The Diabetes Corner

Automated Insulin Pump update

3 “smart pumps” are currently available: the Medtronic 670G, the Tandem Basal IQ and the Tandem Control IQ.

All are semi-closed loop systems which adjust basal rates, but require input regarding bolus dosing.

Although the Medtronic 670G is the most frequently prescribed smart pump, it’s my least favorite.

Problems include Guardian sensor inaccuracies, frequent pump requests for BG testing, inability to adjust BG alerts, and user unfriendly software.

This had led to high dissatisfaction among users, with one study reporting a 40% discontinuation rate in children.

Tandem’s Basal IQ pump adjusts basal insulin rates via an algorithm that predicts glucose levels 30 minutes ahead to avoid hypoglycemia.

Insulin delivery is suspended from 5 minutes to 2 hours if the predicted glucose is <80 mg/dl or if the reading is <70 mg/dl.

Clinical trials report a 30% reduction in hypoglycemia.

https://www.tandemdiabetes.com/providers/products/basal-iq

Tandem’s Control IQ adjusts basal insulin rates to increase time in range (TIR) to the goal 70-180 mg/dl.

Glucose levels are predicted 30 minutes ahead, using the Dexcom G6, with subsequent insulin adjustments

https://www.tandemdiabetes.com/products/t-slim-x2-landing-page-g6?gclid=EAIaIQobChMI8bWEv4Tx6gIVqtSzCh2eVQb_EAAYASAAEgKuQPD_BwE

User satisfaction is high.

Other upcoming systems include Medtronic’s 780G and an updated Tandem Control IQ, both of which will include automatic correction boluses, as well as the Omnipod Horizon paired with the Dexcom G6.

Closed loop pumps, which will automate basal and bolus rates include a new pump from Lily, as well as closed loop pumps from Tidepool, Beta Bionics, CamDiab and BigFoot.

These are good links to an overview of what’s on the horizon

https://uscdiabetes.com/closedloop.html

https://diatribe.org/tandems-control-iq-hybrid-closed-loop-algorithm-submitted-fda

I'll update as more information becomes available.

Is CGM a good option in people with T2DM? Review of debate at the 2020 ADA

This was an interesting debate between Dr Athena Philis-Tsimikas from the Scripps Clinic arguing for CGM, and Dr Elbert Huang from U Chicago, arguing against.

Dr Philis reviewed restrictions imposed by Medicare on CGM use.

The person must have T1 or T2, must test BG at least 4x daily, must be treated with multiple daily injections (MDI) or a pump (CSII,) must frequently adjust their insulin, and must have been seen within 6 months.

The requirements must be documented by the ordering physician every 6 months.

Dr Philis discussed how time consuming it is to document this in every note, as well as complete the CGM form again and again.

I agree, 100%.

She asked us to consider what would happen if Medicare eased restrictions.

This would allow us to discuss CGM early in the course of diabetes, before a person required MDI or CSI.

Dr Philis reviewed 6 studies: Yoo 2008, Allen 2008, Ernhardt 2011, Vigersky 2012, Bailey and Cox 2016.

In these studies, people with T2DM were treated with basal insulin (Ernhardt and Vigersky), or orals and non-insulin injectables (Allen and Cox),

Bailey studied people with early DM and prediabetes.

Each group showed A1c reductions averaging 1% after 8-12 weeks of intermittent CGM use when compared with controls testing via FS.

None of the studies included people treated with MDI or CSII.

In the 2012 Vigersky study, published in Diabetes Care, improvements in glycemic control persisted at 40 weeks, well after CGM use was stopped. These improvements occurred in the absence of medication adjustments.

The authors postulated that CGM use led to positive behavioral changes.

“Feedback impacts behavior”.

Anecdotally, I’ve seen this frequently within my practice.

In the counterpoint, Dr Huang presented sobering economic arguments against CGM.

Medicare spending for DM and DM related complications has increased 3-fold while the population has doubled.

Costs are expected to continue their rapid rise due to escalating insulin prices (3-fold increase from 2002 to 2013) and an obesity epidemic which has been worse than predicted in the US.

“This is not sustainable”.

Dr Huang referenced the DIaMonD study (Annals 2017) in which CGM use resulted in an A1c reduction of 0.6% compared to FS controls after 24 weeks.

The cost was $5336 with CGM vs $3118 with conventional FS testing.

The differential was due to the cost of the CGM.

He noted another study where CGM reduced the HA1c by 0.5% at a cost differential of ~ $4000.

He mentioned that people with T2 will have to balance the cost of CGM with the potential benefit.

He discussed that given COVID related economic hardship, this could mean choosing between fresh food or medications vs CGM.

Dr Huang concluded that CGM costs will need to decrease significantly to become a cost effective option in people with T2.

 

The Endocrine Society 2020 Position Statement on Insulin Affordability

https://www.endocrine.org/advocacy/position-statements/increasing-insulin-affordability#

 

Kidney Disease in Diabetes: Presentation by Dr Katherine Tuttle at 2020 ADA

This was an excellent overview of chronic kidney disease (CKD) in people with diabetes.

