Based on the latest Esc 2019 guidelines for diabetes

1. P R E S E N T E D B Y
Y O U S R A G H Z A L L Y
A S S I S T A N T L E C T U R E R O F C A R D I O V A S C U L A R
M E D I C I N E
A S S I U T U N I V E R S I T Y
E G Y P T
Diabetes and new anti diabetic
drugs

2.  In general, 1.4 million newly diagnosed cases in the
US are being reported every year. If this trend
continues, it is projected that in 2050 one in three
Americans will have diabetes.
 Patients with diabetes have increased risk of serious
health complications including myocardial
infarction, stroke, kidney failure, vision loss, and
premature death.

3.  The traditional presentations of T2DM occurring only in
adults and type 1 diabetes mellitus (T1DM) only in children
are not entirely correctly representative, as both diseases
occur in both age groups. Occasionally, patients with T2DM
may develop the morbid complication of (DKA).
 Children with T1DM typically present with polyuria and
polydipsia and approximately one-third of them present with
DKA, which may also be the first presenting feature.
 The onset of T1DM may be variable in adults, and they may
not present with the classic symptoms that are seen in
children. The true diagnosis may become apparent with
disease progression.
 The heterogeneity of the presentations should be kept in mind
while caring for the patient with T2DM.

6. The ADA and American Association of Clinical
Endocrinologists recommend screening for pre-diabetes
beginning at :
1-age 45 years or earlier for asymptomatic individuals
with
2-strong risk factors such as obesity (BMI ≥ 25 kg/m2),
hypertension and
3-family history (first degree relative with diabetes)

7. Patients diagnosed with prediabetes can be retested
after a year; however, without proper intervention 70%
of individuals diagnosed with prediabetes are most
likely to progress to diabetes in 10 years or even less,
depending on their risk factors .
It is also important to note that prediabetes may be
associated with obesity, dyslipidemia, and hypertension;
therefore, lifestyle changes such as healthy diet, physical
activity, and cessation of smoking, in addition to the
introduction of pharmacological agents, are deemed
important to stop or delay the timeline of development
of diabetes.

9. Cardiovascular risk assessment in diabetics
4

10. Risk modifier

13. In addition, (DCCT/EDIC) (T1DM), the UK Prospective Diabetes Study
(UKPDS), and VADT (T2DM) showed that long follow-up (<_20 years) is
necessary to demonstrate a beneficial effect on macrovascular
complications, and that early glucose control is associated with long-term
CV benefits (legacy effect).
An HbA1c target of <7% (<53 mmol/mol) reduces microvascular
complications, while evidence for an HbA1c target to reduce macrovascular
risk is less compelling.

14. Treatment targets
 A meta-analysis of three major studies—(ACCORD), Action
in Diabetes and (ADVANCE), and the (VADT)—suggested
that in T2DM, an HbA1c reduction of 1% is associated with
a 15% relative risk reduction in non-fatal MI, without
beneficial effects on stroke, CV, or all-cause mortality or
hospitalization for HF.
 Intensive glucose control was beneficial for CV events in
patients with a short duration of DM, lower HbA1c at
baseline, and no CVD.

15. However, HbA1c targets should be individualized, with
more-stringent goals [6.0-6.5% (42-48 mmol/mol)] in
younger patients with a short duration of DM and no
evidence of CVD, if achieved without significant
hypoglycaemia.
Less-stringent HbA1c goals [e.g. <8% (64 mmol/mol) or
<9% (75 mmol/mol)] may be adequate for elderly patients
with longstanding DM and limited life expectancy, and
frailty with multiple comorbidities, including hypoglycaemic
episodes.

16. Several epidemiological studies have shown that high post-challenge
(2 h OGTT) or post-prandial glucose values are associated with
greater CV risk, independent of FPG.
Intervention trials have failed to support the role of post-prandial
glucose as a CVRF independent of HbA1c.
(HEART2D) trial, an RCT that assigned patients with DM
within 21 days after an acute MI to insulin regimens
targeting either post prandial or pre-prandial glucose,
reported differences in FPG, less-than-expected differences
in post-prandial PG, similar levels of HbA1c, and no
difference in risk of future CV events

17. FPG variability has been reported to be a strong predictor of all cause and
CVD-related mortality in patients with DM, suggesting that management
of glucose variability may become an additional goal.
In the intensive arm of the ADVANCE study, an increase in HbA1c and
fasting glucose variability was associated with the risk of macrovascular
events.
Drugs that reduce post-prandial glucose excursions, including glucagon-
like peptide-1 receptor agonists (GLP1- RAs), dipeptidyl peptidase-4
(DPP4) inhibitors, and sodium-glucose co-transporter 2 (SGLT2)
inhibitors, seem an attractive way to reduce glucose variability

18. Several studies, including Diabetes Mellitus Insulin- Glucose
Infusion in Acute Myocardial Infarction 2 (DIGAMI 2),
ADVANCE, and Outcome Reduction With Initial Glargine
Intervention (ORIGIN), have indicated that severe hypoglycaemia is
associated with increased risk of death and an impaired CV
prognosis,
whilst DEVOTE reported decreased hypoglycaemia but failed
to show a difference in MACE.

