Banting Medal for Scientific Achievement
Award Dr. Philipp E. Scherer
The Multifaceted Roles of Adipose Tissue—Therapeutic
Targets for Diabetes and Beyond
• Adiponectin or a adipocyte-derived factor can be:
– Anti-apoptotic (Cardiac Myocytes, Beta cells, Podocytes)
– Pro-angiogenic
– Anti-atherogenic
– Anti-inflammatory
– Pro-adipogenic
– Cause improvements in hepatic insulin sensitivity
– Improve wound healing
Similarities and differences between ADA and
AHA Lipid guidelines by Dr Robert H Eckel
• Dr Robert Eckel reiterated that the ACC/AHA and ADA are in agreement for most
of the recommendations
• The ADA also endorse the statin recommendations of ACC/AHA
Following are some of the differences
• ASCVD risk calculator is not endorsed as it was not adequately tested
• Screening
– At time of diagnosis
– Initial medical evaluation
– Age 40 and periodically (1-2 years)
Highlights
• Treatment
– Lifestyle
•
•
•
•
Decrease saturated fat, trans fat and cholesterol
Omega-3 fatty acids, viscous fiber, plant sterols/stanols
Weight loss (if indicated)
Increase physical activity
• Lifestyle (intensive) and optimise glucose control for increased TG
(≥ 150 mg/dl and/or HDL <40 mg/dl (men) and <50 mg/dl
(women)
• To consider agents beyond statins like fibrates especially for TG
Lipid management in T2DM
By Jennifer G. Robinson
• Maximize statin therapy
• Manage other risk factors
• When considering adding non-statin therapy
– High risk patients
– Maximize statin therapy and lifestyle first
– Use of nonstatins shown to reduce ASCVD events when added to statins
– In completely statin intolerant patients, use of nonstatins shown to
reduce ASCVD events as monotherapy
(Niacin, gemfibrozil, fenofibrate, bile acid sequestrants if TG <300 mg/dl)
New Concepts and treatments of Diabetic
Dyslipidemia
• Epidemiologic, experimental and genetic studies implicate TG-rich lipoproteins
& HDL in the pathogenesis of atherosclerotic CVD
• In the post statin era RCTs have failed to show a significant CVD benefit with TG
lowering or HDL raising treatment
• In the case of fibrates and fish oil there is evidence that individuals with
hypertriglyceridemia and/or low HDL-c may benefit
• Therapies targeting HDL should focus on improved function rather than
alterations in static levels
•
More effective therapies including those that target the underlying pathophysiology of
diabetic dyslipidemia are needed
•
RCTs need to be conducted in this patient population to adequately test that hypothesis
Anti-anginal drug Ranolazine Safely Lowers
HbA1c in Diabetic Patientsby Dr Robert H Eckel
• Phase 3 trial to determine the safety and effectiveness of ranolazine for
glycemic control
• T2DM patients with a baseline HbA1c level ranging from 7% to 10%
– Arm 1: Ranolazine 1000 mg twice daily (n=465)
– Arm 2: Ranolazine with Glimepiride (n= 215)
• Ranolazine monotherapy reduced HbA1c levels 0.56% compared with placebo
by 24 weeks
• Fasting plasma glucose levels were also significantly reduced in the ranolazinetreatment arm
Highlights
•
At week 12: 50% increase in the number of patients who achieved an HbA1c <7% with
ranolazine
•
A significant reduction in fasting and 3-hour postprandial glucagon levels
•
In another arm, patients were treated with glimepiride 4 mg
•
The addition of ranolazine reduced HbA1c levels 0.5% compared with placebo at 24
weeks with reduction in FPG
•
Nearly twice as many patients in the glimepiride/ranolazine arm achieved HbA1c levels
<7% compared with the glimepiride only arm
•
When ranolazine was added to metformin, however, there was no effect on HbA1c levels
•
This effect was seen as metformin dose was halved in the arm in which it was used in
combination with ranolazine
•
This was done as ranolazine decreases the renal clearance of metformin
Triple therapy improves glycemia in type 1
