Donna Mojdami, PGY-5

     Review the key physiologic aberrations defining T2DM Understand the underlying pathologic mechanisms of T2DM pathogenesis Understand the genetic elements of T2DM Examine the non-pharmacologic options in T2DM prevention and supporting evidence Review the data for pharmacologic preventative strategies

Insulin Resistance Type 2 Diabetes Mellitus Relative Impairment of Insulin Secretion Increased v Production

 Type 2 DM is a complex disease resulting from both environmental and genetic factors  The spectrum of disease presentation is very heterogeneous  The hyperglycemia resulting from T2DM itself can contribute to worsening disease state

  Remains the best predictor of T2DM Insulin sensitivity affected by a variety of factors including:  Age  Weight  Ethnicity  Body fat  Physical activity  Medications

Tabak, A.G. et al. Lancet 2009; 373:2215

 Worsening insulin resistance that occurs with weight and age may unmask a defect in insulin secretion leading to hyperglycemia

AND/OR

 Post fasting and post-glucose hyperinsulinemia predict future weight gain which predisposes to hyperglycemia

 Increased weight and lack of activity are striking features of those who develop T2DM UptoDate Accessed September 2011

Fujimoto WY, Bergstrom RW, Boyko EJ, et al. Susceptibility to development of central adiposity among populations. Obesity Res 1995;3(suppl 2):179S–186S

 Central adiposity more strongly linked with insulin resistance

Kahn SE, Prigeon RL, McCulloch DK, et al. Quantification of the relationship between insulin sensitivity and beta-cell function in human subjects: evidence for a hyperbolic function. Diabetes 1993;42:1663-1672.

 As adiposity increases total body insulin sensitivity decreases  Especially abdominal visceral fat  Effects are local and disseminated including reduced sensitivity in muscle and liver  Mediated through the effects of adipokines Kronenberg, H. et al. Williams Textbook of Endocrinology. 2007

 Signalling molecules secreted by adipocytes  Insulin sensitizing: adiponectin  Insulin resistant: TNF-α, IL-6, leptin, resistin  Can affect insulin sensitivity of other tissues  Affect post receptor signalling pathways  Production and secretion of adipokines regulated by adipocyte fat storage and insulin Kronenberg, H. et al. Williams Textbook of Endocrinology. 2007

  FFA levels are elevated in obese individuals and predict progression from IGT to DM Increases in FFA flux into muscle implicated in reduced muscle glucose uptake ( The Randle Hypothesis )  FFAs complete with glucose for oxidation  Rate limiting enzymes in glycolysis inhibited  Glucose accumulates intracellularly and further glucose uptake reduced Kronenberg, H. et al. Williams Textbook of Endocrinology. 2007

 Increased FFAs and adipokines from adipose tissue recruit and activate macrophages  Cytokines e.g. TNF-α, IL-6 decrease insulin sensitivity and promote release of pro inflammatory mediators from adipocytes  Similar mechanism believed to play a role in muscle, liver and contributes to β cell destruction Kronenberg, H. et al. Williams Textbook of Endocrinology. 2007

 Those with insulin resistance who develop T2DM have a concurrent defect in β cell compensatory response  While those with obesity & no T2DM have increase cell mass, individuals with T2DM have reduced β cell mass

 Possible mechanisms of β cell loss  Genetic differences in the mechanisms that drive cell expansion  Ectopic fat deposition in islets  Obesity-induced inflammation  Effect of adipokines

FFAs Adipose Tissue Grundy Nature Reviews Drug Discovery 5, 295–306 (April 2006) | doi:10.1038/nrd2005

    Prevalence of disease varies greatly amongst ethnic groups living in the same region  e.g. Aboriginal Canadians 39% of T2DM patients have at least one parent with the disease In monozygotic twins, when one is affected the other will develop T2DM 90% of the time The lifetime risk for a 1 without family history st -degree relative is 5-10X higher than age- and weight-matched controls Kronenberg, H. et al. Williams Textbook of Endocrinology. 2007

 Both monogenic and polygenic forms exist  The polygenic forms by far outweigh the monogenic types  To date 19 loci have been linked to T2DM  Majority of these loci independently make a very small contribution to diabetes risk

UptoDate Accessed September 2011

  Transcription Factors  Transcription factor 7-like 2 gene (TCF7L2)  Associated with the highest risk of T2DM  Controls insulin release  Heterozygotes RR T2DM 1.45

 Homozygotes RR T2DM 2.41

Grant, S.F. et al. Nature Genetics 2006; 38:320  insulin promoter factor-1 (IPF-1/PDX-1) – MODY4  Mutations prevent binding of protein to insulin gene  Glucokinase gene – MODY2 Acts as glucose sensor in beta cell controlling insulin secretion

  Peroxisome-proliferator-activated receptor (PPAR) gamma 2  Plays role in adipocyte differentiation  Polymorphisms may influence differences in body mass and insulin sensitivity Hepatocyte nuclear factors 4-alpha, 1-alpha, and 1-beta     Transcription factors controlling expression of proteins involved in glucose transport etc.

