Ulf Smith, MD Sahlgrenska University Hospital, Gothenburg, Sweden - PowerPoint PPT Presentation

Asian Chapter Asian Chapter Achieving glycemic control: What are the management options for the next decade Ulf Smith, MD Sahlgrenska University Hospital, Gothenburg, Sweden

Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3 months until A1C is <7% and then at least every 6 months. Nathan D M et al. Diabetes Care 2009;32:193-203

Nathan D M et al. Diabetes Care 2009;32:193-203

Nathan D M et al. Diabetes Care 2009;32:193-203

Progressive Decline in β -Cell Function and Insulin Secretion in Type 2 Diabetes Mellitus ukpds

Diabetes and cardiovascular disease 50-80 % of deaths in people with diabetes are due to cardiovascular disease (CVD) Most important are: Coronary heart disease - 2/3 of patients admitted to CCU have diabetes or IGT Cerebrovascular disease - 2-4 times greater risk to suffer a stroke in people with diabetes Peripheral vascular disease - 15-40 times increased risk of lower limb amputation in people with diabetes vs. general population

Diabetic complications vs HbA1c increase 1 % increase in HbA1c - 10-18 % increased CVD - 12-14 % increased early death - 37 % increased retinopathy/ Sugar Red blood nephropathy cell Low High HbA1c HbA1c Refs Ann Intern Med 141:421, 2004 Diabetologia 48:1749, 2005 BMJ 321:405, 2000

Vascular disease in diabetes and glucose control Microvascular disease – clearly related to glucose/HbA1c levels and intensified control reduces risk (DCCT, UKPDS, ADVANCE etc) Macrovascular disease – more controversial and less clear. Postprandial glucose levels better predictors than fasting glucose levels. But the postprandial state is complex also reflecting, for instance, postprandial lipid levels/elimination

Axelsen M et al. Ann Intern Med 131:27-31, 1999

Table 25 Recommendations for treatment of dyslipidaemia in diabetes Recommendations Class a Level b Ref c In all patients with type 1 diabetes and in the presence of microalbuminuria and renal disease, LDL-C lowering (at least 30%) with statins as the first choice (eventually drug I C combination) is recommended irrespective of the basal LDL-C concentration. In patients with type 2 diabetes and CVD or CKD, and in those without CVD who are over the age of 40 years with one or more other CVD risk factors or markers of target organ damage, the recommended goal for LDL-C is <1.8 I B 15, 16 mmol/L (less than ~70 mg/dL) and the secondary goal for non-HDL-C is <2.6 mmol/L (100 mg/dL) and for apo B is <80mg/dL. In all people with type 2 diabetes LDL-C <2.5 mmol/L (less than ~100 mg/dL) is the primary target. Non-HDL-C I B 15, 16 <3.3 mmol/L (130 mg/dL) and apo B <100 mg/dL are the secondary targets. a Class of recommendation. b Level of evidence. c References. apo = apolipoprotein; CKD = chronic kidney disease; CVD = cardiovascular disease; LDL-C = low-density lipoprotein-cholesterol. ESC/EAS Guidelines

Recommended treatment targets for patients with diabetes and CAD (modified from the European Guidelines for Cardiovascular Disease Prevention) L. Ryden et al. Eur Heart J 28:88-136, 2007

Effect of a Multifactorial Intervention on Mortality in Type 2 Diabetes Peter Gæde, M.D, D.M.Sc., Henrik Lund-Andersen, M.D, D.M.Sc., Hans-Henrik Parving, M.D, D.M.Sc., and Oluf Pedersen, M.D, D.M.Sc. 358:580-591, 2008

N Engl J Med 358:580-591, 2008

Effects of Intensive Glucose Lowering in Type 2 Diabetes The Action to Control Cardiovascular Risk in Diabetes Study Group Methods In this randomized study, 10,251 patients (mean age, 62.2 years) with a median glycated hemoglobin level of 8.1% were assigned to receive intensive therapy (targeting a glycated hemoglobin level below 6.0%) or standard therapy (targeting a level from 7.0 to 7.9%). Of these patients, 38% were women, and 35% had had a previous cardiovascular event. The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes. The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up. N Engl J Med 358:2545-59, 2008

The NEW ENGLAND JOURNAL of MEDICINE ORIGINAL ARTICLE CONCLUSIONS As compared with standard therapy, the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6% reduced 5-year nonfatal myocardial infarctions but increased 5-year mortality. Such a strategy cannot be recommended for high-risk patients with advanced type 2 diabetes. (Funded by the National Heart, Lung and Blood Institute; ClinicalTrials.gov number, NCT00000620.) N Engl J Med 364:818, 2011

Desirable profile of anti-diabetic agents Lower HbA1c and BW • Preserve insulin secretion and β -cell mass • Improve lipid profile and CVD risk • Reduce cancer risk •

