Access the full text.
Sign up today, get DeepDyve free for 14 days.
S. Williams, Denise Abbott, L. Morfis, P. Manwaring, Terence Diamond, L. Howes (1998)
Effects of glibenclamide on blood pressure and cardiovascular responsiveness in non‐insulin dependent diabetes mellitusJournal of Hypertension, 16
S. Persson (2007)
Blood pressure reactions to insulin treatment in patients with type 2 diabetes.The International journal of angiology : official publication of the International College of Angiology, Inc, 16 4
Cockcroft Dw, Gault Mh (1976)
Prediction of Creatinine Clearance from Serum CreatinineNephron, 16
are, 33
Hollander (2007)
Anti-diabetes and anti-obesity medications: effects on weight in people with diabetesDiabetes Spectrum, 20
A. Goldfine (2008)
Assessing the cardiovascular safety of diabetes therapies.The New England journal of medicine, 359 11
S. Knudsen, Esben Laugesen, K. Hansen, Toke Bek, C. Mogensen, P. Poulsen (2009)
Ambulatory pulse pressure, decreased nocturnal blood pressure reduction and progression of nephropathy in type 2 diabetic patientsDiabetologia, 52
J. Wilding, C. Bailey, U. Rigney, B. Blak, W. Beekman, C. Emmas (2016)
Glycated Hemoglobin, Body Weight and Blood Pressure in Type 2 Diabetes Patients Initiating Dapagliflozin Treatment in Primary Care: A Retrospective StudyDiabetes Therapy, 7
W. Cefalu, J. Buse, S. Prato, P. Home, D. Leroith, M. Nauck, I. Raz, J. Rosenstock, M. Riddle (2014)
Beyond Metformin: Safety Considerations in the Decision-Making Process for Selecting a Second Medication for Type 2 Diabetes ManagementDiabetes Care, 37
Trevor Orchard, M. Temprosa, E. Barrett-Connor, S. Fowler, Ronald Goldberg, K. Mather, S. Marcovina, M. Montez, Robert Ratner, Christopher Saudek, H. Sherif, K. Watson (2013)
Long‐term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes StudyDiabetic Medicine, 30
Long Zhou, Huanhuan Liu, Xiaoxiao Wen, Yaguang Peng, Yu Tian, Liancheng Zhao (2017)
Effects of metformin on blood pressure in nondiabetic patients: a meta-analysis of randomized controlled trialsJournal of Hypertension, 35
S. Schinner (2009)
Effects of Intensive Glucose Lowering in Type 2 DiabetesYearbook of Endocrinology, 2009
Steven Bird, A. Hartzema, M. Etminan, J. Brophy, J. Delaney (2013)
Polycystic ovary syndrome and combined oral contraceptive use: a comparison of clinical practice in the United States to treatment guidelinesGynecological Endocrinology, 29
L. Hermann, B. Scherstén, P. Bitzén, T. Kjellström, F. Lindgärde, A. Melander (1994)
Therapeutic Comparison of Metformin and Sulfonylurea, Alone and in Various Combinations: A double-blind controlled studyDiabetes Care, 17
H. Randeree, M. Omar, A. Motala, Mohomed Seedat (1992)
Effect of Insulin Therapy on Blood Pressure in NIDDM Patients With Secondary FailureDiabetes Care, 15
Bernadette Darne, Xavier Girerd, Michel Safar, F. Cambien, Louis Guize (1989)
Pulsatile versus steady component of blood pressure: a cross-sectional analysis and a prospective analysis on cardiovascular mortality.Hypertension, 13 4
R. Wurm, M. Resl, S. Neuhold, R. Prager, H. Brath, C. Francesconi, G. Vila, G. Strunk, M. Clodi, A. Luger, R. Pacher, M. Hülsmann (2016)
Cardiovascular safety of metformin and sulfonylureas in patients with different cardiac risk profilesHeart, 102
M. Safar, P. Nilsson, J. Blacher, A. Mimran (2012)
Pulse Pressure, Arterial Stiffness, and End-Organ DamageCurrent Hypertension Reports, 14
K. Alberti, R. Eckel, S. Grundy, P. Zimmet, J. Cleeman, K. Donato, J. Fruchart, W. James, C. Loria, Sidney Smith (2009)
Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International AsCirculation, 120 16
Jorgensen (2010)
Effects of oral glucose-lowering drugs on long term outcomes in patients with diabetes mellitus following myocardial infarction not treated with emergent percutaneous coronary intervention--a retrospective nationwide cohort studyCardiovasc Diabetol, 9
J. Kwagyan, C. Tabe, S. Xu, Abid Maqbool, V. Gordeuk, O. Randall (2005)
The impact of body mass index on pulse pressure in obesityJournal of Hypertension, 23
M. Safar (2001)
Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factorsCurrent Opinion in Nephrology and Hypertension, 10
C. Jørgensen, G. Gislason, C. Andersson, Ole Ahlehoff, M. Charlot, T. Schramm, A. Vaag, S. Abildstrom, C. Torp-Pedersen, Peter Hansen
O R I G I N a L I N V E S T I G a T I O N Open Access
L. Flores, E. Esmatjes, J. Manzanarez, W. Jiménez, R. Gomis (1998)
Insulin therapy in type 2 diabetic patients: effects on arterial blood pressure and endothelin-1 plasma levels.Diabetes research and clinical practice, 41 3
S. Glasser, D. Halberg, C. Sands, C. Gamboa, P. Muntner, M. Safford (2014)
Is pulse pressure an independent risk factor for incident acute coronary heart disease events? The REGARDS study.American journal of hypertension, 27 4
Wulffele (2004)
The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic reviewJ Intern Med, 256
V. Skov, C. Cangemi, J. Gram, Mette Christensen, E. Grodum, D. Sørensen, W. Argraves, J. Henriksen, L. Rasmussen (2014)
Metformin, but Not Rosiglitazone, Attenuates the Increasing Plasma Levels of a New Cardiovascular Marker, Fibulin-1, in Patients With Type 2 DiabetesDiabetes Care, 37
Jie Hong, Yifei Zhang, S. Lai, Ankang Lv, Q. Su, Yan Dong, Zhiguang Zhou, Wei-li Tang, Jiajun Zhao, Lianqun Cui, D. Zou, Dawang Wang, Hong Li, Chao Liu, Guo-ting Wu, Jie Shen, Dalong Zhu, Weiqing Wang, Weifeng Shen, G. Ning (2013)
Effects of Metformin Versus Glipizide on Cardiovascular Outcomes in Patients With Type 2 Diabetes and Coronary Artery DiseaseDiabetes Care, 36
M. Wulffelé, A. Kooy, P. Lehert, D. Bets, A. Donker, C. Stehouwer (2005)
Does metformin decrease blood pressure in patients with Type 2 diabetes intensively treated with insulin?Diabetic Medicine, 22
H. Gerstein, Michael Miller, R. Byington, D. Goff, J. Bigger, J. Buse, W. Cushman, S. Genuth, F. Ismail-Beigi, R. Grimm, J. Probstfield, D. Simons-Morton, W. Friedewald (2008)
Effects of intensive glucose lowering in type 2 diabetes.The New England journal of medicine, 358 24
K. Landin, Lilian Tengborn, Ulf Smith (1991)
Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factorsJournal of Internal Medicine, 229
