Controversies in Type 2 Diabetes Mellitus

Pratap Sagar Tiwari , Resident, Internal Medicine ,NGMC

Diabetes Mellitus• More than 220 million people worldwide have

diabetes.• In 2004, an estimated 3.4 million people died

from consequences of high blood sugar globally.• More than 80% of diabetes deaths occur in low-

and middle-income countries.• WHO projects that diabetes deaths will double

between 2005 and 2030• Type 2 diabetes comprises 90% of people with

diabetes around the world.

WHO ,Jan 2011 report

Weight Loss in Type 2 DM : Is it worth the effort ?

WHO standard classification of obesity1

BMI Risk of co-morbidities

Normal BMI 18.5-24.9 average

Overweight:    

Pre-obese 25.0-29.9 increased

Obesity class I 30.0-34.9 moderate

Obesity class II 35.0-39.9 severe

Obesity class III  40 very severe

1. Source: The Global Challenge of Obesity and the International Obesity Task Force http://www.iuns.org/features/obesity/tabfig.htm#Table 1

For Asian Population

Global Burden of Obesity1

• In 1995, there were an estimated 200 million obese adults worldwide.

• As of 2000, the number of obese adults has increased to over 300 million.

• In developing countries, it is estimated that over 115 million people suffer from obesity-related problems..

1. Source: http://www.who.int .

Growing epidemic of T2DM in relation to Obesity 1,2,3

1. Mokdad AH et al, Diabetes Care. 2000;23:1278-1283. 2. Mokdad et al. JAMA.1999;282:1519-1522. 3. Mokdad AH et al. JAMA .2001;286:1195-1200

Obesity : Risk factor for DM 1

• Objective :To estimate the prevalence of obesity and diabetes among US adults in 2001.

• Results In 2001 the prevalence of obesity (BMI ≥30) was 20.9% vs 19.8% in 2000, an increase of 5.6%.

• The prevalence of diabetes increased to 7.9% vs 7.3% in 2000, an increase of 8.2%.

• Overweight and obesity were significantly associated with diabetes, high blood pressure and high cholesterol.

• Compared with adults with normal weight, adults with a BMI of ≥40 had an odds ratio (OR) of 7.37 (95% confidence interval [CI], 6.39-8.50) for diagnosed diabetes, 6.38 (95% CI, 5.67-7.17) for high blood pressure, 1.88 (95% CI,1.67-2.13) for high cholesterol levels

1. Mokdad A, Ford E, Bowman B, Dietz W, Vinicor F, Bales V,Marks J. Prevalence of Obesity, Diabetes, and Obesity-Related Health Risk Factors. JAMA. 2003;289(1):76-79. doi: 10.1001/jama.289.1.76

• Can preventing or treating obesity decrease the incidence of T2 Diabetes ?

Diabetes Prevention program :a study 1

• Included 3234 overweight individuals (BMI > 24 kg/m2) with IGT.

• Average age : 51 yrs old• Method: . These participants were randomly assigned to

receive either intensive lifestyle intervention or therapy with Metformin (850 mg twice daily) or placebo.

• The intensive lifestyle intervention involved 16 individual sessions over 24 weeks

• The goals of the lifestyle intervention were to lose 7% of initial body weight, maintain this weight loss, and achieve at least 150 min/week of physical activity using activities that were similar in intensity to brisk walking.

1. Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine, 2002. 346(6): p. 393–403

Behavioral Weight-Loss Program• 16–24 treatment sessions over 6 months 1

• Group format of 10–20 members• Team of professionals (dietitians, exercise

physiologists, behaviorists)• Daily self-monitoring of calories, fat, and activity

(minutes or calories)• Calorie goal of 1,200–1,500 calories per day• Fat gram goal of 20% of calories coming from fat• Exercise goal of 1,000 cal per week (or 150

minutes) of moderate activity 2

1. Wing RR: Behavioral approaches to the treatment of obesity. In Handbook of Obesity. Bray G, Bouchard C, James PT, Eds. New York, Marcel Dekker, 1998, p. 855-73.

2. Pate RR, Pratt M, Blair SN, Haskell WL, Macera CA, Bouchard C, Buchner D, Ettinger W, Heath GW, King AC: Physical activity and public health: a recommendation from the Centers for Disease Control

and Prevention and the American College of Sports Medicine: ACSM's guidelines for exercise testing and prescription. JAMA 273:402-407, 1995.

