Reducing Diabetes Complications in 2019

David E TrachtenbargClinical Professor Family Medicine

Conflict of InterestUPH Methodist/Proctor make

hundreds of thousand dollars a year from pharmaceutical researchPart of this goes to speaker plus some

advisory board feesAn advantage is learning more about

detials of pharmaceuticals and how they are sold.

Ominous OctectThe Ominous Octect

Outline• Acute

o Ketoacidosis will only discuss in passingo Hypoglycemia

• Chronico Microvascular

• Eye• Nerve• Kidney

o Macrovascular• MI• Stroke• PVD, ulcers and amputation

• Othero CHFo Gastroparesiso Pancreatitiso Fatty Liver and NASH

General Risk FactorsHigh FPG variability levels is positively associated with the risk of retinopathy and all-cause mortality in patients with type 2 diabetes.

Zhao Q, Zhou F, Zhang Y, Zhou X, Ying C: Fasting plasma glucose variability levels and risk of adverse outcomes among patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Res ClinPract. 2019 Feb;148:23-31.

Complications Go Together

DR is consistently associated with other complications of diabetes including nephropathy, stroke, cardiovascular disease, lower extremity ulceration and amputation. A patient with DR has an overall worse prognosis than a patient without DR.

Pearce I, Simó R, Lövestam-Adrian M, Wong DT, Evans M: Association between diabetic eye disease and other complications of diabetes: Implications for care. A systematic review. Diabetes Obes Metab. 2019 Mar;21(3):467-478.

Complications and A1C

Hypoglycemia

Glargine U-300 (Toujeo)

Insulin, lasts about 30 hoursIn trials has low rate of hypoglycemiaAlso available in Max version for patients

with insulin resistancePatients need 10-15% more insulin

because of degradation prior to absorption

Degludec (Tresiba)

• Insulin, lasts about 42 hours• In trials has lower rate of

hypoglycemia than glargine U-100• Also available in U-200 version for patients with

insulin resistance• Patients often need less insulin

o Keeping up to date with previous studies and modifying decision making as new studies are reported is difficulto There are both cardiovascular and endocrine considerations for every medicationo The risk of microvascular disease and macrovascular disease must be balancedo Pharmaceutical marketing does not provide unbiased guidelines for decision making

Bright Study

• Similar A1C Lowering• Less hypoglycemia

with glargine U-300?

Diabetic Retinopathy

Early Worsening

Bain SC, Klufas MA, Ho A, Matthews DR: Worsening of diabetic retinopathy with rapid improvement in systemic glucose control: A review. Diabetes Obes Metab. 2019 Mar;21(3):454-466.

Statin therapy was associated with a decreased risk of diabetic retinopathy and need for treatments for vision-threatening diabetic patients with type 2 diabetes and dyslipidemia.

Magliah SF, Bardisi W, Al Attah M, Khorsheed MM: The prevalence and risk factors of diabetic retinopathy in selected primary care centers during the 3-year screening intervals. J Family Med Prim Care. 2018 Sep-Oct;7(5):975-981.

Screening IntervalsExtending screening intervals to 2 years for retinopathy is estimated to miss 5 patients per 1000.

Scanlon PH: Screening Intervals for Diabetic Retinopathy and Implications for Care. Curr Diab Rep. 2017 Sep 5;17(10):96.

Physical ActivityMost studies find physical activity has a favorable effect on retinopathy.

Loprinzi PD1, Edwards MK1, Frith E: Review of the literature examining the association between physical activity and retinopathy. Phys Sportsmed. 2018 Feb;46(1):123-128.

Treatment and PreventionA review of the Cochrane database found effective for treating diabetic retinopathy include photocoagulation and anti-vascular endothelial growth factor agents. Strict glucose and pressure control seem to postpone the onset of retinopathy. For macular edema, antiangiogenic drugs, intravitreal injection and surgical implantation seem to have some benefit.

Mozetic V, Daou JP, Martimbianco AL, Riera R: What do Cochrane systematic reviews say about diabetic retinopathy? Sao Paulo Med J. 2017 Jan-Feb;135(1):79-87.

Diabetic Macular EdemaControl of glucoseControl of blood pressureIntravitreal anti-VEGF drug injectionsIntravitreal corticosteroid injectionsFocal laser photocoagulationVitrectomy

A substantial fraction of eyes respond incompletely to all of these modalities resulting in visual loss

Browning DJ, Stewart MW, Lee C: Diabetic macular edema: Evidence-based management. Indian J Ophthalmol. 2018 Dec;66(12):1736-1750.