M. Monami, D. Balzi, C. Lamanna, A. Barchielli, Giulio Masotti, Eva Buiatti, N. Marchionni, E. Mannucci (2007)
Are sulphonylureas all the same? A cohort study on cardiovascular and cancer‐related mortalityDiabetes/Metabolism Research and Reviews, 23
S. Franklin, Shehzad Khan, N. Wong, M. Larson, Daniel Levy (1999)
Is pulse pressure useful in predicting risk for coronary heart Disease? The Framingham heart study.Circulation, 100 4
Fengdi Liu, Xiaolei Shen, Rong Zhao, Xiao-Xiao Tao, Shuo Wang, Jiajing Zhou, Bo Zheng, Qiting Zhang, Qian Yao, Ying Zhao, Xin Zhang, Xue-Mei Wang, Hui-qin Liu, L. Shu, Jian-Ren Liu (2016)
Pulse pressure as an independent predictor of stroke: a systematic review and a meta-analysisClinical Research in Cardiology, 105
Jeffrey Johnson, S. Majumdar, S. Simpson, E. Toth (2002)
Decreased mortality associated with the use of metformin compared with sulfonylurea monotherapy in type 2 diabetes.Diabetes care, 25 12
Mei‐Ling Lee, Bernard Rosner, S. Weiss (1999)
Relationship of blood pressure to cardiovascular death: the effects of pulse pressure in the elderly.Annals of epidemiology, 9 2
V. Basevi (2011)
Diagnosis and Classification of Diabetes MellitusDiabetes Care, 34
V. Palmieri, R. Devereux, J. Hollywood, J. Bella, Jennifer Liu, Elisa Lee, L. Best, B. Howard, M. Roman (2006)
Association of pulse pressure with cardiovascular outcome is independent of left ventricular hypertrophy and systolic dysfunction: the Strong Heart Study.American journal of hypertension, 19 6
M. Charles, E. Eschwège, P. Grandmottet, Françoise Isnard, J. Cohen, J. Bensoussan, Hervé Berche, O. Chapiro, P. André, P. Vague, I. Juhan-vague, J. Bard, Michel Safar (2000)
Treatment with metformin of non‐diabetic men with hypertension, hypertriglyceridaemia and central fat distribution: the BIGPRO 1.2 trialDiabetes/Metabolism Research and Reviews, 16
H. Gerstein, Michael Miller, F. Ismail-Beigi, J. Largay, C. McDonald, H. Lochnan, G. Booth (2014)
Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trialThe Lancet, 384
J. Evans, S. Ogston, A. Emslie-Smith, A. Morris (2006)
Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metforminDiabetologia, 49
J. Gamble, S. Simpson, D. Eurich, S. Majumdar, J. Johnson (2010)
Insulin use and increased risk of mortality in type 2 diabetes: a cohort studyDiabetes, 12
D. Preiss, S. Lloyd, I. Ford, J. McMurray, R. Holman, P. Welsh, M. Fisher, C. Packard, N. Sattar (2014)
Metformin for non-diabetic patients with coronary heart disease (the CAMERA study): a randomised controlled trial.The lancet. Diabetes & endocrinology, 2 2
Nils Ekström, A. Svensson, Mervete Miftaraj, S. Franzén, B. Zethelius, B. Eliasson, S. Gudbjörnsdottir (2016)
Cardiovascular safety of glucose‐lowering agents as add‐on medication to metformin treatment in type 2 diabetes: report from the Swedish National Diabetes RegisterDiabetes, 18
M. Sutton, M. Rendell, P. Dandona, J. Dole, K. Murphy, R. Patwardhan, J. Patel, M. Freed (2002)
A comparison of the effects of rosiglitazone and glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes.Diabetes care, 25 11
M. Safar, J. Blacher, B. Pannier, A. Guérin, S. Marchais, P. Guyonvarc’h, G. London (2002)
Central Pulse Pressure and Mortality in End-Stage Renal DiseaseHypertension: Journal of the American Heart Association, 39
U. Mogensen, C. Andersson, E. Fosbøl, T. Schramm, Allan Vaag, N. Scheller, C. Torp-Pedersen, G. Gislason, G. Gislason, L. Køber (2014)
Cardiovascular safety of combination therapies with incretin‐based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus – a retrospective nationwide studyDiabetes, 16
J. Cockcroft, I. Wilkinson, M. Evans, P. McEwan, J. Peters, S. Davies, M. Scanlon, C. Currie (2005)
Pulse pressure predicts cardiovascular risk in patients with type 2 diabetes mellitus.American journal of hypertension, 18 11
E. Ferrannini, R. DeFronzo (2015)
Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes.European heart journal, 36 34
D. Giugliano, N. Rosa, Giosué Maro, R. Marfella, R. Acampora, R. Buoninconti, F. D'onofrio (1993)
Metformin Improves Glucose, Lipid Metabolism, and Reduces Blood Pressure in Hypertensive, Obese WomenDiabetes Care, 16
C. Mourão-Júnior, J. Sa, O. Guedes, S. Dib (2006)
Effects of metformin on the glycemic control, lipid profile, and arterial blood pressure of type 2 diabetic patients with metabolic syndrome already on insulin.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas, 39 4
E. Siraj, Daniel Rubin, M. Riddle, Michael Miller, F. Hsu, F. Ismail-Beigi, Shyh‐Huei Chen, W. Ambrosius, Abraham Thomas, William Bestermann, J. Buse, S. Genuth, C. Joyce, C. Kovacs, P. O’Connor, R. Sigal, Solomon Solomon (2015)
Insulin Dose and Cardiovascular Mortality in the ACCORD TrialDiabetes Care, 38
J. Rowe, James Young, K. Minaker, A. Stevens, J. Pallotta, L. Landsberg (1981)
Effect of Insulin and Glucose Infusions on Sympathetic Nervous System Activity in Normal ManDiabetes, 30
M. Schram, P. Kostense, R. Dijk, J. Dekker, G. Nijpels, L. Bouter, R. Heine, C. Stehouwer (2002)
Diabetes, pulse pressure and cardiovascular mortality: the Hoorn StudyJournal of Hypertension, 20
D. Nagi, J. Yudkin (1993)
Effects of Metformin on Insulin Resistance, Risk Factors for Cardiovascular Disease, and Plasminogen Activator Inhibitor in NIDDM Subjects: A study of two ethnic groupsDiabetes Care, 16
P. King, I. Peacock, R. Donnelly (1999)
The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes.British journal of clinical pharmacology, 48 5
J. Gamble, Eugene Chibrikov, L. Twells, W. Midodzi, S. Young, D. MacDonald, S. Majumdar (2017)
Association of insulin dosage with mortality or major adverse cardiovascular events: a retrospective cohort study.The lancet. Diabetes & endocrinology, 5 1
S. Koren, L. Shemesh-Bar, A. Tirosh, R. Peleg, S. Berman, Ramzia Hamad, S. Vinker, A. Golik, S. Efrati (2012)
The effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipids, and inflammation in type 2 diabetes mellitus patients.Diabetes technology & therapeutics, 14 7
M. Wulffelé, A. Kooy, D. Zeeuw, C. Stehouwer, R. Gansevoort (2002)
The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review.Journal of internal medicine, 256 1
