Rationale, design, and baseline characteristics of a clinical trial for prevention of atherosclerosis in patients with insulin-treated type 2 diabetes mellitus using DPP-4 inhibitor: the Sitagliptin Preventive study of Intima-media thickness Evaluation (SPIKE)

Diabetology & Metabolic Syndrome

Hirotaka Watada^1,12  Iichiro Shimomura²  Masahiko Gosho³  Mamiko Tsugawa⁷  Hiroki Yokoyama^1,14  Kazunari Matsumoto⁶  Tsunehiko Yamamoto⁸  Yutaka Umayahara¹  Keisuke Kosugi⁴  Hideaki Kaneto²  Takeshi Osonoi^1,11  Nobuichi Kuribayashi^1,10  Tomio Onuma^1,13  Hidenori Yoshii^1,13  Toshihiko Shiraiwa⁹  Naoto Katakami⁵  Tomoya Mita^1,12 

[1] Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka 558-8558, Japan;Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan;Unit of Biostatistics, Advanced Medical Research Center, Aichi Medical University, 1-1, Yazakokarimata, Nagakute, Aichi 480-1195, Japan;Osaka Police Hospital, 10-31 Kitayamacho, Tennoji-ku, Osaka 543-0035, Japan;Department of Metabolism and Atherosclerosis, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan;Diabetes Center, Sasebo Chuo Hospital, 15 Yamato-cho, Sasebo, Nagasaki 857-1195, Japan;Ikeda Municipal Hospital, 3-1-18, Jonan, Ikeda, Osaka 563-8510, Japan;Kansai Rosai Hospital, 3-1-69 Inabasou, Amagasaki-shi, Hyogo 660-8511, Japan;Shiraiwa Medical clinic, 4-10-24 Houzenji, Kashiwara, Osaka 582-0005, Japan;Misaki Naika Clinic, 6-44-9 Futawahigashi, Funabashi, Chiba 274-0805, Japan;Naka Memorial Clinic, 745-5, Nakadai, Naka City, Ibaraki 311-0113, Japan;Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan;Department of Medicine, Diabetology & Endocrinology Juntendo Tokyo Koto Geriatric Medical Center, Shinsuna 3-3-20, Koto-ku, Tokyo 136-0075, Japan;Jiyugaoka Medical Clinic, Internal Medicine, West 6, South 6-4-3, Obihiro 080-0016, Hokkaido, Japan

关键词: Intima-media thickness (IMT);    Atherosclerosis;    Diabetes;    DPP-4;    Sitagliptin;   

Others  :  805045
DOI  :  10.1186/1758-5996-6-35

 received in 2014-01-16, accepted in 2014-02-26,  发布年份 2014

【 摘 要 】

Background

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is currently used to achieve glycemic targets in patients with type 2 diabetes mellitus (T2DM). The addition of DPP-4 inhibitors to ongoing insulin therapy is expected to reduce insulin dosage, leading to a reduction in the frequency of hypoglycaemia and/or weight gain. Recent studies have demonstrated potential anti-atherosclerotic effects for DPP-4 inhibitors. The aim of the present ongoing study is to assess the effects of sitagliptin on the progression of atherosclerosis in patients with insulin-treated T2DM using carotid intima-media thickness (IMT), an established marker of cardiovascular disease.

Methods and Design

The Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) is a prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group, comparative study. Between February 2012 and September 2012, 282 participants who failed to achieve glycemic control despite insulin therapy were recruited at 12 clinics and randomly allocated to the sitagliptin group (n = 142) or the control group (n = 140). Primary outcomes are changes in maximum and mean IMT of the common carotid artery after 24-month treatment period measured by carotid arterial echography. Secondary outcomes include changes in glycemic control, parameters related to beta-cell function and diabetic nephropathy, occurrence of cardiovascular events and adverse events such as hypoglycaemia, and biochemical markers of vascular function.

Discussion

The present study is designed to assess the effects of sitagliptin on the progression of carotid IMT. Results will be available in the near future, and the findings are expected to provide new strategy to prevent atherosclerosis in patients with insulin-treated T2DM.