Diabetic Neuropathy

Diabetic Nephropathy

Epidemiology• 20-30% of all patients with type 2 diabetes• Prevalance averages 15% with 22% having GFR <60

ml/min• 50% of end stage renal disease• Many patients have diabetic kidney disease without

significant albuminuria (63.7% in one study).• Diabetes is not always the cause in one study 36% of

patients with diabetes had hypertensive nephropathy• Albuminuria tends to increase over 5-15 years• Severe albuminuria untreated can lead to ESRD in 5-7

years• Genetic defects have been detected including defects

in the ACE enzyme.

Diagnosis• Evaluate albuminuria and GFR• Screening yearly• 24 hour urine is the gold standard• albumin/creatinine ratio is best spot test for albuminuria

Normal <30 mg/g is called “normal to mildly increased”.• 30-300 mg/g previously labeled “microalbuminuria.”

Now “moderately increase albuminuria” is proposed.• Over 300 mg/g is defined as severely increased

micoralbminuria. Formerly macroalbuminuria.• Rate of progression from 30-300 mg/g to over 300 mg/g

is 2-3% per year.

Measuring GFR• MDRD• Cockcraft and Gault• EPI• cystostatin C

Stages of Renal Disease• G1 >=90• G2 60-89• G3 30-59

o G3a 45-59o G3b 30-44

• G4 15-19• G5 <15

Frequency of Monitoring Nephropathy

Treatment• Glycemic control with A1C<7%• Blood pressure <140/90 and less than 130/80 in patients with albuminuria• ACE and ARBs for patients with moderately or severely increased

albuminuria. Not recommended for patients with normal blood pressure and normal mildly increased albuminuria.

• Combining ACE and ARBs not advised• Both ACE and ARBs may cause a drop in measured GFR on starting

treatmetn• Research

o spironolactone plus an ACE or ARB may improve outcomes.o vitamin-D

• SGLT-2 medications• DPP-4?• GLP-1 Liraglutide, semaglutide• Diltiazem (may need to be combined with ACE)• Spironolactone• Caloric restriction, weight reduction and bariatric surgery

Referral Criteria

AgentsandRenalDisease

CardiovascularAn LDL <70 does a better job of protecting against cardiovascular disease

Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, Fujita H, Higaki J, Hirata KI, Ishibashi S, Isshiki T, Ito S, Kashiwagi A, Kato S, Kitagawa K, Kitakaze M, Kitazono T, Kurabayashi M, Miyauchi K, Murakami T, Murohara T, Node K, Ogawa S, Saito Y, Seino Y, Shigeeda T, Shindo S, Sugawara M, Sugiyama S, Terauchi Y, Tsutsui H, Ueshima K, Utsunomiya K, Yamagishi M, Yamazaki T, Yo S, Yokote K, Yoshida K, Yoshimura M, Yoshimura N, Nakao K, Nagai R; EMPATHY Investigators: Achieving LDL cholesterol target levels <1.81 mmol/L may provide extra cardiovascular protection in patients at high risk: Exploratory analysis of the Standard Versus Intensive Statin Therapy for Patients with Hypercholesterolaemia and Diabetic Retinopathy study. Diabetes Obes Metab. 2018 Nov 4. doi: 10.1111/dom.13575. [Epub ahead of print]

Intensive Statin Treatment

Itoh H, Komuro I, Takeuchi M, Akasaka T, Daida H, Egashira Y, Fujita H, Higaki J, Hirata KI, Ishibashi S, Isshiki T, Ito S, Kashiwagi A, Kato S, Kitagawa K, Kitakaze M, Kitazono T, Kurabayashi M, Miyauchi K, Murakami T, Murohara T, Node K, Ogawa S, Saito Y, Seino Y, Shigeeda T, Shindo S, Sugawara M, Sugiyama S, Terauchi Y, Tsutsui H, Ueshima K, Utsunomiya K, Yamagishi M, Yamazaki T, Yo S, Yokote K, Yoshida K, Yoshimura M, Yoshimura N, Nakao K, Nagai R: Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. Diabetes Care. 2018 Jun;41(6):1275-1284.

MI

Stroke

PVD and amputation

CHF

Dementia

Pancreatitis

Diabetes 3C

Fatty Liver

Gastroparesis• No consensus on definition exists except delayed gastric

emptying in the absence of mechanical obstruction• Nausea – 92%• Vomiting – 84%• Early satiety – 60%• bloating – 75%• Abdominal pain• weight loss• Risk with type 2 diabetes x7 and type 1 diabetes x30• About 1/3 of patients with gastroparesis have diabetes• Delayed gastric emptying occurs in 27-65% adults with type 1

diabetes and about 30% of patients with type 2 diabetes. Diagnosed dGP was 5% of type 1 patients in a reghistry.

• More common in women. 9.6/100,000 men and 37.8/100,000 women.