Type 2 diabetes is associated with higher pulse pressure. In this study, we assessed and compared effects of classic diabetes treatments on pulse pressure (PP), systolic blood pressure (SBP), and diastolic blood pressure (DBP) in patients with type 2 diabetes. In a retrospective cohort study, 718 non-hypertensive patients with type 2 diabetes were selected and divided into 4 groups including metformin, insulin, glibenclamide+metformin, and metformin+insulin. They were followed for 4 consecutive visits lasting about 45.5 months. Effects of drug regimens on pulse and blood pressure over time were assessed separately and compared in regression models with generalized estimating equation method and were adjusted for age, duration of diabetes, sex, smoking, and body mass index (BMI). Studied groups had no significant change in PP, SBP, and DBP over time. No significant difference in PP and DBP among studied groups was observed (PP:P=0.090; DBP:P=0.063). Pairwise comparisons of PP, SBP, and DBP showed no statistically significant contrast between any 2 studied groups. Interactions of time and treatment were not different among groups. Our results demonstrate patients using metformin got higher PP and SBP over time. Averagely, pulse and blood pressure among groups were not different. Trends of variation in pulse and blood pressure were not different among studied diabetes treatments. Abbreviations: CVD = cardiovascular disease, DBP = diastolic blood pressure, DM2 = type 2 diabetes mellitus, Glb = glibenclamide, Met = metformin, PP = pulse pressure, SBP = systolic blood pressure. Keywords: cardiovascular safety, glibenclamide, insulin, metformin, pulse pressure, systolic and diastolic blood pressure, type 2 diabetes mellitus [3–10] occurrence of cerebrovascular disease and nephropathy. PP 1. Introduction is known to be higher in diseases involving vascular system such Pulse pressure (PP), defined as the difference between systolic as the type 2 diabetes mellitus (DM2). People with DM2 have blood pressure (SBP) and diastolic blood pressure (DBP) is the increased arterial stiffness resulting in a wide PP compared with [1] clinical manifestation of arterial stiffness. The systolic [7] their non-diabetic peers. The risk of CVD is higher in DM2 component of a wide PP increases the cardiac demand by patients; furthermore, increase in their PP is an additional risk exerting higher afterload on the heart which results in myocardial factor for CVD incidence and has a positive association with hypertrophy; while its diastolic element limits cardiac supply by [11] mortality. [2] decreasing coronary perfusion. Hence, wide PP is associated Drugs used to control the blood glucose in DM2 also could with the incidence of cardiovascular disease (CVD) besides the [12–14] modify blood pressure as their side effects ; however, outcomes are not the same. For instance, while metformin could reduce blood pressure, insulin treatment does not have the similar Editor: Masanari Kuwabara. [15–19] effect. Also, even there is not a consensus over the general Funding: This research did not receive any specific grant from funding agencies effect of some antidiabetic agents like metformin and insulin on in the public, commercial, or not-for-profit sectors. [19–23] blood pressure. The authors report no conflicts of interest. a Although several works have been done on the effect of Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, different glucose-lowering therapies on blood pressure; little is School of Medicine, Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. known about their action on PP. Along with their study, Skov [24] Correspondence: Manouchehr Nakhjavani, Endocrinology and Metabolism et al demonstrate that there is no statistically significant Research Center (EMRC), Vali-Asr Hospital, Tehran University of Medical difference between PP of diabetic patients treated with insulin and Sciences, Tehran, P.O. Box: 13145-784, Iran (e-mail: nakhjavanim@tums.ac.ir). its combinations with metformin (Met) or Rosiglitazone or both. Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. We have postulated there should not be any difference between This is an open access article distributed under the Creative Commons the effect of studied hypoglycemic treatments on pulse and blood Attribution-ShareAlike License 4.0, which allows others to remix, tweak, and build pressure of diabetic patients. However, yet, there is not a upon the work, even for commercial purposes, as long as the author is credited and the new creations are licensed under the identical terms. comprehensive study comparing classic treatments applied in DM2. Moreover, there are some confounding factors need to be Medicine (2018) 97:6(e9791) studied. Therefore, in the current study, we assessed and Received: 5 September 2017 / Received in final form: 6 December 2017 / Accepted: 15 January 2018 compared the effect of glucose-lowering regimens including metformin, Met+insulin, glibenclamide+metformin (Glb+Met), http://dx.doi.org/10.1097/MD.0000000000009791 1 Alemi et al. Medicine (2018) 97:6 Medicine and insulin on diabetic patients PP, SBP, and DBP considering cholesterol, triglyceride, high-density lipoprotein cholesterol confounding factors over 45.5 months of follow-up. (HDL), low-density lipoprotein cholesterol (LDL) were deter- mined using direct enzymatic method (Parsazmun, Karaj, Iran). 2. Materials and methods 2.3. Outcome measures and definitions 2.1. Study sample The primary outcome of this study is PP, which is defined as the This study is a part of an open prospective cohort conducted in difference between SBP and DBP. We calculated PP using SBP and the diabetes clinic of Valiasr hospital (Tehran, Iran). Data DBP, measured at the baseline and during each follow-up. collection for this cohort started from 2008. Patients with DM2 The diagnosis of DM2 was made based on fasting blood who had attended Valiasr diabetes clinic have been enrolled in the glucose >126 or 2-hour postprandial glucose >200 or random- original cohort. In the current study, we selected 718 diabetic [26] ized blood glucose >200 or HbA1c >6.5. People with non-hypertensive patients who had been already using metfor- hypertension were defined as those who were taking antihyper- min, Glb+Met, Met+insulin, or insulin only from the ongoing tensive medications. BMI was computed as weight in kilograms cohort study. 