Treatment of Type II DM: The Current Model is Flawed

Richard Amerling, MDAssociate Professor of Clinical MedicineAlbert Einstein College of Medicine

What’s Wrong with our Current Treatment Paradigm? Based largely on experience with Type I

DM Overly focused on glycemic control In Type I DM, hyperglycemia is the disease In Type II DM, hyperglycemia is a symptom Most patients with Type II DM in the US

have metabolic syndrome and obesity Most drug treatment of hyperglycemia

worsens obesity

Case Study: James G 1997: 57 yr. old Bl man

BP 170/100; Wt: 239 lbs. Naldolol 40, amlodipine 2.5, modiuretic Glucose 113; normal BUN/creat

2003: Now 63 years old BP 226/110; Wt: 236 lbs Amlodipine 10, naldolol 120, HCTZ/triamterene Glucose 415; HbA1C 13.8; Chol 315, LDL 210;

Uprot/creat 1.0; 25 OH D <7; aldo 24; renin <2

How would you proceed?

Type I DM: Pathophysiology

Genetic susceptibility to Type I DM

Autoantibodies: ICAs

Target autoantigens in type 1 diabetes mellitus

Glutamic acid decarboxylase Insulin and proinsulin Glycolipids, ganglioside GT3 Carboxypeptidase H, PM-1 polar antigen Islet cell proteins of varying size and unknown function - 37 or 40 kD, 38 kD, 52 kD, 69 kD Peripherin Heat shock protein 65 Insulin receptor Endocrine cell antigens Cytoskeletal proteins - tubulin, actin, reticulin Nuclear antigens - single-stranded DNA and RNA

Type II DM: Pathophysiology

Type II DM: Pathophysiology

Type II DM Trials

UGDP (1970) Showed increased mortality in group

taking sulfonylureas UKPDS (1988) ACCORD (2008) ENHANCE (2008) VADT (2009)

UKPDS: Overview 20 year study 23 Centers Over 5000 patients recruited Aim: to determine the effect of

intensive blood glucose control with sulphonylureas, insulin, or metformin on 21 predetermined clinical end points.

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) Lancet 1998; 352: 854-865

UKPDS: Effect of 10 years' treatment with chlorpropamide, glibenclamide, or insulin on patients with newly diagnosed type 2 diabetes (McCormack: BMJ 2000;320:1720-1723)

Any DM endpoint (%)*

Microvascular disease (%)

Individual macro endpoints**

Median HbA1C

Diet + Ch, Gl, or insulin

35.3 8.2 No signif diff between

Ch 6.7, Gl 7.2, insulin 7.1

Diet only 38.5 10.6 groups for any

7.9

Rel risk reduct

8.2 22.6 individual

Abs risk reduct

3.2 2.4 endpoint***

NNT 10/1 31 42

* Sudden death, death from hyperglycaemia or hypoglycaemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation, vitreous haemorrhage, retinal photocoagulation, blindness in one eye, cataract extraction.**Deaths related to diabetes, all cause mortality, myocardial infarction, stroke, blindness, renal failure, or neurological events.***P value for myocardial infarctions was 0.052 (dietary advice plus drug treatment 14.2% v dietary advice 16.3%). However, because the study was continued after the initial results showed no differences, a breakpoint for significance of 0.05 is debatable.§ 2.7% of this 3.2% was due to a significant reduction in retinal photocoagulation.

UKPDS: Obese patientsAny DM endpoint (%)

Diabetes deaths (%)

All cause mortality (%)

MI (%) Stroke (%)

Microvasc disease (%)

Median Hb A1c (%)

Diet+metfor

28.7 8.2 14.6 11.4 3.5 7.0 7.4

Diet +ch, gl, insulin

36.8 10.8 20.0 14.6 6.3 7.8 All sim met

Diet only

38.9 13.4 21.7 17.8 5.6 9.2 8.0

Rel risk red (met v diet)

26.2 38.8 32.7 36.0 44.4 NS Sig low

Abs risk red (met v diet)

10.2 5.2 7.1 6.4 2.8 NS

NNT 10/1 (met v diet)

