HC, Køber LV, et al. Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome. N Engl J Med. 2015 décembre;373(23):2247–57.
5. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015 Jul 16;373(3):232–42.
6. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus. N Engl J Med. 2013 Oct 3;369(14):1317–26.
7. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after Acute Coronary Syndrome in Patients with Type 2 Diabetes. N Engl J Med. 2013 Oct 3;369(14):1327–35.
8. Roustit M, Khouri C, Boussageon R. Geographic Variations in Controlled Trials. N Engl J Med. 2017 23;376(12):1196–7.
9. Panagiotou OA, Contopoulos-Ioannidis DG, Ioannidis JPA. Comparative effect sizes in randomised trials from less developed and more developed countries: meta-epidemiological assessment. BMJ. 2013 Feb 12;346(feb12 1):f707–f707.
10. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986 Sep 1;7(3):177–88.
Competing interests: No competing interests
Liu et al1 assessed the impact of incretin based treatment on all cause mortality in patients with type 2 diabetes by meta-analysis. Their study showed that current evidence does not support the suggestion that incretin based treatment increases all cause mortality in patients with type 2 diabetes.
Cardiovascular disease and heart failure are major causes of morbidity and mortality in people with type 2 diabetes because they have multiple risk factors called cardiometabolic risk factors.2,3 Obviously, people with type 2 diabetes want anti-diabetes treatments to lower both glucose levels and risk of cardiovascular disease, heart failure, and all cause mortality by controlling cardiometabolic risk factors.4 Therefore, many studies have been performed to estimate these aspects. Unfortunately, although intensive glycemic control has improved surrogate markers of cardiovascular risk in such patients, there has been no significant reduction in the risk of major adverse cardiovascular events (MACE), including nonfatal stroke or myocardial infarction and death from cardiovascular causes.5 To be worst, some glitazone caused more incidence of myocardial infarction in addition to heart failure albeit the former is not true now.6 And some gliptin resulted in heart failure and possible increased mortality.7 In a mouse model, the inhibitors of CD26 (dipeptidyl peptidase-4; DPP-4) aggravated vascular leakage in the retinas suggesting aggravation of retinopathy.8
Two interesing meta-analysis studies related to this subject were published in 2016, however, the results were quite different. One reported that there were clinically important differences in risk of cardiovascular disease, heart failure, and all cause mortality between different diabetes drugs alone and in combination in 469 688 people with type 2 diabetes aged 25-84 years between 1 April 2007 and 31 January 2015. Overall, use of gliptins or glitazones was associated with decreased risks of heart failure, cardiovascular disease, and all cause mortality compared with non-use of these drugs.9 The other one reported that there were no significant differences in the associations between any of 9 available classes of glucose-lowering drugs (alone or in combination) and the risk of cardiovascular or all-cause mortality. Metformin was associated with lower or no significant difference in HbA1C levels compared with any other drug classes.10
Glucose is a polar compound and that its solubility and transportability occur through specialized tissue glucose transporters, particularly in the renal tubule, the small intestine, the brain, and peripheral tissues. Two gene families are involved — the sodium–glucose cotransporters (SGLTs) and facilitated glucose transporters (GLUTs).11,12 Whereas GLUTs facilitate essentially passive transport along membranes, SGLTs are involved in active transport. SGLT2, the most important renal transporter, reabsorbs nearly 90% of the glucose that is filtered by the glomeruli and is minimally expressed elsewhere, and SGLT1 resorbs the remainder. Thus, SGLT2 inhibition is essentially kidney-specific. Therefore, the concept that the inhibition of sodium–glucose transport in the kidney could improve insulin resistance and lower glycated hemoglobin levels in the management of type 2 diabetes re-emerged recently and led to the development of several SGLT2 inhibitors. SGLT2 inhibitors have insulin-independent effects. Preclinical data indicate that these compounds induce weight loss and decrease blood pressure through processes that are distinct from those involved in decreasing plasma glucose levels.13