2 divided by height per square meter (kg/m ). We excluded patients with primary hypertension as well as patients treated with lipid-lowering therapies other than statins. 2.4. Statistical analysis For avoiding the bias resulted by excluding normotensive people who got hypertensive later along follow-up, we traced those Statistical analysis was carried out using Stata (version 12; Stata individuals who were totally 13 people (6 patients on metformin, Corp LP, College Station, TX) for Windows. Baseline patients’ 2 metformin and glibenclamide combination, 1 using the characteristics were presented as mean (SD) for continuous combination of insulin and metformin, and 1 patient using variables and number (percentage) for categorical variables. Chi- insulin). Patients with uncontrolled hypothyroidism or clinical squared test or one-way ANOVA was used as appropriate to hyperthyroidism were not included in the study as well as patients evaluate group differences. with any other interfering endocrinological disease. Those To compare PP, SBP, and DBP among treatment groups, individuals with any history of myocardial infarction, percuta- regression models with generalized estimating equation method neous coronary intervention, stent placement, CCU admission, were used taking into account the correlation between repeated and cerebrovascular accidents were excluded from the study. blood pressure measurements of the same subjects. Treatments as Patients were followed at the Valiasr hospital from the date of indicator variables were main predictors of the model. In the enrollment (the baseline visit) every year for 3 consecutive visits model, the variable “time” was defined as months since the until October 2015 which had been set as the end of the follow- baseline visit. Following, chi-squared test was carried out for up. At each follow-up session, we included only patients who did comparing treatments’ effect in general. For comparing trends in not have any change in the drug which had been previously used. blood and pulse pressure variation over time in each group, the Before enrollment, written informed consents were taken from interaction of treatments and time was compared with and all participants. The ethics committee of the Tehran University of without adjustment for covariates by introducing their product Medical Sciences approved the study protocol. term in regression models with generalized estimating equation method. Age, duration of diabetes, BMI, sex, and smoking were selected as covariates. Post hoc analysis was used as appropriate 2.2. Clinical and laboratory measurements for pairwise comparison following regression analysis with Sidak All the patient’s characteristics, including age, duration of DM2 correction. diagnosis, sex, body weight, height, body mass index (BMI), In order to assess change in pulse and blood pressure over time, blood pressure, total cholesterol, high-density lipoprotein regression models with generalized estimating equation method cholesterol, low-density lipoprotein (LDL) cholesterol, triglycer- were used; in which PP, SBP, and DBP in each studied groups ides, HbA1c, fasting blood glucose (FBS), 1hour post-prandial were compared among visits by adjusting for duration of glucose (1hppg), creatinine concentration, and medication diabetes. (antihypertensive drug, cholesterol-lowering drug, and antidia- The sample size was calculated assuming 5mmHg as the least betic drug) were extracted from the computerized hospitalization detectable variation of pulse and blood pressure (equivalent of records at the baseline and during the follow-up. 0.36 standard deviation), type 1 error of 0.05, and 0.5 as the Age, medication, and the duration of DM2 have been obtained correlation among our repeated measures. Although here by from the participants through the interview at the first visit. having the least total sample size of 120 as the number of patients Weight, height, and the waist circumference were measured at the in the last visit, this study offers the power of 0.99. baseline. Systolic blood pressure and diastolic blood pressure A P value <.05 (2-sided) was set as the significance threshold. measurements were performed on the arm of seated participants after 10minutes of resting using standard mercury sphygmoma- 3. Results nometer. The measurement was repeated after 15minutes and the average was reported. We calculated eGFR using the Cockcroft 3.1. Patients and Gault equation, based on age, sex, weight, and serum [25] Seven hundred eighteen diabetic normotensive patients using creatinine. metformin (189 patients), metformin and glibenclamide (360 After 12hours of fasting, venous blood samples were collected patients), metformin and insulin (63 patients), or insulin only for the biochemical analysis. FBS and 1hppg were measured by (106 patients) were selected from the running cohort study. One the glucose oxidase method. HbA1c was measured by high- hundred seventy two of 718 subjects were selected for the second performance liquid chromatography. Measurement of serum visit; others were excluded due to either lack of the data or change creatinine was performed by Jaffe method. Plasma total 2 Alemi et al. Medicine (2018) 97:6 www.md-journal.com Table 1 Baseline characteristics of studied groups. Metformin N= 189 Glb+Met N= 360 Met+Ins N= 63 Insulin N=106 P value Total N=718 Age, y 52± 11 54± 10 51± 13 49± 15 .001 52± 12 Male/Female (%) 117 (61.9%)/ 72 (38.1%) 206(57.5%)/ 152 (42.5%) 38 (61.3%)/ 24 (38.7%) 52 (49.1%)/ 54 (50.9%) .176 413 (57.8%)/ 302 (42.2%) Smoking (%) 19 (10.2%) 42 (11.8%) 7 (11.1%) 22 (21.0%) .179 90 (12.7%) BMI, kg/m 28.54± 4.72 27.35± 4.47 29.27± 5 25.9± 5.61 <.001 27.62± 4.85 WC, cm 97± 15 94± 10 97± 12 90± 12 <.001 94± 12 SBP, mmHg 123± 19 127± 19 126± 17 121± 20 .016 125± 19 DBP, mmHg 77± 12 77± 12 78± 11 73± 12 .018 77± 12 PP, mmHg 46± 14 50± 14 49± 14 48± 15 .093 48± 14 DDM, y 4.15± 4.54 