Diabetes Prevention program :a study

• 50 % of lifestyle participants achieved the 7% wt loss goal at wk 24, and 38% achieved this goal at study end.

• The intervention was extremely effective in reducing the risk of diabetes. The crude incidence of DM was 11.0, 7.8, and 4.8 cases per 100-person year for placebo, metformin, and lifestyle, respectively.

• Thus, lifestyle intervention reduced the risk of diabetes by 58% compared with placebo, and metformin reduced the risk by 31%.

Look AHEAD Trials• Look AHEAD(Action for Health in Diabetes) is a

large clinical trial designed to determine whether long-term weight loss will improve glycemia and prevent CV events in T2DM.

One-year results of the intensive lifestyle intervention in this trial show

• an average 8.6% weight loss, • significant reduction of A1C, and • reduction in several CVD risk factors 1

• with benefits sustained at 4 years 2

1. Look AHEAD Research Group, Wing RR. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes:one-year results of the look AHEAD trial. Diabetes Care 2007;30:1374–13832. Look AHEAD Research Group, Wing RR: Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Arch Intern Med 2010;170:1566–1575

Successful Weight Loss in Individuals with DM ?

• In one study, 12 DM pt and their non-DM spouses were enrolled together in a behavioral weight loss program. Although patients and spouses were of similar age and wt, those with DM lost only 7.5 kg over 20 weeks, whereas their non-DM lost 13.4 kg .1

• In another comparison of 20 wn with T2DM and 23 non-DM wn treated together in a 16-wk behavioral weight loss program, initial wt losses were comparable (7.4 and 6.4 kg for diabetic and non-diabetic subjects, respectively), but at 1-year FU, those with DM maintained a wt loss of 2 kg, whereas the non-DM retained a wt loss of 5.4 kg .2

1. Wing, R.R., M.D. Marcus, L.H. Epstein, and R. Salata, Type II diabetic subjects lose less weight than their overweight nondiabetic spouses. Diabetes Care, 1987. 10: p. 563–566.2. Guare, J.C., R.R. Wing, and A. Grant, Comparison of obese NIDDM and nondiabetic women; short- and long-term weight loss. Obesity Research, 1995. 3(4): p. 329–335

Why diabetes may be less successful ?

• As glycemic control improves with weight loss, individuals with diabetes may have decreased excretion of calories in their urine, thereby reducing their weight loss.

• As diabetics in poor glycemic control have more elevated energy expenditure, this too may normalize with weight loss and improved glycemic control.

• Physical problems associated with diabetes, including neuropathy, may limit physical activity.

• Finally, many of the medications used to improve glycemic control, including SFU, TZD, and insulin, enhance anabolism and promote weight gain.

ADA 2011 :Recommendations• People with DM should be advised to perform at least 150

min/wk of moderate intensity aerobic physical activity.• In the absence of contraindications ,people with T2DM

should be encouraged to perform resistance training 3 times/week.

• Saturated fat intake < 7 % of total calories.• Alcohol :1 drink /d for women and 2 drink /d for men• Routine supplement with antioxidants is not

recommended.• Bariatric surgery may be considered in diabetes with BMI

>35 Kg/m2 if difficult to control with lifestyle and pharmacological therapy.

Source : American Diabetes Association Home Page Website: www.diabetes.org/

Treatment in T2 DM using Insulin

When to use ???..

• Traditionally, the requirement for insulin was seen as a “last resort,” once maximal combination oral agent therapy has failed and usually more than 10 years after the diagnosis of T2DM .1.

1. Rosenstock J, Wyne K. Insulin Treatment in Type 2 Diabetes. In: Goldstein BJ, Muller-Wieland D (Eds). Textbook of Type 2 Diabetes 2003, pp 131–154.

Why The need for earlier insulin replacement in T2 DM ?

Worldwide, the number of cases of diabetes is expected to increase exponentially, with current estimates suggesting an increase from around 170 million in 2000 to approximately 370 million persons by 2030 .1,2,3

1. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995–2025: prevalence, numerical estimates, and projections. Diabetes Care 21: 1414–1431, 1998.2. Green A, Hirsch NC, Pramming SK. The changing world demography of type 2 diabetes. Diabetes Metab Res Rev 19: 3–7, 2003.3. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 27: 1047–1053, 2004.