Dr Tuttle emphasized that 10% of people with CKD die of kidney failure (ESKD). 

90% of people with CKD die of other causes.

50% die due to heart disease (CVD). This is especially relevant when considering new drug classes such as the SGLT2's.

CVD risk is people with CKD is often overlooked.

50% of people with CKD die due to infections. 

The increased susceptibility and the high rate of death due to infections is especially relevant in the time of COVID.

Dr Tuttle reviewed original studies on the kidney protective effects of ACE inhibitors (RENAAL) and ARB’s (IDNT).

RENAAL (NEJM 2001) reported a 16% reduction in progression to ESKD in subjects treated with losartan compared with those treated with placebo.

IDNT (NEJM 20011) reported as 20% reduction in progression to ESKD in subjects treated with irbesartan compared with placebo or amlodipine.

Death rates weren't reduced in either trial.

In both studies, a large residual risk remained.

The ADA recommendations regarding BP treatment were reviewed.

BP medications are recommended if the BP is greater than 140/90.

The treatment start is reduced to 130/80 if there is more than 30 mg of microabuminuria.

ACE or ARB’s were suggested for kidney protection, irregardless of the BP, if there is more than 30-300 mg micoalbuminuria.

The 2001 ACE and ARB kidney trials were compared with the more recent SGLT2 trials: EMPA-REG, CREEDENCE and DAPA.

All reported reduced risk of heart failure and major CV events: heart attack, stroke, CV death.

The importance of this in a population where CVD accounts for such a significant proportion of deaths was emphasized.

Empagliflozin was also shown to reduced CV death.

Significant kidney benefits were also described.

Kidney function was stabilized, irrespective of the dose used.

Benefits were seen in people with eGFR’s which ranged from 30-90 ml/min.

CREEDENCE was the first kidney study EVER stopped early because of efficacy.

It should also be noted that the benefits occurred in a population where 99% of the subject were already using an ACE or ARB!

Link to a more in-depth review of the SGLT2's: http://www.thediabetesdoc.com/sglt2-inhibitors

The GLP-1’s have also been shown to reduce the decline of eGFR.

GLP-1 link: http://www.thediabetesdoc.com/incretins

 

Single vs Dual Hormone Insulin Pumps: Summary of presentation by Dr Roman Hovarka at the 2020 ADA

This was an excellent review of closed loop insulin pumps using insulin (single hormone) with those using insulin paired with glucagon or pramlintide (dual hormone).

Closed loop means the pump’s insulin delivery is paired with, and constantly adjusted by, a continuous glucose monitor. 

A closed loop pump is also known as an Artificial Pancreas.

The goal of each system is to keep the time in range (TIR, 70-180 mg/dl) > 70% and the time below range (TBR, <70 mg/dl) <3%.

There are 44 single hormone (Insulin) closed loop pump studies underway.

There are 3 insulin-glucagon-pramlinitide insulin pump trials,  2 insulin glucagon pumps trials and 1 insulin pramlinitide trial.

Dr Hovarka reviewed the single hormone Tandem Control-IQ closed loop insulin pump study.

It’s the longest (6 months) and largest (112 people) randomized controlled clinical trial (RCT) of a closed loop system.

People with T1DM aged 14 years and older were randomized to the Tandem closed loop pump or a traditional Tandem insulin pump.

With the Control IQ closed loop pump, TIR increased 11%.

TBR dropped to 0.9%.

The mean BG dropped 13 mg/dl.

The HA1c dropped 0.3%.

Benefits were seen within 1-4 weeks, and were sustained for the duration of the study.

A much shorter RCT, conducted at Cambridge University, studied 86 people with T1 for 12 weeks.

TIR increased 11%, TBR decreased 0.8%, mean BG reduced 14 mg/dl and the HA1c dropped 0.4%.

Challenges of the insulin only closed loops included delayed insulin absorption and action, accounting for the impact of exercise, controlling post prandial glucose elevations, missed boluses, covering large meals, and unexplained glucose variability.

Data from dual hormone pump studies was also reviewed.

The longest dual hormone RCT was an 11 day trial comparing an insulin and glucagon pump with a traditional insulin pump in people with T1DM 18 years and older. 

TIR increased 16.5%, TBR decreased 2.7% and mean BG levels dropped 2.7%.

He also discussed a 24-hour study that compared an insulin-pramlintide closed loop with a traditional insulin pump.

The insulin-pramlintide closed loop pump group noted an 11% increase in TIR with no change in TBR The greatest impact was on post-prandial BG levels.

Daytime hypoglycemia, especially a/w exercise, was reduced in both studies.

Disadvantages of dual hormone systems include the complexity a/w dual chamber pumps, added costs associated with a second hormone and additional pump supplies, the need for two cannulas,  concern regarding glucagon stability at room temperatures, unknown biologic risks of chronic glucagon/pramlinitide use, and the absence of any long term trials

Concern was also raised that insulin can always “override” glucagon and pramlintide if given in sufficient quantity.