Clinical Trial Registration

UMIN000007396

【 授权许可】

   
2014 Mita et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Haffner SM, Lehto S, Ronnemaa T, Pyorala 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(4):229-234.
• [2]Stamler J, Vaccaro O, Neaton JD, Wentworth D: Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993, 16(2):434-444.
• [3]Wright RJ, Frier BM: Vascular disease and diabetes: is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008, 24(5):353-363.
• [4]The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group N Engl J Med 1993, 329(14):977-986.
• [5]Jacob AN, Salinas K, Adams-Huet B, Raskin P: Weight gain in type 2 diabetes mellitus. Diabetes Obes Metab 2007, 9(3):386-393.
• [6]Yki-Jarvinen H: Combination therapies with insulin in type 2 diabetes. Diabetes Care 2001, 24(4):758-767.
• [7]Heller S: Weight gain during insulin therapy in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2004, 65(Suppl 1):S23-S27.
• [8]Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008, 358:2545-2559.
• [9]Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008, 358:2560-2572.
• [10]Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009, 360:129-139.
• [11]Frier BM, Schernthaner G, Heller SR: Hypoglycemia and cardiovascular risks. Diabetes Care 2011, 34 Suppl 2(6):S132-S137.
• [12]Strowig SM, Aviles-Santa ML, Raskin P: Comparison of insulin monotherapy and combination therapy with insulin and metformin or insulin and troglitazone in type 2 diabetes. Diabetes Care 2002, 25(10):1691-1698.
• [13]Nemoto M, Tajima N, Kawamori R: Efficacy of combined use of miglitol in Type 2 diabetes patients receiving insulin therapy-placebo-controlled double-blind comparative study. Acta Diabetol 2011, 48(1):15-20.
• [14]Ose H, Fukui M, Kitagawa Y, Hirata C, Ichio N, Kadono M, Mogami S, Onishi M, Ichida Y, Nakajima T, Hasegawa G, Yoshikawa T, Nakamura N: Efficacy of glimepiride in patients with poorly controlled insulin-treated type 2 diabetes mellitus. Endocr J 2005, 52:563-569.
• [15]Ahmed I, Goldstein BJ: Cardiovascular risk in the spectrum of type 2 diabetes mellitus. Mt Sinai J Med 2006, 73(5):759-768.
• [16]Ahren B: Use of DPP-4 inhibitors in type 2 diabetes: focus on sitagliptin. Diabetes Metab Syndr Obes 2010, 3:31-41.
• [17]Greig NH, Holloway HW, De Ore KA, Jani D, Wang Y, Zhou J, Garant MJ, Egan JM: Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia 1999, 42(1):45-50.
• [18]Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA, Taylor K, Kim D, Aisporna M, Wang Y, Baron AD: Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003, 88:3082-3089.
• [19]Parkes DG, Pittner R, Jodka C, Smith P, Young A: Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro. Metabolism 2001, 50(5):583-589.
• [20]Lovshin JA, Drucker DJ: Incretin-based therapies for type 2 diabetes mellitus. Nat Rev Endocrinol 2009, 5(5):262-269.
• [21]Barrera JG, Sandoval DA, D’Alessio DA, Seeley RJ: GLP-1 and energy balance: an integrated model of short-term and long-term control. Nat Rev Endocrinol 2011, 7(9):507-516.
• [22]Katsuno T, Ikeda H, Ida K, Miyagawa J, Namba M: Add-on therapy with the DPP-4 inhibitor sitagliptin improves glycemic control in insulin-treated Japanese patients with type 2 diabetes mellitus. Endocr J 2013, 60(6):733-742.
• [23]Shimoda S, Iwashita S, Ichimori S, Matsuo Y, Goto R, Maeda T, Matsuo T, Sekigami T, Kawashima J, Kondo T, Matsumura T, Motoshima H, Furukawa N, Nishida K, Araki E: Efficacy and safety of sitagliptin as add-on therapy on glycemic control and blood glucose fluctuation in Japanese type 2 diabetes subjects ongoing with multiple daily insulin injections therapy. Endocr J 2013, 60:1207-1214.