10 19 14 16 36 NS

McCormack: BMJ 2000;320:1720-1723

UKPDS: Complications

“The UK prospective diabetes study 33 suggests that the drugs used were well tolerated, although only hypoglycaemic events and weight gain were reported. Nevertheless, participants in the sulphonylurea and insulin groups gained a mean of 3.1 kg more weight than the diet alone group. Major hypoglycaemic episodes (those requiring third party help) occurred in 0.1%, 0.6%, 0.6%, and 2.3% of participants per year in the diet, chlorpropamide, glibenclamide, and insulin groups respectively (note that benefit was expressed over 10 years). The incidence of minor hypoglycaemic events was 1%, 11%, 18%, and 37% per year, respectively.”

McCormack: BMJ 2000;320:1720-1723

UKPDS: Conclusions (1) “Contrary to expectations, treatment with

sulphonylureas and insulin had no significant benefit on the occurrence of microvascular or macrovascular end points over 10 years in this obese population. Metformin also produced significant reductions in the aggregated diabetes related end points, all cause mortality, and stroke compared with the sulphonylureas and insulin.”

“With regard to the results of these two trials, one message seems to have been lost from many of the commentaries on the UK prospective diabetes study. That is, patients with type 2 diabetes seem to benefit not so much from the overall control of glucose but rather from taking metformin.”

McCormack: BMJ 2000;320:1720-1723

UKPDS: Conclusions (2)

“…it is not known whether reducing the Hb A1c … leads to an improved outcome. To establish a causal relation between a surrogate marker and a clinical outcome, it must be shown that a dose-response relation exists---that is, that a consistent, progressive clinical benefit is seen with progressive reductions in the surrogate marker. In the UKPDS, changes in Hb A1c produced by drug treatment did not seem to correlate with treatment outcomes.”

“In study 33 an absolute reduction of 1% in Hb A1c was observed with chlorpropamide, glibenclamide, or insulin over 10 years compared with diet alone; yet there was virtually no significant reduction in macrovascular outcomes.”

“In study 34, all the drugs produced similar mean absolute differences in HbA1c over the 10 years compared with diet alone, but only metformin produced significant reductions in clinically important macrovascular events.”

McCormack: BMJ 2000;320:1720-1723

UKPDS: Conclusions (3)

“Not only did metformin reduce clinically important events compared with diet alone, it also produced reductions in some outcomes compared with other glucose lowering drugs. This shows that the studies in question were large enough, and of sufficient duration, to show macrovascular benefits.”

“ Clinicians and patients need to be aware of this and consider that either metformin may be conferring benefit independent of, or in addition to, blood glucose reduction, or that sulphonylureas and insulin may have an adverse effect on overall risk.”

McCormack: BMJ 2000;320:1720-1723

The case against aggressive treatment of type 2 diabetes: critique of the UKPDS RM Ewart; BMJ VOLUME 323 13 OCTOBER 2001

Endpoints kept changing Study unblinded Subgroup analysis changed Length of follow up continued to

expand Results not clinically significant

ACCORD Trial

Randomized trial, >10,000 patients, to target glycated Hb of 8.1% vs. 6.0%

No difference in primary outcome (composite non-fatal MI or stroke, CV death)

Higher mortality in intensive group led to study termination

Hypoglycemia and weight gain>10 kg more frequent in intensive Rx group

ACCORD Data (1)

ACCORD Data (2)

ACCORD Data (3)

ACCORD Data (4)

ACCORD Data (5)

ACCORD: Conclusions

Intensive Rx group had relative increase in mortality of 22%

Study not designed to test components

“…if there is any benefit associated with intensive glucose lowering, it may take several years to emerge, during which time there is an increased risk of death.”

ADVANCE Trial

Randomized prospective study, >11,000 pts.