The review suggests that single hormone insulin pumps are appropriate for most people with T1.

The pumps are significantly less complex than dual hormone systems and likely much less expensive.

They will prevent or eliminate nighttime hypoglycemia and prevent severe hypoglycemia.

They provide comparative benefits regarding TIR and HA1c reductions with significantly less complexity compared with dual hormone systems.

Dual hormone pumps may be most advantageous in those especially prone to hypoglycemia.

8 head-to-head trials are underway, with one in press.

These trials will provide more information going forward regarding which pump makes the most sense for each person.

 

The Legacy Effect in Diabetes: Summary of presentations by Drs John Lachin and Rury Holman at the 2020 ADA

Both physicians reviewed two classic studies from the 90’s: the DCCTT (1441 people with T1) and the UKPDS (5102 newly diagnosed with T2).

Long term follow-up of both trials was also discussed.

Dr Lachin focused on the DCCT.

In that trial, 1441 people with T1 diabetes from 1-15 years duration were randomized to conventional therapy (HA1c masked, no BG targets, 1-2 injections per day) or intensive therapy (HA1 known, goals near normal HA1c, treated with MDI or CSII). Study duration was 10 years.

At trial conclusion, the average HA1c was 9% in the conventional group, and 7% in the intensive group.

The intensively treated group had a 63% reduction in eye disease progression, a 39% reduction in microalbuminuria and a 54% reduction in macroabluminuria.

Severe eye disease, laster treatment and other endpoints were likewise improved.

Changes didn't appear until year 4 of the study.

Statistical analysis showed that 95% of the difference in outcomes was due to a reduction in HA1c.

In EDIC, participants were followed for 8 years after the DCCT conclusion in 1993.

During that time, medication oversight was transitioned from trial endocrinologists to PCP’s.

Within 1 year, A1C levels in both groups were identical. 

There was no difference in therapy, as most phsycians intensified treatment regimens based on the DCCT's startling conclusions.

Despite similar HA1c levels and treatments, subjects treated intensively during the DCCT, continuned to have signficantly better outcomes 8 years later.

Better outcomes included a 47% reduction in cumulative risk for proliferative eye disease, a 45% reduction in risk for progression to microablumniuria, and a 30% cumulative risk reduction for progression to macroalbuminura (>300 mg).

The continued benefit of early intensive therapy, despite equivalent levels os subsequent glycemic control, was ascribed to “Metabolic Memory”.

Dr Holman reviewed the UKPDS, a  20-year trial of 5102 people with newly diagnosed type 2 diabetes.

An intensive group was treated with monotherapy (any available) to a goal FBG of <110 mg/dl.

The control group was treated with diet only to the lowest fasting glucose possible.

Rescue therapy was offered if fasting glucoses were 270 mg/dl or higher.

Due to liberal guidelines for rescue, most subjects remained on monotherapy.

At trial end, the HA1c in the intensive treated group was 7%.

The HA1c was 7.9% in the conventional group.

Despite the relatively small difference, there was a 12% reduction in any diabetes endpoint, a 21% reduction in diabetes eye disease, and a 33% reduction in diabetes kidney disease.

Although heart attack risk was reduced 16% with intensive control, this didn’t reach statistical significance.

Later trials reached similar conclusions with a 15% reduction in diabetes endpoints a/w improved glycemic control.

95% of study participants continued in post-trial monitoring for an additional 10 years.

Study meds and HA1c levels were similar in the intensive and control groups within 1 year of the UPKDS trial end.

There were continued risk reduction, some of which increased, in the group that was intensively managed in the UKPDS

Examples of follow-up during the subsequent 10 years were provided.

There was a 25% risk reduction in microvascular disase with intensive control during the UKPDS.

10 years later, despite the same meds and same HA1c as the original control group, there was a 24% reduction in new microvascular disease.

The intial reduction in heart attack risk of 16% in the UKPDS just missed statistical significance with intensive control.

10 years later, the original intensive group showed a significant improvement at 15%.

All cause mortality  was reduced 6% with intensive control in the UKPDS. This didn't reach statistical significance.

10 years later, the reduction was statistically significant at 13%, presumably due to a reduction in deaths due to heart attacks.

Benefits from an initial period of tight glucose control persisted, and in some cases, improved, despite subsequent worsening of glucose control in people with type 2.

This was labeled “The Legacy Effect”.

Dr Holman also reviewed the Metformin arm of the UKPDS.

753 people with >120% IBW were randomized to either metformin (intensive therapy) or diet alone (conventional therapy).

Results were even more impressive.

There was a 32% risk reduction for any diabetes endpoint, a 39% reduction in heart attacks, and a 36% reduction in all cause mortality.

Microvascular disease risk was reduced 29%, but didn't achieve statistical signficance.

A legacy effect was also seen in this group at 10 years.

There was  a 21% reduction in risk for any diabetes enpoint, a 33% reduction in heart attack risk and a 27% reduction in all cause mortality despite 10 years of the same HA1c and the same post study meds.