7.53± 6.15 10.12± 7.26 10.46± 7.47 <.001 7.29± 6.47 eGFR, mL/min/1.73 m 95.58± 34.37 88.81± 26.35 95.91± 28.15 86.76± 30.31 .045 91.24± 29.67 FBS, mg/dL 172.58± 62.71 200.01± 77.86 198.17± 89.79 205.67± 103.28 .001 192.92± 79.58 HbA1C (%) 7.83± 1.82 8.67± 1.9 8.64± 2.08 8.55± 2.15 <.001 8.41± 1.95 TG, mg/dL 164.81± 92.95 191.38± 142.75 167.48± 84.69 150.61± 98.17 .039 177.05± 121.45 Cholesterol, mg/dL 181.64± 42.51 185.09± 47.4 182.88± 39.64 174.84± 45.71 .460 182.8± 45.12 LDL-C, mg/dL 104.44± 35.75 103.44± 35.63 99.33± 33.98 95.8± 47.28 .437 102.53± 36.9 HDL-C, mg/dL 44.48± 11.12 46.29± 22.24 48.71± 15.41 49.83± 16.37 .239 46.38± 18.45 Values reported as mean (SD) or number (percentage). BMI= body mass index, DBP= diastolic blood pressure, DDM= duration of diabetes diagnosis, eGFR= estimated glomerular filtration rate, FBS= fasting blood sugar, Glb= glibenclamide, HbA1C= hemoglobin A1C, HDL-C= high density lipoprotein cholesterol, Ins= insulin, LDL-C= low density lipoprotein cholesterol, Met= metformin, PP= pulse pressure, SBP= systolic blood pressure, TG= triglyceride, WC= waist circumferences. Statistical significance. 3.3. PP, SBP, and DBP change over time in each group in the antidiabetic agent. Similarly, the third visit included 138 and the last visit consisted of 120 subjects. The median time gap PP, SBP, and DBP of patients over visits are shown in Table 2 and between our baseline visit and the first, second, and then last illustrated in Fig. 1A–C. Despite steady blood pressure of other follow-up were 12, 23, and 35.5 months, respectively. October 2 2 groups, PP (X =13.47; P=.003) and SBP (X =8.45; P=.037) of 2015 was set as the end of the follow-up. patients treated with Met+insulin increased over time. Notably, in this group, PP and SBP alteration were limited to the contrast between first and third visit (PP: 95%CI=1.38, 19.34; P=.014; 3.2. Baseline characteristics SBP: 95%CI=1.32, 22.30; P=.111) which did not define a Table 1 shows baseline characteristics in each studied group. The specific change. Notably, including normotensive patients who median age of the study sample was 45.5 years. There was no got hypertensive later had no statistically significant result in this sex composition difference among studied groups. The comparison. baseline PP had no significant variation among study groups. At the baseline, patients on Glb+Met treatment had higher 3.4. PP, SBP, and DBP comparison among studied SBP and patients treated with Glb+Met had higher DBP groups compared with patients using insulin (95% confidence interval [CI]=0.40–11.36, P=.028; 95%CI=0.59–7.50, P As shown in Table 3, without adjustment PP (P<.05), SBP =.012, respectively). There was no statistically significant (P<.01), and DBP (P<.05) all had significant differences among difference among study groups regarding the proportion of studied groups. After adjustment for covariates variation of PP smokers. among groups disappeared (P=.090); but, the difference in DBP Table 2 PP, SBP, and DBP among studied groups at each visit. Treatments Visit 1 Visit 2 Visit 3 Visit 4 X P value PP Met 46± 14 49± 12 50± 12 50± 14 5.57 .134 Glb+Met 50± 14 52± 16 52± 13 52± 8 3.32 .344 Met+Insulin 49± 14 53± 13 59± 20 54± 11 13.47 .003 Insulin 48± 15 49± 13 54± 10 50± 18 2.74 .433 SBP Met 123± 19 126± 15 128± 16 128± 19 4.61 .203 Glb+Met 127± 19 130± 22 132± 16 132± 14 3.11 .374 Met+Insulin 126± 17 131± 14 136± 26 132± 18 8.45 .037 Insulin 121± 20 123± 15 132± 16 126± 16 4.01 .260 DBP Met 77± 12 78±978± 10 78± 11 0.32 .956 Glb+Met 77± 12 78± 12 80± 10 79± 9 1.40 .706 Met+Insulin 78± 11 78± 10 77± 11 77± 11 0.80 .849 Insulin 73± 12 75±778± 10 76± 6 2.14 .544 In order to assess change in pulse and blood pressure, the analysis was conducted using regression models with generalized estimating equation method in which PP, SBP, and DBP in each studied groups were compared among visits by adjusting for duration of diabetes. Significances are reported in P-value. DBP= diastolic blood pressure, Glb= glibenclamide, Met= metformin, PP= pulse pressure, SBP= systolic blood pressure. 3 Alemi et al. Medicine (2018) 97:6 Medicine Figure 1. PP, SBP, and DBP of patients in each visit are illustrated in plots (A)–(C), respectively. DBP=diastolic blood pressure, Glb=glibenclamide, Met= metformin, PP=pulse pressure, SBP=systolic blood pressure. remained with a trend to statistical significance (P=.063) and in blood and pulse pressure variation over time among studied SBP still varied among studied groups (P<.05). Pairwise groups had no difference. Again including normotensive patients comparison of PP and SBP among studied groups showed no who got hypertensive later had no statistically significant result in significant contrast between any 2 groups; but revealed higher these comparisons. DBP in Glb+Met group compared with the insulin group with a trend to statistical significance (95% Cl: 6.26, 0.31; P=.098). 4. Discussion Table 4 shows the complete pairwise comparison of pulse and blood pressure among studied groups. Higher PP in DM2 increases the risk of CVD and its [3,6,27] mortality. DM2 is associated with metabolic syndrome With and without adjustment, treatments and time had no and other cardiovascular risk factors; hence, cardiovascular interaction in predicting PP, SBP, and DBP which showed trends 4 Alemi et al. Medicine (2018) 97:6 www.md-journal.com insulin to metformin or vice versa on blood pressure and most Table 3 importantly pulse pressure. Results of comparison of PP, SBP, and DBP among studied Among mechanisms in which sulfonylurea could lead to the groups. higher CVD morbidity, Williams has shown glibenclamide a b Treatments Treatments Time increases nocturnal SBP in diabetic patients. We did not find Unadjusted Adjusted Unadjusted Adjusted any study assessing mainly the effect of sulfonylurea on PP in [44] PP 0.026 0.090 0.188 0.223 DM2; although St John Sutton et al provided data showing a SBP 0.006 0.028 0.269 0.326 statistically significant decrease in diabetic patients PP after 52 DBP 0.012 0.063 0.743 0.846 weeks treatment with Glyburide. Also, we observed no change in SBP, DBP, and PP of diabetic patients treated