HNF 4-alpha  MODY1 HNF 1-alpha  HNF 1-beta  MODY3 MODY5

 Lifestyle Approach  Diet  Exercise  Weight loss  Pharmacologic Therapies  Metformin  TZDs  Alpha-glucosidase inhibitors  Orlistat  Inhibition of angiotensin II  Estrogen therapy

 Systematic review examining the role of diet ALONE in T2DM prevention  5 relevant RCTs were identified and reviewed based on two large trials  The DaQing IGT and Diabetes Study (Diabetes Care, 1997)  The Oslo Diet and Exercise Study (Diabetes Care, 1997) Nield L, Summerbell CD, Hooper L, Whittaker V, Moore H. Dietary advice for the prevention of type 2 diabetes mellitus in adults. Cochrane Database of Systematic Reviews 2008, Issue 3.

 Both trials utilized diets with  Reduced energy intake and simple sugars  Increased fruit and vegetable intake  Frequent support by dietary advisors  Every 3-6 months

 The Oslo Diet and Exercise Study found significant changes in variables at 1-year including  Insulin resistance   Fasting insulin (-7 ± 4 vs. 4 ± 6 pmol/L) Blood glucose (-0.2 ± 0.1 vs. 0.0 ± 0.1 mmol/L)  Plasma  Lipid profile  Weight (-6.8 ± 19.5 vs. 1.1 ± 13.8 kg)  BMI (-1.3 ± 0.2 vs. 0.4 ± 0.1 kg/m²)

 Da Qing IGT and Diabetes Study found a reduction of 33% in the incidence of diabetes at 6 years  Based on 2-hr plasma BG >11.1 mmol/L  Incidence of T2DM per 100 person-years  Diet group 10.0 (95% CI 7.5 to 12.5)  Control group 15.7 (95% CI 12.7 to 18.7)

Dietary Advice for the Prevention of Type 2 Diabetes Mellitus in Adults  Authors’ Conclusions:  Energy-controlled diets with reduced simple sugars and increased fruits & vegetables minimize the risk factors associated with development T2DM  An over-riding factor is the frequent support and guidance of dietary advisors  More well-designed long term studies needed

 RCT examining the effects of low-fat diet on the incidence of T2DM  Without exercise or weight loss goals  48, 835 healthy, post-menopausal subjects ages 50-79 years Tinker, L.F. et al. Arch Int Med 2008; 168:1500

• After 8 years no difference in incidence of self reported DM • Incidence 7% in each group, HR 0.96

 Diet alone is not a significant contributor to T2DM prevention  Weight loss in the setting of dietary changes may be a bigger contributor  Diet plays an important role in overall lifestyle interventions

 Systematic review of 10 prospective cohort studies examining moderate-intensity physical activity and T2DM  Exercise defined as activity of moderate intensity including walking  3-6 METs per hour  Activities included bicycling (>20 min/d), gardening (>20 min/d), brisk walking (max 2.5h/wk) Jeon, C.Y. et al. Diabetes Care 2007; 30:744

• BMI-adjusted RR 0.83 (17% decrease in risk) A 30% Decrease in Risk

(for walking) • BMI-adjusted RR 0.83

 Moderately intense physical activity confers significant reduction in the risk of T2DM  A risk reduction is observed even if no weight loss is achieved (~ 17% risk reduction)

    RCT examining the effects of a weight reduction strategy in reducing risk of T2DM in those with IGT 522 overweight subjects, majority females, mean age 55 years Intervention included  Weight reduction 5%  Reduction in total fat intake to <30% of energy consumed  Saturated fat <10% total energy intake   Fiber intake ≥ 15g per 1000 kcal Moderate exercise at least 30 min/d Intervention subjects received guidance on diet and exercise Tuomilehto, J. et al. NEJM 2001; 344:1343

  T2DM diagnosed at 1-year in 86 subjects  27 intervention group  59 control group Absolute incidence of T2DM  Intervention: 32 cases per 1000 patient-years  Control: 78 cases per 1000 patient-years