Gastroparesis Cardinal Symptom Index

On a 0-5 scale with 0 being none and 5 being very severe1. Postprandial fullness/early satiety2. Nausea/vomiting3. Bloating

Grade 1 – Mild intermittent symptoms controlled with diet or avoidanceGrade 2 – Moderatly sever symptoms, but no weight loss requiring medicationGrade 3 – Refractory to medication and unable to maintain oral nutrition. Frequent ED visits and fluids. Requiring surgergical therapy

Gastric Scintigraphy

Interpretation• Positive if over 60% delay at 2 hours or 10% at 4

hours.

Glycemic control• Pills may need to be avoided• GLP may need to be avoided• Insulin after meals. Consider regular• Consider square waver for pump

Diet• Small low fat meals 4-5 times per day• Avoid carbonated beverages• Chew food thoroughly, eat slowly (20-30 min per

meal)• Consider blenderizing food• Get fats from liquid• Fluids throughout day (solids are affected much

more than liquids by gastroparesis)• Sit or walk for 1-2 hours after meals.• If problems with solids can try bulk of calories from

liquids.

Medications• metoclpramide• erythromycin stops working after about 4 weeks• domperidone – FDA investigational• cisapride• bethanicol• botulism• pyloroplasty – no controlled studies• gastric electrical stimulation• ginger???

The Problem• Diabetes patients have cardiovascular risk that is

equivalent to a patient who has had a myocardial infarction

• Medications for diabetes can increase or decrease the risk significantly

• The decision making for best care is complex and changing

Overview of Data

Overview of Diabetes Medications & CV Disease• Lowering A1C primarily reduces the incidence of

microvascular complications (primarily neuropathy, nephropathy and retinopathy)

• Different diabetes medications have significantly different effects on macrovascular disease (primarily MI, stroke)

• Congestive heart failure is a diabetic complication and diabetes medications affect it differently than microvascular and macrovascular disease.

• Pharmaceutical marketing has promoted SGLT-2 and GLP medications for CV disease, but all of the diabetes medications must be evaluated for CV effect for each patient

• The data shows other medications also contribute to the risk

Selected StudiesTrial medication(s) Population CV outcomes Mortality MI Stroke CHF Comments

Meta-analysis of ADVANCE, ACCORD, VADT, UKPKS

Regular vs Intensive insulin therapy 27,049 patients NS 9% reduction - - 2.48 times more hypoglycemia. Individual trials showed no reduction and ACCORD showed increased mortality. Hypoglycemia less common with degludec.

ORIGIN glargine vs usual care 12,537 patients NS

DEVOTE degludec vs glargine DM-2 patients NS Less hypoglycemia with degludec

UKPDS metformin vs usual care 4209 patients with DM-2 30% reduction 36% 39% reduction No difference between usual care and intensive care groupUGDP tolbutamide Increased CV deaths Study terminated early

TOSCA.IT pioglitizone vs sulfonylurea 3028 with DM-2 Only 11% with CV disease Risk 0.72 NS NS Risk 0.36 Only non-fatal MI and stroke counted.

Meta-analysis Rosiglitazone Possible increase 43% increase

BARI-2D Rosiglitazone vs no glitizone 2368 patients with DM-2 NS 0.72 risk

RECORD Rosiglitazone with orals vs other orals NS

CAROLINA linagliptin vs glimepiride 6072 Results pending

CARMELINA linagliptin vs placebo 7053 DM2 Results pending

FREEDOM CVO exenatide implantable vs placebo 4156 Results pending. Preliminary NS difference

EXSCEL exenatide weekly vs placebo 14780 Results pending. Preliminary NS difference

HARMONY abiglutide vs placebo 9400 Results pending

REWIND duaglutide vs placebo 9622 Results pending

PIONEER-6 oral semaglutide vs placebo 3176 Results pendings

DECLARE-TIMI dapagliflozin vs placebo 17276 Results pending

VERTIS-CV ertugliflozin vs placebo 8000 Results pending

PROActive Pioglitazone vs placebo 5238 high risk patients NS NS NS 16% reduction Increased incidence of CHF hospitalization

IRIS (Stroke) Pioglitizpne vs placebo 3876 insulin resistance patients 0.76 risk NS

SAVOR-TIMI Saxagliptin vs placebo 16,492 NS NS NS Increased risk of hospitalization for heart failure

EXAMINE Alogliptin vs placebo 5380 with acute MI or unstable angine NS NS Increased risk of hospitalization for HF in patients without a history of HF

TECOS Sitagliptin vs placebo 14,671 NS NS ` NS No increased risk of HF hospitalizationELIXA Lixisenatide vs placebo 6,068 MI or unstable angina past 6 mo NS NS NS NS

LEADER Liratlugide vs placebo 9,340 DM-2 at high risk Risk 0.78 Risk 0.87 Risk 0.78 Nephropathy progression reduced.