When should insulin be started ?

When should insulin be started in T2DM depends on two critical scenarios :1.Can early insulin therapy “rest” the b cell and preserve its function and integrity? 2.Is early insulin therapy needed to reach glycemic targets for cardioprotection?

Early Insulin Therapy and B cell preservation ???

• Evidence :1. B-cell dysfunction is a fundamental underlying genetic

abnormality in the pathogenesis of T2DM that cannot develop solely because of insulin resistance. Early b-Cell dysfunction is the key for the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and finally to T2DM .1

2. As insulin fails to suppress lipolysis, the increased concentrations of free fatty acids (FFAs) combined with progressive hyperglycemia act negatively on pancreatic b cells and insulin-sensitive tissues to further inhibit both insulin secretion and peripheral action .2

1. Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus.J Clin Invest 104: 787–794, 1999.2. McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 7–18, 2002.

• Evidence for B cell lossIn a study of pancreatic tissue from 124 autopsies, relative b-cell

volume, frequency of b-cell apoptosis, b- cell replication, and the formation of new islets from exocrine ducts were measured .1

I. Relative B-cell volume was decreased by 63 and 44% in both obese and lean persons with T2DM respectively, in comparison with healthy age- and weight-matched non-diabetic controls.

II. In addition, subjects with prediabetes also exhibited a 40% decreased relative b-cell volume, suggesting this is etiologically important in the development of T2DM due to a predominance of b-cell apoptosis, which was increased 10-fold in lean subjects and threefold in obese subjects with T2DM.

1. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased betacell apoptosis in humans with type 2 diabetes. Diabetes 52: 102–110, 2003.

• Early feature of pathogenesis : B cell loss• Glucotoxicity + lipotoxicity = ↑ B cell

apoptosis B cell dysfunction /b cell loss

Indeed, insulin therapy in T2DM can improve peripheral insulin action by correcting glucotoxicity and lipotoxicity and, by also inducing “b-cell rest,” can potentially enhance insulin secretion and thereby potentially reduce b-cell loss and/or preserve b-cell integrity.

Hypothesis :Early insulin replacement -resting the B cell

Short-term intensive insulin therapy studies performed over the period of 20 years that demonstrated improved insulin action and increased endogenous insulin secretion probably induced by reversing glucotoxicity and lipotoxicity .1

Israeli study : 2-week period of intensive insulin therapy. Once the intensive insulin therapy was stopped, most of the patients continued with sustained adequate glycemic control for long periods of time (9 to >50 months with a median of 26 months) without pharmacologic intervention to reduce blood glucose .2

2. Pratipanawatr T, Cusi K, Ngo P, Pratipanawatr W, Mandarino LJ, DeFronzo RA. Normalization of plasma glucose concentration by insulin therapy improves insulin-stimulated glycogen synthesis in type 2 diabetes. Diabetes 51: 462–468, 2002.22 Ilkova H, Glaser B, Tunckale A, Bagriacik N, Cerasi E. Induction of long-term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 20: 1353–6, 1997

Korean Study1

• 16-month Korean trial in 92 patients with T2DM of longer duration disease .

• Overall,34% of the patients went into “remission” that lasted an average of 14 months after 54 ± 39 days on intensive insulin therapy using an insulin pump.

• Note: The criteria for remission was sustained FPG of <108 mg/dL and PPG of <180 mg/dL .

• Result : Remission rates were higher when patients started intensive insulin therapy with a shorter diabetes duration (3.3 ± 3 years vs. 9.1 ± 4 years for the remission and non-remission groups, respectively; p < 0.001) ..

1. Park S, Choi SB. Induction of long-term normoglycemia without medication in Korean type 2 diabetes patients after continuous subcutaneous insulin infusion therapy. Diabetes Metab Res Rev 19: 124–130, 2003.

Early Insulin Therapy and Cardioprotection1

Epidemiological analysis of the UKPDS data showed a continuous association between the risk of CV complications and glycemia and showed that for each 1% decrease in HbA1c there were significant reductions in major DM-related endpoints, that is,• a 37% reduction in microvascular endpoints, •a significant 43% reduction in amputation or death from peripheral vascular disease, •a significant 14% reduction in combined fatal and non-fatal myocardial infarction.

1. Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321: 405–412,2000

ADA 2011 Current Recommendation:1

Currently, initiation of insulin therapy is generally considered only if the HbA1c level remains >7% despite maximized oral combination therapy.

1. Source : American Diabetes Association Home Page Website: www.diabetes.org/

Diabetes and Complications

• An association between the complications of diabetes and elevated blood glucose levels was postulated in the early part of this century.

• Some of these studies have also demonstrated that treatment that lowers blood glucose reduces the risks of diabetic retinopathy, nephropathy, and neuropathy..

University Group Diabetes Program (UGDP) study 1

• Result : showed no benefit of glycemic control in new-onset type 2 diabetic patients .

• However, in the UGDP, there were only 200 subjects in each treatment group.

• HbA1c was not available as a reliable method for measuring chronic glycemia, and

• The difference in glucose control between the most intensively treated group and the other treatment groups was only a fasting plasma glucose of 30 mg/dl (1.7 mmol/l). ∼

• Of note, a major concern emanating from the UGDP was the observation that the sulfonylurea agent (tolbutamide) and a biguanide (phenformin) used to reduce hyperglycemia were associated with increased cardiovascular mortality.

1. University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. Diabetes 19(Suppl. 2):747–830, 1970

Kumamoto Study1

• Subjects: 110 lean Japanese • Results :multiple insulin injections resulting in

better glycemic control (HbA1c = 7.1%) compared with conventional treatment (HbA1c = 9.4%) significantly reduced the microvascular complications of diabetes.

1. Ohkubo Y, Kishikawa H, Araki E, Miyata T, Isami S, Motoyoshi S, Kojima Y, Furuyoshi N, Shichiri M: Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study.Diabetes Res Clin Pract 28:103–117, 199

Veterans Affairs Diabetes Feasibility Trial 1

• Study randomized 153 men to intensive or conventional therapy .

• Despite a 2% absolute HbA1c difference in glycemic control between the two groups, the trial reported no significant difference in cardiovascular events in a follow-up period of only 27 months.

1. Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee HS: Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial: Veterans Affairs Cooperative Study on Glycemic Control and Complications in Type II Diabetes. Arch Intern Med 157:181–188, 199

The United Kingdom Prospective Diabetes Study (UKPDS) 1,2,3

• Subjects : 5,102 patients with newly diagnosed type 2 diabetes in 23 centers within the U.K. between 1977 and 1991.

• Patients were followed for an average of 10 years to determine 1. whether intensive use of pharmacological therapy to lower blood

glucose levels would result in clinical benefits 2. whether the use of various sulfonylurea drugs, the biguanide drug

metformin, or insulin have specific therapeutic advantages or disadvantages.

• In addition, patients with type 2 diabetes who were also hypertensive were randomized to “tight” or “less tight” blood pressure control to ascertain the benefits of lowering blood pressure.

1. UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 2. UK Prospective Diabetes Study Group: Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes (UKPDS 38). BMJ 317:703–713, 1998 3. UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing risk of both macrovascular and microvascular complications in type 2 diabetes (UKPDS 39). BMJ 317:713–720, 1998

Summary of the main results and conclusion of UKPDS

• Retinopathy, nephropathy, and possibly neuropathy are benefited by lowering blood glucose levels in T2DM with intensive therapy, which achieved a median HbA1c of 7.0% compared with conventional therapy with a median HbA1c of 7.9%. The overall microvascular complication rate was decreased by 25%.

• These results materially increase the evidence that hyperglycemia causes, or is the major contributor, to these complications.

Summary of the main results and conclusion of UKPDS

• Epidemiological analysis of the UKPDS data showed a continuous relationship between the risks of microvascular complications and glycemia, such that for every percentage decrease in HbAlc (e.g., 9 to 8%), there was a 25% reduction in diabetes-related deaths, a 7% reduction in all-cause mortality, and an 18% reduction in combined fatal and nonfatal myocardial infarction.

• The study showed that lowering blood pressure to a mean of 144/82 mmHg significantly reduced strokes, diabetes-related deaths, heart failure, microvascular complications, and visual loss.

Targets for HbA1c in patients with type 2 diabetes ???

ACCORD (Action to control Cardiovascular Risk in Diabetes) trial 1

• 10 251 middle aged and older participants with type 2 diabetes at high risk of cardiovascular disease events were randomised into a standard therapy group aiming for HbA1c 7.0–7.9% and an intensive control group aiming for HbA1c of <6% (normoglycemia).