• [24]Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H: Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 2010, 59(4):1030-1037.
• [25]Goto H, Nomiyama T, Mita T, Yasunari E, Azuma K, Komiya K, Arakawa M, Jin WL, Kanazawa A, Kawamori R, Fujitani Y, Hirose T, Watada H: Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces intimal thickening after vascular injury. Biochem Biophys Res Commun 2011, 405:79-84.
• [26]Mita T, Watada H: Glucagon like Peptide-1 and atherosclerosis. Cardiovasc Hematol Agents Med Chem 2012, 10(4):309-318.
• [27]Matsubara J, Sugiyama S, Sugamura K, Nakamura T, Fujiwara Y, Akiyama E, Kurokawa H, Nozaki T, Ohba K, Konishi M, Maeda H, Izumiya Y, Kaikita K, Sumida H, Jinnouchi H, Matsui K, Kim-Mitsuyama S, Takeya M, Ogawa H: A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice. J Am Coll Cardiol 2012, 59:265-276.
• [28]Ervinna N, Mita T, Yasunari E, Azuma K, Tanaka R, Fujimura S, Sukmawati D, Nomiyama T, Kanazawa A, Kawamori R, Fujitani Y, Watada H: Anagliptin, a DPP-4 inhibitor, suppresses proliferation of vascular smooth muscles and monocyte inflammatory reaction and attenuates atherosclerosis in male apo E-deficient mice. Endocrinology 2013, 154:1260-1270.
• [29]White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F, Investigators E: Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013, 369:1327-1335.
• [30]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, Committee S-TS: Investigators: Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013, 369:1317-1326.
• [31]Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA: 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008, 359(15):1577-1589.
• [32]Yamasaki Y, Kodama M, Nishizawa H, Sakamoto K, Matsuhisa M, Kajimoto Y, Kosugi K, Shimizu Y, Kawamori R, Hori M: Carotid intima-media thickness in Japanese type 2 diabetic subjects: predictors of progression and relationship with incident coronary heart disease. Diabetes Care 2000, 23(9):1310-1315.
• [33]Yoshida M, Mita T, Yamamoto R, Shimizu T, Ikeda F, Ohmura C, Kanazawa A, Hirose T, Kawamori R, Watada H: Combination of the Framingham risk score and carotid intima-media thickness improves the prediction of cardiovascular events in patients with type 2 diabetes. Diabetes Care 2012, 35(1):178-180.
• [34]Okayama KI, Mita T, Gosho M, Yamamoto R, Yoshida M, Kanazawa A, Kawamori R, Fujitani Y, Watada H: Carotid intima-media thickness progression predicts cardiovascular events in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2013, 101(3):286-292.
• [35]Society TJD: Treatment Guide for Diabetes, ed by the Editorial Committee Members o “ Treatment Guide for Diabetes” (Araki E, Iwamoto Y, Kadowaki T, Kashiwagi A, Kitaoka M, Nanjo K, Tajima N). Bunkodo Co, Ltd, Tokyo, Japan 2010.
• [36]Katakami N, Mita T, Yoshii H, Onuma T, Kaneto H, Osonoi T, Shiraiwa T, Kosugi K, Umayahara Y, Yamamoto T, Yokoyama H, Kuribayashi N, Jinnouchi H, Gosho M, Watada H, Shimomura I: Rationale, design, and baseline characteristics of a trial for the prevention of diabetic atherosclerosis using a DPP-4 inhibitor: the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-a). J Atheroscler Thromb 2013, 20(12):893-902.
• [37]Terminology and Diagnostic Criteria Committee JSoUiM: Subcommittee for preparing guidelines for ultrasound diagnosis of carotid artery: standard method for ultrasound evaluation of carotid artery lesions. Jpn J Med Ultrasonics 2009, 36:501-518.
• [38]Yanase T, Nasu S, Mukuta Y, Shimizu Y, Nishihara T, Okabe T, Nomura M, Inoguchi T, Nawata H: Evaluation of a new carotid intima-media thickness measurement by B-mode ultrasonography using an innovative measurement software, intimascope. Am J Hypertens 2006, 19(12):1206-1212.