SUSTAIN-6 Semaglutide vs placebo 3,297 with DM-2 at high risk Risk 0.74 Risk 0.61 Decreased progression of nephropathy. Increased risk of retinopathy.

EMPA_REG Empagliflozin vs placebo 3,297 Established CVD Risk 0.85 Decreased Risk 0.67 NS Risk 0.65 Decreased risk of renal failure

CVOT Canagliflozin vs placebo 10,142 DM-2 Risk 0.86 Increased amputation Risk 1.97

STOP-NIDDM Acarbose vs placebo 1429 with IGT Reduced Reduced 36% reduction in new onset diabetes

Acarbose Meta-analysis Acarbose vs placebo 2180 Reduced Redu ced

ACE Acarbose vs placebo 6522 NS NS Ns NS NS NS difference in CV outcomes. Less development of diabetes

ETDRS (retinopathy) Aspirin vs placebo 3711 NS Risk 0.91

JPAD Aspirin vs placebo Risk 0.80NS Bleeding in 2% of aspirin group vs 0.9% placebo

POPADAD Aspirin vs placebo 1,276 with diabetes and asymptomatic PAD NS Ns Ns NS No difference in amputation.

Metaanalysis by AHA and ACC Aspirin vs placebo for patients with diabetes 9% MI reduction 10% stroke reduction

ARRIVE Aspirin vs placebo Results pending

ASPREE Aspirin vs placebo Results pending

ASCEND Aspirin vs placebo Results pending

ACCEPT-D Aspirin vs placebo Results pending

ASPEN

ASCOT-LLA

CARDS LDL 70-189

Heart Protection Study Simvastatin 40 mg or placebo 20,536 22% reduction Reduced CV events

Meta-analysis Statin vs placebo 71,344 Decreased Decreased Decreased Decreased

IMPROVE-IT Ezetimibe+simvastatin vs simvastatin plus placebo 4,933 with diabetes Risk 0.856 .ODYSSEY COMBO-II Alirocumab vs ezetimibe 18,00 35% with diabetes Pending

FOURIER evolocumab 27,564 36/7% wotj doabetes Risk 0.85

Roumie Et Al Metformin vs sulfonlyurea Cohort study 126,867 Risk 1.32 No difference in A1C.

Roumie Et Al Metformin vs thiazolidinedione Subset of study above Risk 1.44

Usaman et al SGLT-2 vs placebo Meta-analysis 17,417 Risk 0.83 NS Risk 0.79 Risk 0.85 NS difference 0.64 risk

Overview of Older Medications• Sulfonylurea medications appear to increase the

risk of CV events and CHF• Metformin appears to be neutral for CV events• Acarbose appears to decrease the risk of CV

events• The DPP-4 medications appear to be neurtral for CV

events, but saxagliptin (Onglyza) may increase the risk of CHF

• Tight insulin control appears to increase the risk of CV events

• Pioglitizone appears to be neurtral for CV events, but increases the risk of CHF hospitalization

SGLT-2 Medications

• EMPA_REG study of empagliflozin vs placebo. o 3,297 patients with established CVDo Decrese risk of CV event to 0.85o Decreased risk of MI to 0.67o Decreased risk of CHF hospitalization to 0.65o Decreased overall mortality and rate of progression of renal disease

• Canvas Study of canagliflozin vs placeboo 10,142 patient with DM-2o Decreased risk of CV even to 0.86o However, increased amputation risk to 1.97

• Other studies pending• Significant reduction and this is probably a class

effect. SGLT-2 medications decrease CHF hospitalization unlike GLPs. However, SGLT-2 do not lower A1C as much if starting <=8%.

GLP Medications• ELIXA with Lixisenatide vs placebo NS differences• LEADER with Liratlugide vs placebo with 22%

reduction in CV events and mortality. Also decreased progression in nephropathy

• SUSTAIN-6 with semaglutide vs placebo with 25% reduction in CV events and 39% reduction plus decreased progression of nephropathy. Possible increased progression of retinopathy.

• Other studies pending• To date, looks like outcomes may not be a class

effect.

Why Reduction with GLPor SGLT-2

• Mechanisms unknown. Theories for include:• Improved vascular reactivity• Sustained diuresis• Decreased albuminuria• Decreased serum uric acid• Shift in fuel metabolism to ketone bodies• Weight loss• BP lowering• Antiinflammatory effects

Cost Effectiveness• Because of cost the newer agents should be used

selectively.• However, they may be more effective than other

measures. For example, there is still controversy about the effectiveness of aspirin for primary prevention and a meta-analysis showed only a 9% reduction of events with increased risk of bleeding.

Recommendations• Pilot inpatient consultative service with cardiology

and endocrinology to target patient with diabetes and documented CV disease.

• Monitoring to evaluate outcomes including:o Diabetes care costo Readmissionso CV events including MI, Stroke and CHFo Mortality

The End