Type 2 diabetes mellitus and the cardiometabolic syndrome: impact of incretin-based therapies

Figures & data

Figure 1 The “ticking clock” hypothesis. Glucose abnormalities increase cardiovascular risk even before the diagnosis of diabetes is made. Multivariate relative risks and 95% confidence intervals of myocardial infarction (MI) or stroke according to diabetes status. The Nurses’ Health Study, N = 117,629 women, aged 30–55 years; follow-up 20 years (1976–1996). Adapted with permission from Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25(7):1129–1134.¹¹ Copyright © 2002 American Diabetes Association.

Note: ^aAdjusted; n = 1,508, diabetes at baseline; n = 5,894, new-onset diabetes.

Figure 2 Glycated hemoglobin (HbA_1c) and heart disease in type 2 diabetes. HbA_1c predicts CHD in type 2 diabetes. Rates for total CHD events by category of HbA_1c concentration and known diabetes in 4,462 men and 5,570 women aged 45–79 years. Adapted with permission from Khaw KT, Wareham N, Bingham S, Luben R, Welch A, Day N. Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk. Ann Intern Med. 2004;141(6):413–420.¹² Copyright © 2004 American College of Physicians.

Note: ^aP < 0.001 for linear trend across HbA_1c categories.
Abbreviation: CHD, coronary heart disease.

Table 1 Conversion table

	Convert mmol/L to mg/dL	Convert mg/dL to mmol/L
Blood glucose	Multiply by 18	Divide by 18 or multiply by 0.055
TC, LDL-C, HDL-C	Multiply by 38.67	Divide by 38.67 or multiply by 0.025
Triglycerides	Multiply by 88.57	Divide by 88.57 or multiply by 0.011

Abbreviations: TC, total cholesterol; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol.

Figure 3 Understanding cardiovascular outcome studies in type 2 diabetes mellitus. These data highlight the importance of balancing the benefits and risks of antidiabetes medications when making treatment decisions using agents that minimize the risk of hypoglycemia and weight gain, and possibly lead to weight loss.

Note: So given epidemiology, pathophysiology, aim for <6.0%, start early, use right meds, without hypoglycemia and visceral weight gain. Adapted with permission from del Prato S. Megatrials in type 2 diabetes. From excitement to frustration? Diabetologia. 2009;52(7):1219–1226.³⁰ Copyright © 2009 Springer.
Abbreviations: ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; ASCD, atherosclerotic cardiovascular disease; CV, cardiovascular; DCCT/EDIC, Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications; DM, diabetes mellitus; HbA_1c, glycated hemoglobin; PROACTIVE, Prospective Pioglitazone Clinical Trial in Macrovascular Events; UKPDS, United Kingdom Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial.

Figure 4 Actions of gastrointestinal hormones on key tissues in glucose homeostasis. Both GIP and GLP-1 promote insulin biosynthesis, insulin secretion, and islet β-cell survival. GLP-1 exerts additional actions, including inhibition of glucagon secretion and gastric emptying, and induction of food intake. GIP has a direct effect on adipocytes coupled to energy storage. In contrast, CCK and gastrin do not regulate plasma glucose levels but could be important for stimulation of islet neogenesis. Reprinted with permission from Girard J. The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions. Diabetes Metab. 2008;34(6 Pt 1):550–559.³⁹ Copyright © 2008 Elsevier.

Abbreviations: CCK, cholecystokinin; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1.

Figure 5 Glucose-stimulated secretion of insulin and potential mechanisms of interference by selected medications. Also, the potential mechanism by which GLP-1 may overcome these hyperglycemic effects. Adapted with permission from Van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-meidated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest. 2009;39(2):81–93.⁵⁰ Copyright © 2009 John Wiley and Sons.

Abbreviations: AC, adenyl cyclase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GIP, glucose-dependent insulinotropic polypeptide; GK, glucokinase; GLP-1, glucagon-like peptide-1; GLUT2, glucose transporter 2; PKA, protein kinase A; SUR, sulfonylurea receptor; TCA, tricaroboxylic acid (Kreb’s cycle).

Table 2 Perioperative glycemic guidelines used at the University of Pennsylvania

	Medications		Identify patient	Preoperative day	Operative day	Postoperative day 1−x	Until discharge
	Preadmin	In-hospital
CABG/operations requiring insulin drips			At risk, HbA 1c ~5.8 and >
Non-diabetes mellitus
		IV insulin drip			✓	✓ (until AM day 3)
		Incretina				Start	✓
		SFU/Pio/MET as below					✓
		CF fast-analog				✓ (when off drip)	✓
IFG/IGT/DM
	Incretina			✓ or start	✓	✓	✓
	SFU/glinide			✓	X	X	Consider
	Piob			✓		✓	✓
	METc			X	X	X	Only if stable
		IV insulin drip			✓	✓ (stop AM day 3)
	Basal insulin
	Bolus insulin					If normal PO- may not need if on incretin	If normal PO
		CF fast-analog				✓ (when off drip)	✓
Non-CABG
Non-diabetes mellitus					Postoperative bloodglucose >180	Postoperative blood glucose >180
	Incretin					Start
	SFU/Pio/MET as below						✓
	CF aspart					✓	✓
IFG/IGT/DM
	Incretina		✓ or start	✓	✓	✓	✓
	SFU/glinide			✓	X	X	Consider
	Piob			✓	X	✓	✓
	METc			X	X	X	Only if stable
	Basal insulin			✓	✓	✓	✓
	Bolus insulin			If normal meals		If normal PO-may not need if on incretin	If normal meals
	CF fast-analog					✓	✓

a Notes: Incretin administration: exenatide may be administered when patient is either NPO or PO (when operative-associated nausea is gone). DPP-IV inhibitors administered only when patient is PO.

b Pioglitazone can only be administered if the patient does not have a history of congestive heart failure.

c Metformin Cr < 1.5 male, < 1.4 female, age <70 years.

Abbreviations: CABG, coronary artery bypass graft; HbA_1c, glycated hemoglobin; IV, intravenous; SFU, sulfonylurea/glinide; Pio, pioglitazone; MET, metformin; CF, correction factor; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; DM, diabetes mellitus; PO, per oral; DPP-IV, dipeptidyl peptidase-IV inhibitor; NPO, nothing by mouth; X, not given; ✓, given.

Hu FB Stampfer MJ Haffner SM Solomon CG Willett WC Manson JE Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes Diabetes Care 2002 25 7 1129 1134 12087009

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Khaw KT Wareham N Bingham S Luben R Welch A Day N Association of hemoglobin A1c with cardiovascular disease and mortality in adults: the European prospective investigation into cancer in Norfolk Ann Intern Med 2004 141 6 413 420 15381514

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del Prato S Megatrials in type 2 diabetes. From excitement to frustration? Diabetologia 2009 52 7 1219 1226 19373446

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Girard J The incretins: from the concept to their use in the treatment of type 2 diabetes. Part A: incretins: concept and physiological functions Diabetes Metab 2008 34 6 Pt 1 550 559 19036624

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Van Raalte DH Ouwens DM Diamant M Novel insights into glucocorticoid-meidated diabetogenic effects: towards expansion of therapeutic options? Eur J Clin Invest 2009 39 2 81 93 19200161

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