• [39]Yokoyama H, Katakami N, Yamasaki Y: Recent advances of intervention to inhibit progression of carotid intima-media thickness in patients with type 2 diabetes mellitus. Stroke 2006, 37(9):2420-2427.
• [40]Iida KT, Shimano H, Kawakami Y, Sone H, Toyoshima H, Suzuki S, Asano T, Okuda Y, Yamada N: Insulin up-regulates tumor necrosis factor-alpha production in macrophages through an extracellular-regulated kinase-dependent pathway. J Biol Chem 2001, 276(35):32531-32537.
• [41]Mita T, Goto H, Azuma K, Jin WL, Nomiyama T, Fujitani Y, Hirose T, Kawamori R, Watada H: Impact of insulin resistance on enhanced monocyte adhesion to endothelial cells and atherosclerogenesis independent of LDL cholesterol level. Biochem Biophys Res Commun 2010, 395(4):477-483.
• [42]Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, Bursell S, Yanagisawa M, King GL, Kahn CR: The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. J Clin Invest 2003, 111(9):1373-1380.
• [43]Schneider DJ, Absher PM, Ricci MA: Dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells. Circulation 1997, 96(9):2868-2876.
• [44]Janka HU, Ziegler AG, Standl E, Mehnert H: Daily insulin dose as a predictor of macrovascular disease in insulin treated non-insulin-dependent diabetics. Diabete Metab 1987, 13:359-364.
• [45]Liu QZ, Knowler WC, Nelson RG, Saad MF, Charles MA, Liebow IM, Bennett PH, Pettitt DJ: Insulin treatment, endogenous insulin concentration, and ECG abnormalities in diabetic Pima Indians. Cross-sectional and prospective analyses. Diabetes 1992, 41(9):1141-1150.
• [46]Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B, Diabetes C, Complications Trial/Epidemiology of Diabetes I, Complications Study Research G: Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005, 353:2643-2653.
• [47]Gaede P, Vedel P, Parving HH, Pedersen O: Intensified multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: the Steno type 2 randomised study. Lancet 1999, 353(9153):617-622.
• [48]Shah Z, Kampfrath T, Deiuliis JA, Zhong J, Pineda C, Ying Z, Xu X, Lu B, Moffatt-Bruce S, Durairaj R, Sun Q, Mihai G, Maiseyeu A, Rajagopalan S: Long-term dipeptidyl-peptidase 4 inhibition reduces atherosclerosis and inflammation via effects on monocyte recruitment and chemotaxis. Circulation 2011, 124:2338-2349.
• [49]Lim S, Choi SH, Shin H, Cho BJ, Park HS, Ahn BY, Kang SM, Yoon JW, Jang HC, Kim YB, Park KS: Effect of a dipeptidyl peptidase-IV inhibitor, des-fluoro-sitagliptin, on neointimal formation after balloon injury in rats. PloS one 2012, 7:e35007.
• [50]Satoh-Asahara N, Sasaki Y, Wada H, Tochiya M, Iguchi A, Nakagawachi R, Odori S, Kono S, Hasegawa K, Shimatsu A: A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients. Metabolism 2013, 62(3):347-351.
• [51]Matsubara J, Sugiyama S, Akiyama E, Iwashita S, Kurokawa H, Ohba K, Maeda H, Fujisue K, Yamamoto E, Kaikita K, Hokimoto S, Jinnouchi H, Ogawa H: Dipeptidyl peptidase-4 inhibitor, sitagliptin, improves endothelial dysfunction in association with its anti-inflammatory effects in patients with coronary artery disease and uncontrolled diabetes. Circ J 2013, 77:1337-1344.
• [52]Fadini GP, Boscaro E, Albiero M, Menegazzo L, Frison V, de Kreutzenberg S, Agostini C, Tiengo A, Avogaro A: The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care 2010, 33(7):1607-1609.
• [53]Green JB, Bethel MA, Paul SK, Ring A, Kaufman KD, Shapiro DR, Califf RM, Holman RR: Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 2013, 166(6):983-989. e987
• [54]Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A, Paolisso G: Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis 2013, 227(2):349-354.