diabetes by Dr. Nitesh D. Kuhadiya
• A retrospective analysis of 10 patients on CGMS treated with
insulin, liraglutide and dapagliflozin
• At baseline, patients had been receiving liraglutide added to insulin
therapy for 11 months
• Mean HbA1c, 8%; mean age, 56 years; mean age of diabetes
diagnosis, 29 years; mean BMI: 29 kg/m2
• Dapagliflozin 5 mg daily was added at baseline and increased to 10
mg at 1 week
Highlights
• At the end of 12 weeks of triple therapy, reductions were seen in
• Mean hba1c (0.66%, p = 0.0004)
• Mean glucose level (28 mg/dl, P = 0.016)
• Mean body weight (2 kg, P = 0.02)
• Mean BMI (1 kg/m2, P = 0.02)
• Total insulin dose was 0.7 u/kg daily and was unchanged from baseline
• An 11% increase in time spent in the target glycemic range of 70 mg/dL
to 160 mg/dL was seen
• While time spent with glycemic levels greater than 160 mg/dL decreased
by 13% (P < .05 for both)
• No additional hypoglycemia was observed (< 70 mg/dL)
Dulaglutide Provides Greater Blood Sugar
Reduction as Compared to Liraglutide
• Phase 3, randomized, parallel-arm, placebo-controlled, 52-week study
• Comparison of safety and efficacy of once-weekly dulaglutide 0.75 mg to oncedaily liraglutide 0.9 mg
• Conducted in 487 Japanese T2DM patients with average baseline A1C of 8.1%,
• Primary objective: To evaluate whether dulaglutide 0.75 mg was superior to
placebo in reducing A1C from baseline at 26 weeks
• A comparison of dulaglutide and liraglutide at 26 and 52 weeks was also done
• Patients initially assigned to placebo were switched to dulaglutide 0.75 mg at 26
weeks for the remainder of the trial
Highlights
• At 52 weeks, dulaglutide 0.75 mg demonstrated statistically greater A1C
reductions compared to liraglutide 0.9 mg (-1.39 percent vs. -1.19 percent)
• Dulaglutide 0.75 mg provided statistically greater reductions in the average selfmonitored blood glucose levels compared to liraglutide 0.9 mg (-53.1 mg/dL vs. -
46.8 mg/dL)
• Dulaglutide 0.75 mg significantly lowered average post-meal blood glucose levels
from baseline compared to liraglutide 0.9 mg (-63.7 mg/dL vs. -55.4 mg/dL)
• Mean body weight did not change in either treatment group and both agemts
were well-tolerated in the study
Canagliflozin + Metformin XR Superior to
Either monotherapy
• Phase 3, 26-week study, 1,186 T2DM patients inadequately
controlled with diet and exercise randomized to
• Canagliflozin 100 mg in combination with metformin XR (median
2,000mg/day)
• Canagliflozin 300 mg in combination with metformin XR
• Canagliflozin 100 mg
• Canagliflozin 300 mg
• Metformin XR
Highlights
• Both Cana + Met group: statistically superior HbA1C reductions
(-1.77 and -1.78, respectively) vs. patients receiving either
canagliflozin 100mg (-1.30), 300mg (-1.37) , or metformin XR (1.42) alone
• Patients taking canagliflozin in combination with metformin XR
also had a significant reduction in weight compared to patients
treated with metformin XR alone
Real-World Data on Canagliflozin in
Managed Care Setting
• To describe the characteristics, treatment utilization, and outcomes of
patients treated with canagliflozin in the real world within the first 6 months
of it being commercially available
• Retrospective cohort study from Optum Research Database (ORD) involving
3234 patients
• Cana 100 mg (N=2141), Cana300 mg (N=1093)
•
Patients treated with canagliflozin when first available in the US typically had poorly
controlled HbA1c levels at baseline and had received multiple prior
antihyperglycemic agents
•
Following the first canagliflozin claim, they had an improvement in HbA1c levels and
used fewer antihyperglycemic agents
Highlights
Impact of Canagliflozin Added on to Insulin and
Metformin in Type 2 Diabetes: A Substudy of the
CANVAS Trial
• Substudy of CANVAS
• 432 patients with T2DM at high risk of CVD with a mean age of
61 years & mean A1C of 8.2%