A similar finding was not observed in the intensive BP portion of the trial.

Dr Holman ended his presenstation with a mathematical model of a 50 year-old man with newly diagnosed diabetes and an HA1c of 8%

If his A1 remained at 8% for 10 years, but then reduced to 7% for 10 years, he would reduce his risk of death by 6.6%.

If his A1 was instead immediately reduced to 7%, and maintained at that level, the risk reduction for death was increased 3-fold to 18.6%.

Both speakers concluded with the recommendation to manage glucose levels proactively, rather than reactively.

 

Heart Failure and Diabetes: Summary of 2020 ADA presentation by Drs Connelly and McMurray

Another excellent presentation.

Heart failure (HF) is a common, progressive disease in people with T2DM. Up to 1 in 5 people with T2DM will develop.

The associated mortality rate is 50% within 5 years of diagnosis, higher than prostate cancer or breast cancer.

Dr C emphasized that HF a syndrome due to structural and/or functional changes.

It can occur with preserved Ejection Fraction (HFp) or reduced Ejection Fraction (HFr).

A normal EF, determined by ECHO is >53%. People with HFp have EF’s of 50% or greater. People with HFr have EF’s of <40%.

60% of HF diagnoses are due to coronary artery disease (CAD).

The Canadian Cardiology Society recommends a cardiac ECHO and B-NP blood test in assessment.

https://my.clevelandclinic.org/health/diagnostics/16814-nt-prob-type-natriuretic-peptide-bnp

HFp accounts for 50% of HF. The mortality risk is the same as with HFr.

While 2/3 of people with HFp die due to CV disease, 80% with HFr die due to CV disease

People with T2DM are at increased risk of HF.

DM is considered a major risk factor.

The UKPDS suggested that for every 1% increase in the A1c, HF risk increased 8%

The most common cause of HF in people with type 2 DM is CAD.

The need for early diagnosis was emphasized.

When questioned whether all people with T2 should be screened, Dr Connelly said no.

He suggested instead that screening be reserved for those with suggestive history such as shortness of breath with exertion.

Dr McMurray reviewed diabetes drug trials which assessed HF.

There have been 5 DPP-4 cardiovascular outcome trials (CVOTs)

Except for the SAVOR trial (saxagliptin with an increased risk of HFh), all drugs in this class were neutral.

He mentioned his surprise that despite a lack of CV benefit, the DPP-4's are the most commonly prescribed new diabetes drug class in the US.

I agree!

He reviewed 7 GLP-1 CVOT trials.

Although all showed significant reductions in risk of MI, CV death and stroke, their impact on HF didn’t reach clinical significance.

There are many more upcoming trials of this drug class pending, including some at our site.

I reviewed both drug classes on this page: http://www.thediabetesdoc.com/incretins

He reviewed 4 SGLT2 CVOT trials.

All (Jardiance, Invokana and Farxiga) showed a major reduction in HF hospitalizations, as well as reductions in MI and CV death.

He mentioned reduced morbidity and mortality in people with type 2 DM and kidney disease when treated with the SGLT2’s.

I reviewed this drug class on this page: http://www.thediabetesdoc.com/sglt2-inhibitors

He commented on the lack of data re HF risk reduction with metformin, the sulfonylureas, insulin, the DPP-4’s and the GLP-1’s.

He reviewed the DAPA-HF trial.

It reported a significant 26% reduction in CV death and HF hospitalizations in people with and without diabetes who were treated with Farxiga. Improvements were seen quickly.

He concluded that there is overwhelming evidence the SGLT2’s reduce the risk of HF hospitalization in people with T2 diabetes.

The drugs can be used to treat, as well as prevent, HF.

Given the frequency of HF in people with T2DM, as well as siginficant associated morbidity and mortality, consideration should be given to the SGLT2's in anybody with T2 diabetes.

 

Can Technology eliminate hypoglycemia? Summary of Dr Richard Berganstal's presentation at 2020 ADA

This was part of a debate about the role of technology, specifically continuous glucose monitors (CGMs), in the prevention of hypoglycemia.

Results from the International Hypoglycemia Study Group which linked severe hypoglycemia with a significantly increased risk of death from any cause and CVD were reviewed.

Dr Bergental suggested that CGM minimized the “ripple effect” of hypoglycemia, in addition to identifying BG patterns.

He compared the accuracy of CGMs, which have an average MARD (the mean absolute relative difference) of 9%, with a 2017 study of 17 BG meters with MARDs that ranged from 5.6% to 20.8%. 9 of the meters studies had MARDs >10%.

The most accurate BG meters, in order were the Contour Next > One Touch VerioIQ > Freestyle Freedom Lite > AccuCheck Nano > AccuCheck Aviva Plus > Freestyle Lite. 

A study which included 60 million BG tests via FS and Flash CGM from Europe was reviewed.

