Transcript Glycemic Control in Type II DM

Treatment of Type II DM: The
Current Model is Flawed
Richard Amerling, MD
Associate Professor of Clinical Medicine
Albert 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: 837-853
Effect 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
42
31
* 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 patients
Any DM
endpoint
(%)
Diabetes
deaths
(%)
All cause
mortality
(%)
MI (%)
Stroke
(%)
Microvasc
disease
(%)
Median
Hb A1c
(%)
Diet+metf
or
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/lowcalorie 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, energyrestricted diets in inducing weight loss for up to 1
year.”
Arch Intern Med. 2006 Feb 13;166(3):28593. 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 12month 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