• All patients were taking an insulin dose of at least 30 IU/day and
a metformin dose of at least 2000 mg/day
• The study group’s mean FPG was 166 mg/dL, the mean BMI was
34.9 kg/m2, and the mean insulin dose was 93 IU per day
Highlights
• Compared with the 146 patients taking placebo, A1C went down
significantly for patients at both the 100 mg and 300 mg doses
• All 3 groups started with a mean baseline A1C of 8.2%
• A1C level for placebo group went up by 0.03%
• A1C for the group taking 100 mg went down by 0.64%
• A1C for group taking 300 mg went down 0.79%
• Both doses of canagliflozin produced better results for FPG,
body weight, and SBP than metformin and insulin alone
Intranasal ‘Puff’ of Glucagon May Safely,
Effectively Treat Hypoglycemia by Dr Jennifer
Lynn Sherr
• 45 pediatric T1DM patients received either IM or intranasal (IN)
glucagon at 7 centres
• The two youngest cohorts (4-<8; 8-<12 yrs) were randomized to one
IM or two IN administrations
• Oldest group (n=12, 12-<17 yrs): Received either 1 mg of IM glucagon
or 3 mg intranasal glucagon in randomized crossover manner
• Glucagon was administered 5 minutes after their blood glucose was
lowered to <80 mg/dL
Highlights
• A sharp rise in glucose was observed in all age groups following either
IM or IN dosing
• Nausea (with or without vomiting) occurred with 67% of IM sessions
v.s 42% of IN sessions
Novel Combination therapy IDegLira for
T2DM by Prof. John Buse
• 26-week, phase III study compared the efficacy and safety of IDegLira
vs. insulin glargine (IG) in T2DM uncontrolled on IG (20-50U)
• Adults (n=557, A1c 7-10%) were randomized to either once-daily
IDegLira or continued IG uptitration, both + metformin
• Initial doses were 16 dose steps (16U IDeg + 0.6 mg Lira) for IDegLira
(maximum 50 dose steps) and pre-trial dose for IG (mean 32U; no
maximum).
•
Fasting self-measured blood glucose titration target was 71-90 mg/dL
for both arms
Highlights
• Mean A1c decreased from 8.4 to 6.6% (IDegLira) and from 8.2 to 7.1% (IG)
(p<0.001)
• Mean fasting plasma glucose decreased similarly in both arms from 160 to
110 mg/dL
• Weight decreased from 88.3 to 86.9kg (IDegLira) and increased from 87.3 to
89.1kg (IG) (p<0.001)
• More subjects achieved the composite endpoints with IDegLira vs. IG
• IDegLira was superior to IG in A1c reduction, risk of hypoglycemia and weight
change
• IDegLira offers clinical advantages over IG in intensifying therapy while
minimising insulin dose requirements, in subjects uncontrolled on IG
Bihormonal Bionic Pancreas Effective in
Patients across various age & BMI ranges
• Results of a comparative trial in 19 children (aged
6–11 years) with type 1 diabetes attending a
diabetes summer camp were consolidated with
past data
• Glucose regulation by automated bihormonal
(insulin and glucagon) bionic pancreas was
compared with insulin pump therapy under
medical supervision for 5 days each
• The children chose their own meals and
participated in all camp activities
• Both groups of preadolescents were monitored
remotely for severe hypoglycemia
Highlights
• After 24 hours of autonomous adaptation, the bionic pancreas
• Produced a lower mean continuous glucose level compared with the
insulin pump (138 ± 11 vs 168 ± 30 mg/dL; P < .001)
 Less time spent <60 mg/dL (1.2% vs 2.8%; P < .001)
 More time between 70 to 180 mg/dL (80.6% vs 57.6%; P < .001)
 Less time spent >180 mg/dL (16.5% vs 36.3%; P < .001)
• Hypoglycemia requiring oral carbohydrates was observed less frequently
in children with the bionic pancreas compared with children with the
insulin pump (once per 1.1 vs 1.8 days; P = .04)
Using technology for better outcomes
• Need for standardisation of CGM reports as there are different CGM
devices producing different reports
• A standard report for CGM based on Expert Panel Input was suggested