Increased frequency of BG testing resulted in less hypoglycemia and less hyperglycemia. Benefits were observed in people with T1 and T2 DM

Somewhat surpsingly, hypoglycemia was reduced by 43% when flash CGM (the Libre) was substituted for FS testing.

Another study reported a 72% reduction in hypoglycemia with substitution of flash CGM for FS testing.

The presentation ended with a review of “smart” insulin pump studies.

   Low Glucose Suspend Pumps reduced hypoglycemia by 38% (NEJM 2013)

   Predictive Low Glucose Suspend Pumps reduced hypoglycemia by 59% (DC 2017)

   Closed Loop Pumps reduced hypoglycemia by 100% (JAMA 2016, NEJM 2019)

The presentation was a strong argument for CGM therapy in people with type 1 and 2 diabetes.

Please give me a call if you'd like to discuss any of the above.

 

Cardiovascular Outcome Trials (CVOTs) in Type 2 Diabetes: Should they be continued? 

This is a summary of presentations by Drs Sanjay Paul, Milton Packer, Steve Nissen, Ann Nevar and others on June 12, 2020 during the first day of the 2020 ADA Virtual Conference.

In 2008, the FDA instituted guidelines that mandated all new diabetes drugs be studied for associated risk of atherosclerotic events. These recommendations followed concerns raised by Dr Nissen regarding the CV safety of rosilgtiazone (Avandia). Those concerns were later largely proved incorrect. 26 CVOT's were completed with 197, 832 subjects enrolled. 8 of the trials documented CV benefits. 1 trial documented renal benefit. The guidelines were rescinded in March 2020, perhaps on a background of industry pressure (the CVOT trials are very expensive), because "not one of the trials identified unacceptable CV risk".

Dr Nissen raised several interesting points questioning this decision.

Heart failure (HF), the most common diabetes related CV complication, was not a primary endpoint. Instead, Major Adverse Cardiovasular Events (MACE: CV death, heart attack, stroke) were the primary focus.

Although Saxagliptin (a DPP-4 inhibitor) was neutral re MACE, HF hospitalizations increased.

Canagliflozin (Invokana, a SGLT2 inhibitor) had a favorable MACE, but amputations were increased 2-fold.

Aleglitazar (never to market) was neutral re MACE, but caused a 5kg weight gain.

The CVOT's also identified class differences regarding CV risk.

Semaglutide (Ozempic, GLP-1) had signficant CV benefits, while Lixisenatide (Adlyxin) was neutral.

Prior to the FDA guidelines, Big Pharma trials limited their studies to low-risk CV subjects. This resulted in almost complete absence of CV safety data.

Pharma also relied on studies that showed favorable ancillary benefits such as weight loss, lower BG etc. They used this to imply the "potential" for favorable CV benefits. 

This was especially true for the heavily promoted DPP-4 inhibitors (Januvia, Tradjenta). CVOT's later proved there was no MACE benefit!

Dr Nissen concluded that since CVOTs have indentified unexpected safety outcomes (HF and amputations), identified class differencec (Semaglutide vs Lixi) and disproved ancillary studies (the DPP-4's), they should be continued.

I agree!

 

The Medtronic Advanced Hybrid Closed Loop Study (AHCL): Summary of Dr Bruce Bode's presentation at the 2020 virtual ADA

Please verify anything you read in this summary from primary sources (such as https://clinicaltrials.gov/ct2/show/NCT03959423). It's my best recollection, but not perfect.

Dr Bode presented data from the AHCL sutdy. This was a 16-center in home trial of 157 people with Type 1 Diabetes. Ages ranged from 14-75 years old with an average HA1c of 7.5%, average age of 38 years old and average 23 year duration of diabetes. 

The pump is a 600 series pump which must be in manual mode for 48 hours for the "Smart Guard" system to be initiated.

Basal rates are adjusted every 5 mintues to achieve a target sensor glucose of 100 mg/dl or 120 mg/dl. The target will be set by the user. This differs from the 670G will has a sensor glucose target of 120 mg/dl.

Correction boluses are delivered to a sensor glucose of 120 mg/dl. This differs from the 670G which will use correction boluses only to 150 mg/dl.

Automatic correction boluses are a unique feature of this system (not available on the 670G).

Insulin activity ranges can be adjusted from 2-4 hours. 

The pump is designed to maximize TIR via the auto basal and auto bolus features.

Following a 2-weeek run in, subjects were randomized to 45 days using the 100 mg/dl sensor goal and 45 days using the 120 mg/dl sensor goal.

The results were impressive.

TIR overall increased from 54% to 73% using the 120 mg/dl sensor target. It increased to 79% using the 100 mg/dl target. This was accomplished without an increase in hypoglycemia.

Among subjects 14-21 years old, TIR increased from 18% to 59% using 120 mg/dl sensor target. It increased to 62% using the 100 mg/dl target.

There were only 1.3 exits per week from automatic to manual mode, a HUGE improvement vs the 670G. This was one of the key findings in the study.

Participants spent 95% of the time in the closed loop system.