Therefore, a randomized clinical trials with empagliflozin, a SGLT2 inhibitor, was performed in patients with type 2 diabetes at high risk of cardiovascular events taking multiple drugs for a non-inferiority purpose. However, surprisingly, patients who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care.14 Unlike the patients who were enrolled in some earlier trials to assess cardiovascular risk with intensive glucose control, those in the EMPA-REG OUTCOME trial were specifically at very high cardiovascular risk. Nearly half the patients had a history of myocardial infarction, and about three quarters had evidence of coronary artery disease, a quarter had previous stroke, and a fifth had peripheral vascular disease. A majority of the patients had more than a 10-year history of type 2 diabetes. Most patients were taking multiple medications for hyperglycemia, hypertension, and dyslipidemia. It seems likely that the observed risk reduction in the study was multifactorial. Atherosclerotic plaque areas in the aortic arch/valve were significantly smaller in the empagliflozin groups than in the control or glimepiride groups. Insulin resistance and circulating concentrations of TNF-α, IL-6, monocyte chemoattractant protein-1 (MCP-1), serum amyloid A and urinary microalbumin decreased after empagliflozin treatment, and this significantly correlated with plaque size. Empagliflozin treatment reduced weight and fat mass, lipid droplets in the liver, fat cell size, mRNA expression of Tnf, Il6 and Mcp-1 (also known as Ccl2) and the infiltration of inflammatory cells in plaque and adipose tissue compared with the control or glimepiride group. Empagliflozin treatment increased adiponectin levels.15 The addition of an SGLT2 inhibitor to standard care may ultimately alter vascular reactivity, as well as cardiac and cardiorenal function by controlling cardiometabolic risk factors. Other trial of canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]) also showed quite similar remarkable effects. In patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo.16
Dapagliflozin (DECLARE–TIMI58, NCT01730534) will be released at the end of 2017. Now some hope seems to be real that the risk of cardiovascular death in patients with type 2 diabetes and cardiovascular disease can indeed be modified. If other SGLT2 inhibitor such as ipragliflozine has similar effects called class effect, then, the guideline of the American Diabetes Association may be modified from the current ones recommending to use metformin monotherapy as initial treatment for patients with type 2 diabetes and selection of additional therapies based on patient-specific considerations.
Funding: None, Disclosures: None
1. Liu J, Li L, Deng K, Xu C, Busse JW, Vandvik PO, Li S, Guyatt GH, Sun X. Incretin based treatments and mortality in patients with type 2 diabetes: systematic review and meta-analysis. BMJ. 2017;357:j2499.
2. Haffner SM, Lehto S, Rönnemaa T, Pyörälä K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior
myocardial infarction. N Engl J Med. 1998; 339: 229-34.
3. Khan SS, Butler J, Gheorghiade M. Management of comorbid diabetes mellitus and worsening heart failure. JAMA. 2014;311:2379-80.
4. Koh KK. Letter by Koh Regarding Article, "Randomized trials to evaluate cardiovascular safety of antihyperglycemic medications: A worthwhile effort?" Circulation. 2016;134:e650-e651.
5. Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011; 364: 818-28.
6. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457-71.
7. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26.
8. Lee CS, Kim YG, Cho HJ, Park J, Jeong H, Lee SE, Lee SP, Kang HJ, Kim HS. Dipeptidyl peptidase-4 inhibitor increases vascular leakage in retina through VE-cadherin phosphorylation. Sci Rep. 2016;6:29393.
9. Hippisley-Cox J, Coupland C. Diabetes treatments and risk of heart failure, cardiovascular disease, and all cause mortality: cohort study in primary care. BMJ. 2016;354:i3477.
10. 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.
11. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255-70.
12. Abdul-Ghani MA, Norton L, DeFronzo RA. Renal sodiumglucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol. 2015;309:F889-900.
13. Ingelfinger JR, Rosen CJ. Cardiovascular risk and sodium-glucose cotransporter 2 inhibition in type 2 diabetes. N Engl J Med. 2015;373:2178-9.
14. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes.N Engl J Med. 2015;373:2117-28.
15. Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, Choi SH, Jang HC, Lee HS, Park KS, Kim YB, Lim S. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE -/- mice fed a western diet. Diabetologia. 2017;60:364-76.
16. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Jun 12. doi: 10.1056/NEJMoa1611925. [Epub ahead of print]
Competing interests: No competing interests