with Glb+Met. The analysis was conducted by regression models with generalized estimating equation method in [47] which PP, SBP, and DBP were used as dependent variables separately and studied groups Similarly, Herman et al had found no blood pressure (treatments) as indicator variables used as main predictors. Also, covariates including age, duration of difference among patients treated with different combinations diabetes, BMI, and smoking were used in adjusted models. Following, differences of PP, SBP, and DBP of metformin and Glyburide. Again, there has been a lack of among studied groups was assessed by chi-squared test comparing main predictors’ effects. For studies about the effect of Glb+Met combination treatment on assessing differences in trends in PP, SBP, and DBP variation over time among studied groups, the same analysis was done taking into account interactions of time and treatments as main predictors. PP. Significances are reported in P-value. DBP= diastolic blood pressure, PP= pulse pressure, SBP= There are studies reporting increased cardiovascular events systolic blood pressure. and mortality by insulin treatment in DM2 patients especially by [49–51] applying intensive blood glucose control. On another hand, safety of different glucose-lowering therapies is a critical issue and some studies have reported an insignificant association between [52,53] several studies have already been done comparing cardiovascular insulin use and cardiovascular morbidity and mortality. [28–31] outcomes of different antidiabetic treatments. Here we focused on the role of pulse and blood pressure and There have not been enough studies comparing the outcome of found no significant change in SBP and DBP of diabetic patients different modalities of glucose-lowering therapy regarding PP. In treated with insulin; however, DBP in patients treated with this study, we have demonstrated pulse and blood pressure of insulin in this study was lower than patients on Glb+Met with a DM2 patients treated with classic glucose-lowering treatments trend to statistical significance. There are studies showing blood including Met, Glb+Met, Met+insulin, and insulin had no pressure elevation secondary to insulin initiation in diabetic [21,19] significant change over time. Importantly, we have shown there patients ; however, our finding is consistent with Flores [20] was no difference in PP, SBP, and DBP among patients treated et al which reported no rise in blood pressure secondary to [54] with these medications. insulin therapy. Furthermore, Rowe et al had already Many studies have reported metformin reduces cardiovascular demonstrated insulin infusion could lead to increase in PP; events and mortality compared with other antidiabetic although, we observed no difference in PP of patients treated with [29,32,33] agents. However, the role of blood pressure in this risk insulin over the follow-up. reduction has not been elucidated yet. Although some authors As noted before, there have not been enough studies comparing [34,35] have reported a decrease in SBP or DBP by using metformin, these classic glucose-lowering treatments according to their effect [24] there are studies reporting a nonsignificant effect of this on PP. Skov et al already demonstrated that effect of different [36,37] medication on patients blood pressure. We did not find combinations of insulin, metformin, or Rosiglitazone on PP did any significant change of PP, SBP, and DBP in patients treated not vary. We also have shown there is no difference in trends of with metformin over follow-up. There have not been enough PP, SBP, and DBP variation over time among studied groups studies on the effect of metformin on PP; however, Wulffelé which has not been reported before. [37] et al demonstrated a decrease in nocturnal PP of diabetic In our study, after adjustment for covariates and pairwise patients including both normotensive and hypertensive cases comparisons, no significant contrast between any 2 groups was after 16 weeks treatment with metformin. observed. However, in crude analysis SBP, DBP, and PP were It seemed PP and SBP of patients treated with Met+insulin different among treatment groups. The effect of adjustment increased over time, but this variation was only between first and showed covariates confounding effects and could be explained by third visit which could not reliably define a trend. Formerly, following facts. First, with prolonged duration of DM2, vessels [38] Mourão-Junior et al demonstrated the addition of metformin would be exposed to hyperglycemic media longer which to diabetic patients controlled with insulin had no effect on blood facilitates arterial stiffening. Also, duration of diabetes itself [55] pressure. Studies should be done for clarifying the effect of adding has shown to be associated with pulse pressure. Second, Table 4 Results of pairwise comparison of studied groups regarding PP, SBP, and DBP. PP SBP DBP Treatments 95% CI P 95% CI P 95% CI P Glb+Met Vs Met 0.343,5.19 .121 0.26,7.21 .084 1.03,3.65 .603 Met+Ins Vs Met 0.87,7.10 .216 0.80,9.50 .148 1.93,4.26 .902 Insulin Vs Met 1.92,6.14 .669 5.45,6.08 1.000 5.20,1.86 .764 Met+Ins Vs Glb+Met 3.01,4.39 .997 3.79,5.55 .997 3.07,2.79 1.000 Insulin Vs Glb+Met 4.03,3.40 1.000 8.55,2.23 .546 6.26,0.31 .098 Insulin Vs Met+Ins 5.51,3.51 .993 9.94,1.86 .361 6.52,0.85 .233 All comparisons are done with adjustment for covariates using regression models with generalized estimating equation method in which PP, SBP, and DBP were used as dependent variables and studied groups (treatments) used as predictors. 95% CI of differences are reported. P values are corrected by the Sidak method. CI= confidence interval, DBP= diastolic blood pressure, Glb= glibenclamide, Ins= insulin, Met= metformin, P=P value, PP= pulse pressure, SBP= systolic blood pressure. 