While the 670 exits automode if the glucose is >250 mg/dl for 3 hours or >300 for 1 hour. Neither of these will precipitate an exit from the AHCL pump.

Time below range and above range was also significantly reduced.

The HA1c decreased 0.5%.

Insulin activity time reduced marginally by only 10 minutes. Adjustments to this setting doesn't appear to have major clinical impact.

I have some concerns since great pre-release results from the 670G clinical trials, presented at the 2017 ADA, haven't been replicated clinically. 

Nonetheless, this is a major development.

Of note, every person except one at Dr Bode's site elected to remain on the pump at study end.

The FLAIR Study: Summary of Dr Richard Bergenstal's 2020 ADA presentation

Interesting study which compared the semi-closed loop 670G pump with the closed loop AHCL.

It's the first pump study which compared two automated insulin delivery systems (AIDs). Prior studies compared AIDs with MDI or pumps without sensors.

Prior insulin pump studies enrolled tech savy middle-aged "pumpers" with excellent glycemic control.

The FLAIR  population was instead limited to subjects 14-29 years old. They're traditionally the most difficult to manage due to lifestyle.

Enrollment was open to subjects with HA1c's up to 11% . 26 % of FLAIR subjects had HA1c levels from 8.6 to11%. 

Finally, subjects were allowed to enroll irregardless of prior therapy or exposure to technology.

20% of the subjects were treated with MDI.

38% of the subjects had never used a CGM.

The investigator's goal was to broaden entry so that conclusions might apply to the general population of people with type 1.

The primary endpoint was daytime hyperglycemia.

111 subjects completed the study at 7 clinical sites in the US, Israel and Europe.

The mean entry HA1c was 7.9%.

All subjects were transitioned from their baseline regimen to a 670G.

Each subject was subsequently treated with a 670G for 90 days and the AHCL for 90 days.

The goal was to achieve a time in range (TIR) of 70-180 for >70% of the day with <1% of the day spent with glucose levels <54 mg/dl. 

The time below range (TBR, or <70 mg/dl) goal was <4%.

What they found...

Hyperglycemia (>180 mg/dl) during the day (6AM to MN) decreased significantly from 42% at baseline to 37% with the 670G and 34% with the AHCL.

The 3% improvement with transition from the 670G to the AHCL was significant.

TIR increased from 45% at baseline to 63% on the 760G and 65% using the AHCL.

Hypoglyemia <54 decreased from 0.5% on the 670G to 0.46% on the AHCL. This occurred despite improved daytime glycemic contorl.

Subjects were able to achieve TIR >70% and TBR <4% during 12% of the day at baseline.

This increased to 21% with the 670G and 30% with the AHCL.

Subjects with the greatest improvement were those who entered the study on MDI without CGM.

HA1c levels decreased from 7.9% at baseline to 7.6% on the 670G and 7.4% on the AHCL at the end of 12 weeks.

Autoexits dropped from 5.7 times per week using the 670G to 1.7 times per week on the AHCL.

Results were achieved without an increase in adverse advents.

The authors concluded that the AHCL provided a significantly better HA1c, more TIR, less hypoglycemia and less daytime hyperglycemia compared to the 670G.

Subject satisfaction was good.

The Omnipod 5 Closed Loop System: Summary of Dr Bruce Buckingham's presentation at the 2020 ADA

The Ominpod system works with the Dexcom G6 CGM.

Targets are adjustable from 110-150 mg/dl.

This was a small (193 subjects), short duration (~ 3months) study with enrollment criteria as follows: age 6-70 years old, more than 6 months of T1 and HA1c <10%.

The mean entry HA1c was 7.8% among children (6-14 years old) and 7.1% in the adults.

The primary endpoint was time in range (TIR, 70-180 mg/dl).

Study design was confusing as presented.

I think it included 14 days of baseline therapy (not specified in the talk re pump or MDI), follwed by 3 days on the Omnipod 5 with a 130 mg/dl target, 3 days with a 140 mg/dl target, and 3 days with a 150 mg/dl target. This was followed by 5 days of free choice target, then 3 months with a selected target.

At the end of the trial, TIR had increased from 66% to 73% in adults, and 51% to 65% in children. There was a significant reduction in hypopglycemia.

Subjects remained in automode for 97% of the trial.

The Medtronic data was more impressive. This might reflect the presenter style.

Hoping more data is forthcoming.

Are Low Energy diets best in people with diabetes? Summary of Dr John Wilding's presentation at the 2020 ADA

Dr Wildin'g s presentation was the first in a discussion of diet options in people with diabetes.

He reviewed energy deficient diets (1200-1800 kcal/day), meal replacement diets (800-1200 kcal/day) and very low energy diets (VLED, <800 kcal/day)

Low energy weight loss trials in people with prediabetes or diabetes include the Diabetes Prevention Trials in the US and Finland (both with a 58% reduction in progression to diabetes a/w ad 5.6 kg weight loss), the LOOKAHEAD trials and the UK Diabetes Prevention Program.