i.e. Ambulatory Glucose Profile (AGP)
• Based on the research at the International Diabetes Centre (IDC) AGP
has been developed as a novel way to address data interpretation
• Glucose data, collected over several days or weeks, are analysed as if
they occurred within a single 24 hour period and plotted in a series of
bands around the median
• AGP is designed to be quick to generate and easy to interpret
Highlights
Conclusion
• Data drives improvement
– Use of SMBG and CGM data is associated with improved HbA1c values and
positive behavior change
• Presentation of data impacts use
– Consistent definitions and visual display
• A standard glucose report improves ease of use, interpretation,
clinical and behavioral decision-making
– Ambulatory glucose profile (AGP) is a standard glucose report
A game as a tool for continuing
medical education
• 135 primary-care physicians (including 52 residents) were randomized in
southern Brazil to receive education about insulin therapy from
– The game (70 physicians) or
– From traditional instruction (65 physicians)
• The physicians replied to a questionnaire to assess their baseline
knowledge, skills, attitudes, and satisfaction
• Those who were randomized to the "game group" played the
InsuOnLine game, which included patient-case scenarios, on their
computers, at their own speed
Highlights
• The physicians in the control group attended 3 to 4 hours of
traditional lectures with clinical-case discussions
• The content of the game and the lectures was similar and based
on guideline recommendations for insulin therapy
• The primary outcome was insulin-prescribing skills and knowledge,
as measured by a questionnaire
• Secondary outcomes were beliefs about insulin and satisfaction
with the activities
Highlights
• The mean insulin-therapy-knowledge score (% of right answers) improved
from 52% at baseline to 85% after the traditional education (P < .001), and
to 92% after the game-based education (P < .001)
• The mean improved score was higher in the group that received gamebased education than in the group that received traditional education
• Almost all the participants (96%) found that the game was fun
• Most participants considered the game to be more effective than
attending a lecture to learn about insulin therapy
Low Vitamin D Levels Common in
Painful Diabetic Neuropathy
• 45 T2DM patients — 17 with painful neuropathy, 14 with painless neuropathy,
and 14 with no neuropathy — along with 14 healthy volunteers
• All had vitamin D levels measured between May and September and answered
questionnaires to assess sunlight exposure and neuropathy symptoms
• They also underwent detailed clinical, neurophysiological, and lower-limb skin
intra-epidermal nerve-fiber density (IENFD) assessments
• They were divided into three groups based on the Neuropathy Impairment Score
of the Lower Limb (NIS-LL) and the Douleur Neuropathique 4 (DN4)
Highlights
• After adjustment for age, BMI, and sunlight exposure, vitamin D levels were
significantly lower in the painful-neuropathy group, at 34.34 nmol/L vs
– 53.22 for painless neuropathy
– 50.00 for no neuropathy
– 64.95 for the healthy volunteers (P = .01)
• Main group differences were significant between painful and painless neuropathy
(P = .02) and painful neuropathy vs healthy controls (P = .002)
• There was a significant positive correlation between vitamin D levels and sunlight
exposure (P = .003)
Diabetics Develop HF Sooner and Die Younger
After HF: Fremantle Diabetes Study by Dr
Timothy Davis
• Community-based, observational study involving 1296 T2DM
patients and followed for an average of 12 years
• Mean age: 64 years, and duration of diabetes: 4 years
• 8.6% of subjects had a prior hospitalization for heart failure
• Of the 1185 individuals without HF at baseline, 31.8% were