5 Alemi et al. Medicine (2018) 97:6 Medicine [11] Cockcroft JR, et al. Pulse pressure predicts cardiovascular risk in patients hypoglycemic medications such as metformin are selected based [56] with type 2 diabetes mellitus. Am J Hypertens 2005;18:1463–7. on patients’ characteristics such as BMI which is formerly [12] Charles MA, et al. Treatment with metformin of non-diabetic men with [57] reported to have a positive association with pulse pressure. hypertension, hypertriglyceridaemia and central fat distribution: the Together, different BMI, DM2 duration, and age of patients BIGPRO 1.2 trial. Diabetes Metab Res Rev 2000;16:2–7. [13] Preiss D, et al. Metformin for non-diabetic patients with coronary heart among this study groups could lead to a significant crude result. disease (the CAMERA study): a randomised controlled trial. Lancet This study is among few studies comparing PP of diabetic Diabetes Endocrinol 2014;2:116–24. patients treated with different antidiabetic regimens. Our study is [14] Bird ST, et al. Polycystic ovary syndrome and combined oral highlighted by having a large and targeted sample size and using contraceptive use: a comparison of clinical practice in the United States generalized estimating equation analysis. Notably, we excluded to treatment guidelines. Gynecol Endocrinol 2013;29:365–9. [15] Koren S, et al. The effect of sitagliptin versus glibenclamide on arterial hypertensive patients as well as patients treated with lipid- stiffness, blood pressure, lipids, and inflammation in type 2 diabetes lowering therapies other than statins due to the interference their mellitus patients. Diabetes Technol Ther 2012;14:561–7. various treatments could cause. Including normotensive people [16] Orchard TJ, et al. Long-term effects of the Diabetes prevention program who got hypertensive later along follow-up had no statistically interventions on cardiovascular risk factors: a report from the DPP Outcomes Study. Diabet Med 2013;30:46–55. significant outcome, showing this exclusion had not biased the [17] Wilding J, et al. Glycated hemoglobin, body weight and blood pressure in final result. However, we had some limitations. First, studied Type 2 diabetes patients initiating dapagliflozin treatment in primary groups were not randomized; although, we adjusted results for care: a retrospective study. Diabetes Ther 2016;7:695–711. some known covariates to compensate for the lack of [18] Wulffele MG, et al. The effect of metformin on blood pressure, plasma randomization in this prospective cohort study. Furthermore, cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med 2004;256:1–4. randomized clinical trial (RCT) design limits the follow-up time [19] Persson SU. Blood pressure reactions to insulin treatment in patients with and restricts trends study of pulse and blood pressure, an analysis type 2 diabetes. Int J Angiol 2007;16:135–8. requiring long follow-up period. Second, we had no control [20] Flores L, et al. Insulin therapy in type 2 diabetic patients: effects on group to compare treatment groups with; consequently, we were arterial blood pressure and endothelin-1 plasma levels. Diabetes Res Clin Pract 1998;41:151–5. not able to demonstrate each drug net effect on patients’ blood [21] Randeree HA, et al. Effect of insulin therapy on blood pressure in pressure. Although we evaluated and compared the effect of 4 NIDDM patients with secondary failure. Diabetes Care 1992; antidiabetic medication regimen on pulse pressure over time, 15:1258–63. further studies needed to investigate other cardiovascular safety [22] Williams S, et al. Effects of glibenclamide on blood pressure and issues. cardiovascular responsiveness in non-insulin dependent diabetes melli- tus. J Hypertens 1998;16:705–11. [23] Zhou L, et al. Effects of metformin on blood pressure in nondiabetic 5. Conclusion patients: a meta-analysis of randomized controlled trials. J Hypertens 2017;35:18–26. There was no statistically significant difference in PP, SBP, and [24] Skov V, et al. Metformin, but not rosiglitazone, attenuates the increasing DBP among patients treated with classic antidiabetic regimens plasma levels of a new cardiovascular marker, fibulin-1, in patients with type 2 diabetes. Diabetes Care 2014;37:760–6. including metformin, Glb+Met, Met+insulin, and insulin alone. [25] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum Trends in PP, SBP, and DBP variation over time were not different creatinine. Nephron 1976;16:31–41. among studied glucose lowering modalities. These hypoglycemic [26] Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 regimens also did not affect PP, DBP, and SBP over time. (Suppl):S62–9. [27] Palmieri V, et al. Association of pulse pressure with cardiovascular However, further studies are needed to improve our understand- outcome is independent of left ventricular hypertrophy and systolic ing of these findings. dysfunction: the Strong Heart Study. Am J Hypertens 2006;19:601–7. [28] Cefalu WT, et al. Beyond metformin: safety considerations in the decision-making process for selecting a second medication for type 2 References diabetes management: reflections from a diabetes care editors’ expert [1] Safar ME, et al. Pulse pressure, arterial stiffness, and end-organ damage. forum. Diabetes Care 2014;37:2647–59. Curr Hypertens Rep 2012;14:339–44. [29] Wurm R, et al. Cardiovascular safety of metformin and sulfonylureas in [2] Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as patients with different cardiac risk profiles. Heart 2016;102:1544–51. cardiovascular risk factors. Curr Opin Nephrol Hypertens 2001; [30] Goldfine AB. Assessing the cardiovascular safety of diabetes therapies. N 10:257–61. Engl J Med 2008;359:1092–5. [3] Glasser SP, et al. Is pulse pressure an independent risk factor for incident [31] Alberti K, et al. Harmonizing the metabolic syndrome a joint interim acute coronary heart disease events? The REGARDS study. Am J statement of the international diabetes federation task force on Hypertens 2014;27:555–63. epidemiology and prevention; national heart, lung, and blood institute; [4] Darne B, et al. Pulsatile versus steady component of blood pressure: a American heart association; world heart federation; international cross-sectional analysis and a prospective analysis on cardiovascular atherosclerosis society; and international association for the study of mortality. Hypertension 1989;13:392–400. obesity. Circulation 2009;120:1640–5. [5] Franklin SS, et al. Is