He arrived at the following conclusions:

   LED's with a focus on healthy, whole foods were successful, especially if combined with exercise and regular counseling.

   Modest energy restriction (500 kcal) with normal food is easy to understand, inexpensive and effective. in the UK, their program resulted in a 2.1 kg weight loss.

   LED's with meal replacement are more effective initially but must include a transition to normal food

   The effects of all approaches diminish over time

Are Low Carb diets best in people with diabetes? Summary of Jessica Turton APD presentation at the 2020 ADA

Jessica Turton, a dietitian from Australia, reviewed high carb (>225 g/d), moderate carb (130-225 g/d), low carb (<130 g/d) and very low carb (20-50g/d) diets in people with diabetes.

She discussed 25 randomized controlled trials (RCTs) in people with type 2 diabetes.

Study size ranged from 24-419 subjects.

Most of the studies compared low and moderate carb diets with high carb diets.

She noted the following

   No difference in HA1c levels after 12 and 24 months

   A 2.9 pound weight loss after 12 months on the LC diet

   Increased HDL and lower TG at 24 months. Significance wasn't noted on the charts, so I presume the reductions weren't clinically significant.

   LDL levels were unchanged.

She discussed findings from 9 RCTs in China that compared low and high carb diets in people with type 2 diabetes

   There was a 0.44% reduction in HA1c in the low carb group after 24 months

   There was a 2.6 pound weight loss at 12 months.

   There were significant improvements, ableit small, in HDL and TG

She ended her presentation with a discussion of 9 studies in people with type 1 diabetes

   2 of the studies were controlled. The remaining 7 were not.

   Study enrollment ranged from 1(!) to 48 subjects

   "Insufficient evidence to support use of LC diets in people with type 1".

I wasn't impressed with data that was presented.

   The longest trial was only 24 months.

   Study enrollments were small. The largest was 419 subjects.  Compare this with 2779 subjects enrolled in the DPP and 5145 subjects enrolled in LOOKAHEAD.

   Benefits re weight loss were surprisingly small, with loss of <3 pounds after 2 years of severe carbohydrate restriction.

   HA1c reductions were non-existent or minimal at <0.5%.

   No information presented regarding study drop-out rates.

   No information regarding treatments used by subjects. 

   Studies not blinded. Impossible to rule out investigator preferences.

   No CV outcome trials.

I didn't hear anything that would motivate me to recommend a carb restricted diet.

Is the Mediterranean Diet best for people with diabetes? Summary of Dr Miguel Martinez Gonzalez presentation at the 2020 ADA

Key ingredients: olive oil (abundant use), fish, nuts, legumes, fruit, vegetables and wine.

In the MedDiet, fish replaces red and processed meat. 3x per week intake is recommended

2 servings per day of vegetables are recommended with at least one salad.

3 servings of fruit per day, ideally with substitution for a dessert.

Nuts and legumes are recommeded 3x per week

Wine is consumed as part of the diet. It should always be with meals, in moderation.

There have been 50+ prospective, observational cohort studies that documented a reduction in CV events a/w the MedDiet. Adverse events have not been reported.

Predimed is the largest randomized, controlled trial of the MedDiet

   7447 subjects with type 2 diabetes (50%) or at least 3 CV risk factors were enrolled 

   Male subjects ranged in age from 55-80 years old. Female subjects ranged from 60-80 years old.

   Subjects were randomized to a MedDiet with extra virgin olive oil (2543), MedDiet with 30 g/day walnuts, hazelnuts, almonds (2454) and a control group (2450) that followed the AHA diet

   The trial was stopped  at 4.8 years due to a 30% reduction in CV events in the MedDiet cohorts.

   2013 NEJM: https://www.nejm.org/doi/full/10.1056/NEJMoa1200303

The 2013 trial was retracted due to an error in randomization. It was re-published in 2018

   2018 NEJM: https://www.nejm.org/doi/full/10.1056/NEJMoa1800389   

The conclusions remained the same with a persistent robust reduction in CV events.

https://www.hsph.harvard.edu/nutritionsource/2018/06/22/predimed-retraction-republication/

Given the significant morbidity and mortality associated with CVD, the MedDiet is an appropriate option for all of us.

 

Creative Meal Time Boluses: Summary of presentation by Margaret Pellizzani RN CDE at ADA 2020

This was an interesting presentation by a Pediatric DNE re alternative bolus methods.

Risk for hypoglycemia, variable insulin sensitivity, activity, stress and existing co-morbidities will impact any decisions.

Make sure to discuss with your physician, review above variables prior to making any adjustments in your regimen.

Normal boluses using MDI or insulin pumps were discussed. These are the most common boluses delivered with a meal.

The bolus should be administered 15-20 minutes before a meal if using a conventional prandial insulin such as insulin lispro, aspart and glulisine.

Extended or Square Wave (Medtronic pumps) boluses via insulin pumps were discussed. This bolus is delivered over a designated time.

Extedned boluses are typically used to cover extended meals such as buffets (or very long meals) or gastroparesis.