• The primary outcome was first occurrence of nonfatal myocardial infarction, nonfatal stroke or cardiovascular death.

1. 1he ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(Suppl):211–33.

Higher mortality in intensive control arm of ACCORD

• Median HbA1c achieved in the intensive treatment group was 6.4% compared with 7.5% in the standard treatment group. 1

• A higher rate of mortality was noted in the intensive arm, with 257 deaths compared with 203 deaths in the standard arm.

• The NHLBI concluded that in patients with type 2 diabetes at especially high risk for heart disease, very intensive glucose lowering treatments aimed at normalising blood glucose to an HbA1c of <6% may be detrimental.

National Heart, Lung and Blood Institute. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, February 6, 2008. Available at www.nhlbi.nih.gov/health/prof/heart/other/accord/index.htm [Accessed March 2008].

ADA 2011 recommendation1

Perform the A1C test •at least 2 X Yr in patients who have stable glycemic control. •quarterly in patients whose therapy has changed or who are not meeting glycemic goals.A1C goal : < 7 %

1. Source : American Diabetes Association Home Page Website: www.diabetes.org/

Thankyou

References :•ADA 2011 Guideline.•http://www.who.int•Mokdad AH et al. JAMA .2001;286:1195-1200•Controversies In treating diabetes ;a clinical and research aspect by Derek LeRoith•American Diabetes Association Home Page Website: www.diabetes.org/•Control and Complications in Type II Diabetes. Arch Intern Med 157:181–188, 199•McGarry JD. Banting Lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51: 7–18, 2002.•Butler AE et al. Beta-cell deficit and increased betacell apoptosis in humans with type 2 diabetes. Diabetes 52: 102–110, 2003.•The ACCORD Study Group. Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: design and methods. Am J Cardiol 2007;99(Suppl):211–33.•Home PD et al.Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD): A Multicentre, Randomized, Open-Label Trial. Lancet 2009•UK Prospective Diabetes Study Group: Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865, 1998 •National Heart, Lung and Blood Institute. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Trial, February 6, 2008. Available at www.nhlbi.nih.gov/health/prof/heart/other/accord/index.htm [Accessed March 2008].•Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee HS: Cardiovascular events and correlates in the Veterans Affairs Diabetes Feasibility Trial: Veterans Affairs Cooperative Study on Glycemic Look AHEAD Research Group, Wing RR. Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes:one-year results of the look AHEAD trial. Diabetes Care 2007;30:1374–1383•Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. New England Journal of Medicine, 2002. 346(6): p. 393–403•www.emedicine.com

Special thanks to Dr Pradeep ,Resident ,Pediatrics for statistical help

Rosiglitazone and risk of myocardial infarction

???

Rosiglitazone and its risk

• Two recent independent meta-analyses – • 1st: including 42 trials involving 27 847 participants 1

• 2nd: including four trials involving 14 291 patients with at least 12 months of follow up 2 – found an increase in the risk of myocardial infarction associated with rosiglitazone.

• In both meta-analyses, participants given rosiglitazone for treatment or prevention of type 2 diabetes had an increase in the risk of myocardial infarction in the order of a 40% excess over controls. 1,2

1. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356:2457–71.2. Singh S, Loke YK and Furberg CD. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 2007;298:1189–95.

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) 1

• A Long Term, Randomised Study in Patients With T2DM, Comparing the Combination of Rosiglitazone and Either Metformin or SFU With Metformin Plus SFU on Cardiovascular Endpoints and Glycaemia”

• The primary outcome, cardiovascular hospitalization or CV death, occurred in 321 and 323 participants assigned to the rosiglitazone and metformin/SFU groups, respectively (HR, 0.99; 95% CI, 0.85-1.16).

• MI, and stroke was not significant (HR, 0.93; 95% CI, 0.74-1.15) for rosiglitazone vs metformin/SFU.

1. Home PD, Pocock SJ, Beck-Nielsen H et al. The Lancet 2009; 373:2125-2135

RECORD Study :summary 1

• The RECORD study suggests that rosiglitazone is probably safe and effective in carefully selected patients.

• As with all therapies, one must ask whether the risks are worth the benefits, and whether another available option might be the wiser choice .

1. Home PD et al.Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD): A Multicentre, Randomized, Open-Label Trial. Lancet 2009