Treatment of Type 2 Diabetes – oral agents A general trend is to use oral agents that do not induce hypoglycemia (i.e., maintain the normal regulation by glucose on insulin secretion • Metformin • TZD (pioglitazone) • DPP4 inhibitors • GLP-1 analogues (  -glucosidase inhibitors)

Systematic Review: Comparative Effectiveness and Safety of Oral Medications for Type 2 Diabetes Mellitus Shari Bolen, MD, MPH; Leonard Feldman, MD; Jason Vassy, MD, MPH; Lisa Wilson, BS, ScM; Hsin-Chieh Yeh, PhD; Spyridon Marinopoulos, MD, MBA; Crystal Wiley, MD, MPH; Elizabeth Selvin, PhD; Renee Wilson, MS; Eric B. Bass, MD, MPH; and Frederick L. Brancati, MD, MHS Data Sources: The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched from inception through January 2006 for original articles and through November 2005 for systematic reviews. Unpublished U.S. Food and Drug Administration and industry data were also searched. Study Selection: 216 controlled trials and cohort studies and 2 systematic reviews that addressed benefits and harms of oral diabetes drug classes available in the United States. 147:386-399, 2007

147:386-399, 2007

Weighted mean difference in blood pressure, laboratory values, and body weight with use of oral medications for type 2 diabetes mellitus 147:386-399, 2007

Weighted mean difference in blood pressure, laboratory values, and body weight with use of oral medications for type 2 diabetes mellitus 147:386-399, 2007

Weighted mean difference in blood pressure, laboratory values, and body weight with use of oral medications for type 2 diabetes mellitus 147:386-399, 2007

Treatment of Type 2 Diabetes – oral agents A general trend is to use oral agents that do not induce hypoglycemia (i.e., maintain the normal regulation by glucose on insulin secretion • Metformin • TZD (pioglitazone) • DPP4 inhibitors • GLP-1 analogues (  -glucosidase inhibitors)

β -Cell function parameters during 3 years of EXE (n = 16) and GLAR (n = 20) treatment Bunck M C et al. Diabetes Care 2011;34:2041-2047

Atherogenic Lipoprotein Profile Metabolic Syndrome Type 2 Diabetes Large VLDL Increased CAD Risk Small dense HDL LDL

B. Eliasson et al. Diabetologia DOI 10.1007/s00125-011-2447-3

B. Eliasson et al. Diabetologia DOI 10.1007/s00125-011-2447-3

1,0 0,4 0,5 Change in A1c (%) 0,0 P<0.001 P<0.001 -0,5 -0,4 -1,0 Placebo -1,0 ALO 25 mg ALO 25 mg+PIO 30 mg -1,5 Figure 3a. Mean ( ± SE) change from baseline to week 16 in HbA1c. Baseline values PBO 6.6%, ALO 6.8%, ALO/PIO 6.6%. P-values for the LS mean treatment difference compared with PBO. White bars, PBO; grey bars, ALO; dark grey bars, ALO/PIO. B. Eliasson et al. Diabetologia DOI 10.1007/s00125-011-2447-3

14 Placebo ALO 25 mg *** *** *** ALO 25 mg +PIO 30 mg 12 10 *** GLP-1 (pmol/L) 8 6 ** *** * ** 4 ** ** 2 * 0 * -1 0 1 2 3 4 5 6 7 8 Time (h) Figure 4a. Mean ( ± SE) postprandial active GLP-1 at week 16. P-values for the LS mean treatment difference compared with PBO: * <0.05, ** <0.01, *** <0.001. White triangles, PBO; grey triangles, ALO; black triangles, ALO/PIO. B. Eliasson et al. Diabetologia DOI 10.1007/s00125-011-2447-3

25 20 *** Glucagons (ng/L) ** 15 *** ** ** ** *** * 10 *** *** ** ** *** 5 Placebo ALO 25 mg ALO 25 mg +PIO 30 mg 0 -1 0 1 2 3 4 5 6 7 8 Time (h) Figure 4b. Mean ( ± SE) postprandial glucagon at week 16. P-values for the LS mean treatment difference compared with PBO: * <0.05, ** <0.01, *** <0.001. White triangles, PBO; grey triangles, ALO; black triangles, ALO/PIO. B. Eliasson et al. Diabetologia DOI 10.1007/s00125-011-2447-3

5 Placebo ALO 25 mg ALO 25 mg +PIO 30 mg 4 Triglycerides (mmol/L) *** 3 *** *** *** *** ** *** 2 ** *** *** *** *** 1 -1 0 1 2 3 4 5 6 7 8 Time (h) Figure 2a. Mean ( ± SE) postprandial triglycerides at week 16. P-values for the LS mean treatment difference compared with PBO: * <0.05, ** <0.01, *** <0.001. White triangles, PBO; grey triangles, ALO; black triangles, ALO/PIO. B. Eliasson et al. Diabetologia DOI 10.1007/s00125-011-2447-3