hospitalized for HF or died from HF during the follow-up period
• T2DM patients were > 2 times more likely to develop HF (HR:
2.36) during the 12-year follow-up
Highlights
In conclusion
• Diabetic patients have their first heart-failure event 4 to 5 years
before individuals without diabetes
• Diabetic patients die 4 years earlier after their heart-failure event
• 30% of type 2 diabetics went on to develop or die from heart
failure
Sulfonylureas does not increase the risk of
all-cause or cardiovascular mortality
• A meta-analysis
• 47 randomized, controlled clinical trials (>52 weeks duration)
involving 37,650 patients in this latest meta-analysis
• Overall, the use of a SU as first-line or second-line therapy was not
associated with an increased risk of total mortality (odds ratio [OR]
1.12; 95% CI 0.96–1.30) or cardiovascular mortality (OR 1.12; 95%
CI 0.87–1.52)
• Similarly, there was no significant association with sulfonylurea use
and the risk of MI or stroke
TECOS: No CVD Risks or Heart Failure With Sitagliptin in
High-Risk Diabetic Patients by Dr Eric Peterson
• TECOS: Trial Evaluating Cardiovascular Outcomes with Sitagliptin
• 14,671 patients with T2DM and established CVD randomized to
sitagliptin or placebo on top of their existing therapy
• Baseline HbA1c: ranging from 6.5% to 8.0%
• Mean duration of diabetes: 11.6 years
• Primary end point: cardiovascular death, nonfatal MI, nonfatal stroke,
or hospitalization for unstable angina
• Secondary end point: first confirmed event of cardiovascular death,
nonfatal myocardial infarction, or nonfatal stroke
Highlights
Outcome
Sitagliptin Placebo
Hazard ratio (95% CI)
(n=7332) (n=7339)
Primary outcome (cardiovascular
death, nonfatal MI, nonfatal
stroke, or unstable angina)
11.4
11.6
0.98 (0.89–1.08)
Cardiovascular death, nonfatal MI,
or nonfatal stroke
10.2
10.2
0.99 (0.89–1.10)
Cardiovascular death
5.2
5.0
1.03 (0.89–1.19)
Hospitalization for unstable angina
1.6
1.8
0.90 (0.70–1.16)
Fatal or nonfatal MI
4.1
4.3
0.95 (0.81–1.11)
Fatal or nonfatal stroke
2.4
2.5
0.97 (0.79–1.19)
Hospitalization for heart failure
3.1
3.1
1.00 (0.83–1.20)
Hospitalization for heart failure or
cardiovascular death
7.3
7.2
1.02 (0.90–1.15)
Highlights: Kaplan–Meier Curves for Primary and Secondary
Outcomes
Among patients with T2DM and established CVD, adding sitagliptin to usual
care did not appear to increase the risk of major adverse cardiovascular
events, hospitalization for heart failure, or other adverse events
“Real World” effect of weight loss in T2DM:
Why WAIT study
• 129 obese patients with type 2 diabetes who took part in the Why WAIT (Weight
Achievement and Intensive Treatment)
• Participants were provided with
– Structured menus of 1500 calories/day for women and 1800 calories/per
day for men
– A progressive, gradual, balanced, individualized exercise plan
• Participants were switched to antihyperglycemic medications that cause weight
loss or do not affect weight
• At the end of the 12-week program: Weight loss of 9.7%
• Average HbA1c dropped from 7.5% to 6.5%, & medication use fell by 50% to 60%
•
After 1 year, the patients were divided into 2 groups, based on their weight loss:
– Group A (n=61): Patients who not maintained a weight loss of at least 7%
– Group B (n=68): Patients who had maintained this level of weight loss
•
After 5 years in Group A:
– Patients maintained a weight loss of 3.5%
– Mean HbA1c levels decreased to 6.7% at 12 weeks and then increased to 7.7% at 1
year and 8.0% at 5 years
•
After 5 years in Group B:
– Patients had lost 9.0% of their initial weight
– Mean HbA1c levels decreased to 6.49% at 12 weeks, and increased, but to a lesser
extent, to 6.8% at 1 year and 7.3% at 5 years
– increased to 7.7% at 1 year and 8.0% at 5 years
In conclusion, weight loss when maintained results in durable A1c
lowering in T2DM at 5 years
Thank You