 Effect of lifestyle intervention persisted 3 years after end of study  No further intervention provided during 3 year follow up period  36% reduction in incidence during 3-year follow-up (vs. 58% during study period)

   Evaluated the potential for a lifestyle-intervention program or metformin to delay or prevent onset of T2DM in at-risk subjects RCT of 3234 overweight subjects with IFG or IGT Intensive Lifestyle Intervention  Weight reduction of ≥ 7%  Low calorie, low fat diet  Moderate intensity activity ≥ 150 min/wk  Case managers providing long term individual and group sessions Knowler, W.C. et al. NEJM 2002; 346:393

Intervention • Metformin 850mg bid • Standard lifestyle recommendations • Placebo • Standard lifestyle recommendations • Intensive lifestyle modification

• Weight loss averages • Placebo 0.1 kg • Metformin 2.1 kg • Lifestyle intervention 5.6 kg

• Crude Incidence of T2DM (per 100 person-years) • Placebo 11 cases • Metformin 7.8 cases • Lifestyle intervention 4.8 cases

 Glycemic changes  Similar reduction in mean FPG in first year between metformin and lifestyle intervention groups  – 6 mg/dL in metformin, lifestyle intervention groups  + 1 mg/dL in placebo group  Lifestyle intervention more effective in restoring normal post oral load PG

Diet Exercise 577 Subjects with IGT randomly assigned Interventions Diet + Exercise Control

 Diet Protocol  Non-obese  25-30 kcal/kg  55-65% CHOs, 10-15% protein, 25-30% fat  Reduce intake of simple sugars, alcohol, increase vegetable intake  Obese  Individual dietary goals set to achieve weight loss 0.5-1 kg per month to goal BMI 23  Both groups received individual and group counselling

 Exercise protocol  Participants encouraged to increase activity by 1 unit daily

 Reduction in incidence rates compared to control  Diet-only 33%  Exercise-only 47%  Diet + exercise 38%

 The benefit of dietary modification derives more from its effect on weight reduction  Physical activity reduces incidence of diabetes regardless of weight loss  Intensive lifestyle interventions involving dietary and activity modification along with weight loss is the most effective

    Diets should focus on calorie-restriction, limiting simple sugars and increasing fruit and vegetable intake Exercise should be at least of moderate intensity (3-6 mets) at least 20 min per day Weight loss should be at least 5% of baseline weight The value of longterm counselling and follow-up should not be overlooked

 Major effect to reduce hepatic glucose output in the presence of insulin  Additional effects in improving glucose utilization by liver and muscle especially post meals

 The DPP showed that metformin is effective in reducing risk of T2DM in those with IGT Diabetes Prevention Research Group. NEJM 2002; 346:393  Incidence of T2DM 31% lower than placebo, crude incidence 7.8 cases per 100 person-years  But remains less effective than lifestyle intervention  Beneficial particularly in young, obese subjects especially women with history GDM

 Meta analysis of randomized trials examining T2DM risk reduction with metformin in high risk subjects  Pooled results of 31 trials and 4570 participants

• Metformin decreased new onset T2DM by 60%, OR 0.6

 Benefits also seen in  BMI reduction by 5.3% compared to placebo or no treatment  Improved calculated insulin resistance (HOMA-IR)  Reduction of 23% compared to control

 Primary Effects  Improve glucose utilization by muscle  Decrease hepatic glucose production  Increase insulin secretion  Mediate effects through PPARs which regulate gene expression

 Several TZDs have been evaluated for their impact on reducing T2DM risk  Rosiglitazone  Pioglitazone  Troglitazone

 Evaluated rosiglitazone 8mg daily to delay or prevent T2DM in 5269 subjects with IFG and/or IGT  Patients followed for median 3 years  Primary outcome composite of incident diabetes or death DREAM Investigators. Lancet 2006; 368:1096

• 60% risk reduction compared to placebo

 Interestingly associated with an increase in weight  2.2 kg more in the rosiglitazone group than placebo  Majority of weight gain in the hips resulting in lower waist-to-hip ratio

 TRIPOD Study – Troglitazone Diabetes 2002; 51:2796 Buchanan, T.A. et al.  T2DM prevention in 300 women with history GDM for median 30 mo  Annual incidence DM 5.4 vs. 12.1% (placebo)  Removed from market due to hepatic dysfunction and failure

 ACT-NOW Study – Pioglitazone NEJM 2011; 364:1104 DeFronzo, R.A. et al.  600 subjects with IGT and ≥1 components metabolic syndrome  Diabetes developed 5.0 vs. 16.7% (placebo) at median 2.4 years  Weight gain and edema more frequent in treatment arm  No difference in incidence of cardiovascular events