pulse pressure useful in predicting risk for coronary [32] Evans JM, et al. Risk of mortality and adverse cardiovascular outcomes heart disease? The Framingham heart study. Circulation 1999; in type 2 diabetes: a comparison of patients treated with sulfonylureas 100:354–60. and metformin. Diabetologia 2006;49:930–6. [6] Lee ML, Rosner BA, Weiss ST. Relationship of blood pressure to [33] Johnson JA, et al. Decreased mortality associated with the use of cardiovascular death: the effects of pulse pressure in the elderly. Ann metformin compared with sulfonylurea monotherapy in type 2 diabetes. Epidemiol 1999;9:101–7. Diabetes Care 2002;25:2244–8. [7] Schram MT, et al. Diabetes, pulse pressure and cardiovascular mortality: [34] Landin K, Tengborn L, Smith U. Treating insulin resistance in the Hoorn Study. J Hypertens 2002;20:1743–51. hypertension with metformin reduces both blood pressure and metabolic [8] Safar ME, et al. Central pulse pressure and mortality in end-stage renal risk factors. J Intern Med 1991;229:181–7. disease. Hypertension 2002;39:735–8. [35] Giugliano D, et al. Metformin improves glucose, lipid metabolism, and [9] Knudsen ST, et al. Ambulatory pulse pressure, decreased nocturnal blood reduces blood pressure in hypertensive, obese women. Diabetes Care pressure reduction and progression of nephropathy in type 2 diabetic 1993;16:1387–90. patients. Diabetologia 2009;52:698–704. [36] Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk [10] Liu FD, et al. Pulse pressure as an independent predictor of stroke: a factors for cardiovascular disease, and plasminogen activator inhibitor in systematic review and a meta-analysis. Clin Res Cardiol 2016;105: NIDDM subjects: a study of two ethnic groups. Diabetes Care 677–86. 1993;16:621–9. 6 Alemi et al. Medicine (2018) 97:6 www.md-journal.com [37] Wulffelé MG, et al. Does metformin decrease blood pressure in patients [46] Ekstrom N, et al. Cardiovascular safety of glucose-lowering agents as with Type 2 diabetes intensively treated with insulin? Diabet Med add-on medication to metformin treatment in type 2 diabetes: report 2005;22:907–13. from the Swedish National Diabetes Register. Diabetes Obes Metab [38] Mourão-Ju nior CA, et al. Effects of metformin on the glycemic control, lipid 2016;18:990–8. profile, and arterial blood pressure of type 2 diabetic patients with metabolic [47] Hermann LS, et al. Therapeutic comparison of metformin and syndrome already on insulin. Braz J Med Biol Res 2006;39:489–94. sulfonylurea, alone and in various combinations. A double-blind [39] Hong J, et al. Effects of metformin versus glipizide on cardiovascular controlled study. Diabetes Care 1994;17:1100–9. outcomes in patients with type 2 diabetes and coronary artery disease. [48] Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on Diabetes Care 2013;36:1304–11. cardiovascular disease in type 2 diabetes. Eur Heart J 2015;36:2288–96. [40] Jorgensen CH, et al. Effects of oral glucose-lowering drugs on long term [49] Gamble JM, et al. Insulin use and increased risk of mortality in type 2 outcomes in patients with diabetes mellitus following myocardial infarction diabetes: a cohort study. Diabetes Obes Metab 2010;12:47–53. not treated with emergent percutaneous coronary intervention–a retrospec- [50] Group T.A.t.C.C.R.i.D.S.Effects of intensive glucose lowering in Type 2 tive nationwide cohort study. Cardiovasc Diabetol 2010;9:54. diabetes. N Engl J Med 2008;358:2545–59. [41] King P, Peacock I, Donnelly R. The UK Prospective Diabetes Study [51] Gerstein HC, et al. Effects of intensive glucose lowering in type 2 (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J diabetes. N Engl J Med 2008;358:2545–59. Clin Pharmacol 1999;48:643–8. [52] Gamble JM, et al. Association of insulin dosage with mortality or major [42] Gerstein HC, et al. Effects of intensive glycaemic control on ischaemic adverse cardiovascular events: a retrospective cohort study. Lancet heart disease: analysis of data from the randomised, controlled Diabetes Endocrinol 2017;5:43–52. ACCORD trial. Lancet 2014;384:1936–41. [53] Siraj ES, et al. Insulin dose and cardiovascular mortality in the ACCORD [43] Monami M, et al. Are sulphonylureas all the same? A cohort study on trial. Diabetes Care 2015;38:2000–8. cardiovascular and cancer-related mortality. Diabetes Metab Res Rev [54] Rowe JW, et al. Effect of insulin and glucose infusions on sympathetic 2007;23:479–84. nervous system activity in normal man. Diabetes 1981;30:219–25. [44] St John Sutton M, et al. A comparison of the effects of rosiglitazone and [55] Cockcroft JR, et al. Pulse pressure predicts cardiovascular risk in patients glyburide on cardiovascular function and glycemic control in patients with type 2 diabetes mellitus. Am J Hypertens 2005;18:1463–7. with type 2 diabetes. Diabetes Care 2002;25:2058–64. discussion 1468-9. [45] Mogensen UM, et al. Cardiovascular safety of combination therapies [56] Hollander P. Anti-diabetes and anti-obesity medications: effects on with incretin-based drugs and metformin compared with a combination weight in people with diabetes. Diabetes Spectrum 2007;20:159–65. of metformin and sulphonylurea in type 2 diabetes mellitus–a [57] Kwagyan J, et al. The impact of body mass index on pulse pressure in retrospective nationwide study. Diabetes Obes Metab 2014;16:1001–8. obesity. J Hypertens 2005;23:619–24.
Medicine – Wolters Kluwer Health
Published: Feb 1, 2018
You can share this free article with as many people as you like with the url below! We hope you enjoy this feature!
Read and print from thousands of top scholarly journals.
Already have an account? Log in
Bookmark this article. You can see your Bookmarks on your DeepDyve Library.
To save an article, log in first, or sign up for a DeepDyve account if you don’t already have one.
Copy and paste the desired citation format or use the link below to download a file formatted for EndNote
Access the full text.
Sign up today, get DeepDyve free for 14 days.
All DeepDyve websites use cookies to improve your online experience. They were placed on your computer when you launched this website. You can change your cookie settings through your browser.