Intensive Rx group: glycated Hb <6.5%, use of gliclazide plus other drugs

Primary endpoints included macro and microvascular events

Overall “positive” outcome resulted from 20% relative reduction in incidence of nephropathy (4.1% vs. 5.2%)

ADVANCE Endpoints

Macro: CV Deaths, nonfatal MI or stroke

Micro: New or worsened nephropathy (microalbuminuria, doubling creatinine, RRT, death from renal disease, retinopathy

ADVANCE Baseline

ADVANCE: Results

ADVANCE Results

ADVANCE: Results

ADVANCE: Comment Most of micro benefit due to decreased

development of macroalbuminuria (2.9 vs. 4.1%, p<0.001)

No effect on doubling of Screat No change in retinopathy BP significantly lower in intensive Rx group More hospitalizations in intensive Rx group More hypoglycemia: 150 severe events vs.

81 in standard group. 53% vs 38% over study

VADT Trial

Randomized, prospective, study of 1791 veterans poorly controlled with type 2 DM to intensive vs. standard glycemic control

High baseline incidence of CV disease and long duration of DM

Intensive goal was absolute decrease of 1.5% for glycated Hb.

Primary outcome: Time to 1st occurrence of CV event

VADT Methods and Outcomes Primary outcome: Time to any of a

composite of CV events: MI, stroke, CV death, new or worsened CHF, CV or vascular surgery including amputation for gangrene.

Microvascular: Nephropathy, retinopathy and neuropathy all evaluated and tracked

VADT Medication protocol

BMI>27: metformin and rosiglitazone BMI<27: glimepiride and

rosiglitazone Insulin added to intensive group pts

who did not achieve glycated Hb<6% and in standard group pts with level <9%

VADT Results

No significant difference in any component of primary outcome or in overall death rate

No difference in microvascular complications

Higher adverse event rate in intensive group

VADT Results

VADT Results

VADT Microvascular

A Rational Approach to DM II Therapy aimed at metabolic syndrome Primary goal should be weight

reduction Low carbohydrate diet is key Eliminate HFCS Regular exercise: Walking is best Metformin Permissive hyperglycemia and

glycosuria

Low Carb Diets: Data

Systematic review of randomized controlled trials of low-carbohydrate vs. low-fat/low-calorie diets in the management of obesity and its comorbidities “Evidence … demonstrates that low-

carbohydrate/high-protein diets are more effective at 6 months and are as effective, if not more, as low-fat diets in reducing weight and cardiovascular disease risk up to 1 year.” Obes Rev. 2009 Jan;10(1):36-

50. Hession, et al.

Low Carb Diets: Data

Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. “Triglyceride and high-density lipoprotein

cholesterol values changed more favorably in individuals assigned to low-carbohydrate diets”

“Low-carbohydrate, non-energy-restricted diets appear to be at least as effective as low-fat, energy-restricted diets in inducing weight loss for up to 1 year.”

Arch Intern Med. 2006 Feb 13;166(3):285-93. Nordman, et al

Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial.

Weight loss was greater for women in the Atkins diet group compared with the other diet groups at 12 months, and mean 12-month weight loss was significantly different between the Atkins and Zone diets (P<.05). Mean 12-month weight loss was as follows: Atkins, -4.7 kg (95% confidence interval [CI], -6.3 to -3.1 kg), Zone, -1.6 kg (95% CI, -2.8 to -0.4 kg), LEARN, -2.6 kg (-3.8 to -1.3 kg), and Ornish, -2.2 kg (-3.6 to -0.8 kg).

At 12 months, secondary outcomes (low-density lipoprotein, high-density lipoprotein, and non-high-density lipoprotein cholesterol, and triglyceride levels), for the Atkins group were comparable with or more favorable than the other diet groups.

Gardiner, et al. JAMA. 2007 Mar 7;297(9):969-77

Follow up: James G

Treated with low carb diet, exercise Naldolol to carvedilol, added

eplerenone, ergocalciferol, telmisartan, atorvastatin

Metformin 1 g BID started 2007: Wt down to 202; BP 140/70

LDL 61 HDL 69; HbA1C 5.0; Umicroalb 3.1; 25-OH D 42

Off metformin since 2006

Treatment of Type II DM

In most patients, weight reduction should be primary goal

Diet (low carb), exercise are mainstay Short term permissive hyperglycemia Metformin is drug of choice; serious side

effects are very rare Insulin only for documented insulin

deficiency Newer agents: Use with caution! SGLT2 inhibitors: A promising alternative