 Inhibit the alpha-glucosidase enzymes in the upper GI tract  Convert complex carbohydrates into simple sugars  Inhibitors slow absorption of glucose and slow post-prandial BG increase  Both acarbose and vogibose have been studied for preventing onset T2DM

 Randomized trial of acarbose 100mg tid vs. placebo in 714 subjects with IGT  Primary outcome development of T2DM on yearly OGTT Chiasson, J.L. et al. Lancet 2002; 359:2072

• Absolute reduction in risk of 8.7% compared to placebo based on two • abnormal OGTTs Risk reduction present even after adjustment for weight reduction

 Treatment with acarbose also improved weight  0.5 kg weight loss on acarbose vs. 0.3 kg weight gain on placebo  Treatment increased probability of reversion to normal glucose tolerance over time  19% in treatment arm withdrew because of GI side effects (vs. 5% in control arm)

 Pancreatic lipase inhibitor  Inhibits complete hydrolysis of fats into constituents thereby increasing fecal fat excretion  Used in weight loss and weight management

 Lifestyle changes along with placebo or orlistat compared in obese subjects with normal or impaired glucose tolerance  Diagnosis of T2DM made with single abnormal 2h OGTT  Patients followed over 4 years  Primary endpoints  Time to onset of T2DM  Change in body weight Torgerson, J.L. et al. Diabetes Care 2004; 27:155

• Cumulative incidence rates of 6.2 vs. 9% (all patients) over 4 years and 18.8 vs. 28.8% (IGT patients)

 In subjects with normal glucose tolerance progression rate to T2DM very low and insufficient to detect statistically significant difference

   Present data suggests weak effect of ACEi’s and ARBs in preventing diabetes Initial data suggesting benefit derived from trials where T2DM development not a primary endpoint (cardiovascular trials) Potential mechanism may involve  Increased insulin sensitivity  Protective effect on pancreas via increased blood flow Carlsson, P.O. et al. Diabetologia 1998; 41:127

  DREAM Study Bosch, J. et al. NEJM 2006; 355:1551  Ramipril 15mg/d at median 3 years did not significantly decrease the incidence of T2DM  17.1 vs. 18.5% (placebo), HR 0.91

NAVIGATOR Trial McMurray, J.J. et al. NEJM 2010; 362:1477  Subjects with IGT and ≥ 1 risk factors for CVD  Valsartan (160mg/d) with all patients receiving lifestyle intervention  Median follow-up 5 years, T2DM developed 33 vs. 37% (placebo) (significant)

 The Heart and Estrogen/Progestin Replacement Study (HERS) Kanaya, A.M. Ann Intern Med 2003; 138:1  Secondary CHD prevention trial in post-menopausal women  Post hoc analysis of 2029 subjects with normal or impaired glucose tolerance over 4.1 years  Cumulative incidence T2DM 6.2% for combined estrogen/progestin vs. 9.5% for placebo

 Women's Health Initiative combined estrogen progestin trial Margolis, K.L. et al. Diabetologia 2004; 47:1175  Evaluated combined estrogen-progestin therapy in 15,600 post-menopausal women from WHI  After 5.6 years cumulative incidence treated DM 3.5% (combo treatment) vs. 4.2% (placebo)

 Metformin and thiazolidinediones most efficacious in reducing risk of T2DM  Some agents also have additional benefit of reversing IGT (TZDs, alpha glucosidase inhibitors)  Many available agents limited by side-effects and safety  Acarbose, orlistat, TZDs, estrogen

 In those with IGT, structured program of lifestyle modification including moderate weight loss & regular physical activity recommended  In those with IGT, pharmacologic therapy with  Metformin or alpha glucosidase inhibitor should be considered  TZD to be considered in those with IGT/IFG and no history CVD

 Patients with IGT, IFG or HbA1c 5.7-6.4% should be referred to support program targeting  Weight loss 7% body weight  Moderate activity 150 min/wk  Follow-up counselling is important for success  Consider metformin for prevention in those at highest risk especially those who show progression of hyperglycemia

 T2DM is a complex, heterogeneous disease  Both environment and genetics contribute to pathogenesis  Insulin resistance is the best predictor of T2DM onset  Adiposity and inflammation play key roles in insulin resistance and β cell damage

 19 candidate gene loci have been identified  TCF7L2 polymorphism confers the highest risk for T2DM  Intensive lifestyle modification including diet, physical activity and weight loss most efficacious in T2DM prevention  Metformin is the most effective and safest of pharmacologic options for prevention