The Medtronic 670 G pump is unable to deliver extended boluses. Users most often add “phantom carbs” in attempt to duplicate.

The Tandem Control IQ system allows extended bolus of up to 2 hours.

Combination or Dual Wave (Medtronic pumps) boluses are a mixture of a normal and extended bolus.

These boluses are most often used with high fat, high protein, and mixed high fat/protein meals.

Carb counting is one of the most frustrating aspects of insulin management.

Although there are many reasons for this, it’s due at least in part to the fact that most meals have fat and protein, as well as carbohydrates.

The fat and protein will delay gastric emptying, leading to a lag in glucose absorption that may be significant as the content of each increases.

High protein content may delay the after meal glucose peak by 1.5-4 hours

Protein alone has a different impact than protein when combined with carbohydrates

Calculating a meal bolus based on carbohydrate content only will thus lead to after meal hyperglycemia, that may be delayed by up to 4 hours.

The following options, from a variety of clinical trials, were discussed.

Each was designed to improve glycemic coverage of high fat/high protein meals

    Add up to 66% more insulin to a calculated bolus dose. Administer as a combination bolus

    If the meal contains more than 40 grams of fat, add 30-35% to the calculated pre-meal dose

    Always use combination boluses. Increase the meal insulin:carb ratio (ICR) by up to 60% for the standard bolus. Deliver the remainder as an extended bolus over 90-300 minutes with an increased ICR of up to 70%

    Increase meal bolus by up to 65%

    If the meal has >40g fat and >25g protein, increase the ICR by 25-30%. Use a combination bolus. Administer 30-50% as a regular bolus. Deliver the remaining insulin as an extended bolus over 2-2.5 hours

As you can surmise for the signifcant variations in the options discussed, there isn’t one regimen which works well for everyone.

Creative bolusing requires careful, daily adjustments.

CGM data is critical to identify glucose trends, risks for hypoglycemia, and the impact of bolus adjustments up to 4-5 hours following insulin administration.

If you're interested in exploring some of the options discussed above, please give me a call.

 

Creative Boluses with MDI in T1DM: Summary of ADA 2020 presentation by Amy Fischl, RD

Very well organized presentation which reviewed impact of carbs, fat, protein, fiber and coffee on MDI in people with T1

Presumptions we make when using the insulin:carb ratio (ICR) to make insulin decisions

   We presume the ratio we select is accurate

   We presume we’re able to accurately assess carb content.

   Although some studies report that most are able to assess carb content within 10-15 grams, other studies report that ½ of subjects estimated content incorrectly

   We presume that only carbs will impact BG levels

Studies looking at the impact of fat and protein on MDI were reviewed.

Both may impact BG levels up to 6-12 hours after a meal

CGM is critical to accurately access their impact

The fat studies:

   Enrollment ranged from 7-33 subjects

   High fat diets ranged from 35-55g. They were compared to low fat diets which ranged from 2-5g.

   Fat caused a 2-3 hour delay in insulin response due to delayed gastric emptying. This resulted in a 3-5 hour delay in after meal hyperglycemia

   After meal glucose levels increased with high fat content. The amount of the increase wasn’t mentioned.

   Increased insulin may be required for high fat meals

   There are marked interindividual variartions in response.

The protein studies

   Enrollment ranged from 12-38 subjects

   High protein diets ranged from 12.5 to 100g

   The response is delayed 1-1/2 hours

   Glucose levels increased 40 mg/dl with protein meals of 75 g or more. Lower amounts of proteint had minimal impact on glucose levels

   Additions of carbs to the protein meal increased BG impact 

Two models to cover protein and fat during a meal with MDI were discussed

   #1: if eating >40g fat and >25g protein with a carb meal, the ICR should be increased 30-50%

        50% of the total bolus is given pre-meal

        50% of the total bolus is given 1.5 hours after the meal

        Response is assessed after each injection so that percentages and timing can be adjusted

        Very labor intensive!

   #2: If eating <100g carb during a meal, calculate the carb portion of your meal using the baseline ICR

         Multiply the ICR by 2 for coverage of the protein content

         No increase in insulin for the fat component

“Not all high fat and high protein meals will result in predictable blood glucose excursions”

There are three opinions when considering the impact of fiber or sugar alcohols when calculating meal boluses

   Subtract all fibers and sugar alcohol from total carb count. They have no impact on BG.

   If the total content of either is >5g, subtract ½ of the total from the total carb content. They have some impact on BG.

   Subtract none. They're the same as carbs.

   Again, have to consider interindividual response.

200 mg of caffeine, independent of carbs, increases glucose levels in people w/o diabetes

   Anecdotal reports of caffeine raising glucose levels 30-60 mg/dl in people with diabetes using CGM

   University of Chicago recommends consider an additional ½-2 unit bolus with coffee if BG rise documented by CGM

This was one of the best presentations I've attended.

It will be difficult to assess most adjustments without CGM I think.

If you're interested in trying any of the programs outlined in this presentation, please give me a call.