24. Pharmacological treatment
 An “ominous octet” that leads to hyperglycemia, which occur in
isolation or in combination, has been proposed for eight
pathophysiological mechanisms underlying T2DM .
 These include :
 (i) reduced insulin secretion from pancreatic β-cells,
 (ii) elevated glucagon secretion from pancreatic α cells,
 (iii) increased production of glucose in liver,
 (iv) neurotransmitter dysfunction and insulin resistance in the
brain,
 (v) enhanced lipolysis,
 (vi) increased renal glucose reabsorption,
 (vii) reduced incretin effect in the small intestine, and
 (viii) impaired or diminished glucose uptake in peripheral tissues
such as skeletal muscle, liver, and

25. When to start treatment?
Pharmacological treatment of T2DM should be initiated
when:
1-glycemic control is not achieved ,or
2-if HbA1C rises to 6.5% after 2–3 months of lifestyle
intervention.
Not delaying treatment and motivating patients to initiate
pharmacotherapy can considerably prevent the risk of the
irreversible microvascular complications such as retinopathy
and glomerular damage .
• Monotherapy with an oral medication should be started
concomitantly with intensive lifestyle management.
•If the HbA1C level rises to 7.5% while on medication or if the
initial HbA1C is ≥9%, combination therapy with two oral
agents,or with insulin, may be considered.

33. Bigaunides (Metformin)
 Metformin is a herbical material, that is the drug of choice for
the treatment of T2DM.
 Mech:1-activates adenosine monophosphate activated protein
kinase in the liver, increase the glucose uptake by the liver and
inhibiting gluconegenesis, through complex mitochondrial
enzymes.2-increase insulin senstivity by activating insulin
receptor expression and enhance tyrosine kinase activity
3-Recently they suggest lipid lowering effect due to PPAR-
pathway ativity.
 Advantage:1-low risk of hypoglycemia
2-modest weight loss
3-delay the progression of T2DM, reduces mortality.
4-reduce infalmmatory markers and improve endothelial
dysfunction (plasminogen activator)

34. Metformin (cont.)
 Once ingested, metformin (with a half-life of
approximately 5 h) is absorbed by organic cation
transporters and remains unmetabolizewd and the
main site of excrtetion is the kindney and thus CI if
GFR<30ml/min.
 the dose should be reduced and patients should be
advised to discontinue the medication if nausea,
vomiting, and dehydration arises from any other
cause (to prevent ketoacidosis).
 It is important to assess renal function prior to
starting this medication

35.  Extended release preparations seldom cause any
gastrointestinal issues. Very rarely, metformin may
cause lactic acidosis, mainly in subjects with severe
renal insufficiency.
 Another potential problem arising from the use of
metformin is the reduction in the drug’s efficiency as
diabetes progresses. Metformin is highly efficient
when there is enough insulin production; however,
when diabetes reaches the state of failure of β-cells
and resulting in a type 1 phenotype, metformin loses
its efficacy.

37. Incretin mimetics
 Incretin effect is the difference in insulin secretory
response from an oral glucose load in comparison to
glucose administered intravenously.
 The incretin effect is responsible for 50–70% of total
insulin secretion after oral glucose intake .
 The two naturally occurring incretin hormones that play
important roles in the maintenance of glycemic control:
glucose-dependent insulinotropic polypeptide (GIP, or
incretin) and glucagon-like peptide (GLP-1); these
peptides have a short half-life, as these are rapidly
hydrolyzed by DPP-4 inhibitors within 1½ min.

38.  In patients with T2DM, the incretin effect is reduced or absent. In
particular, the insulinotropic action of GIP is lost in patients with
T2DM.
 Incretins decrease gastric emptying and causes weight loss.
Because of impact on weight loss, these medications may find
increasing use in diabesity.
 The 2 drug classes include GLP-1 receptor agonists and DPP-4
inhibitors.
 Clinical data have revealed that these therapies improve glycemic
control while reducing body weight (specifically, GLP-1 receptor
agonists) and systolic blood pressure in patients with T2DM .
 Furthermore, hypoglycemia is low (except when used in
combination with a sulfonylurea) because of their glucose-
dependent mechanism of action

39. GLP-1 Receptor Agonists
 The currently GLP-1 receptor agonists available are
exenatide and liraglutide.
 These drugs exhibit increased resistance to
enzymatic degradation by DPP4. In young patients
with recent diagnosis of T2DM, central obesity, and
abnormal metabolic profile, one should consider
treatment with GLP-1 analogs that would have a
beneficial effect on weight loss and improve the
metabolic dysfunction.
 GLP-1 analogs are contraindicated in renal failure

40. Exenatide.
 Exenatide, an exendin-4 mimetic with 53% sequence
homology to native GLP-1, is currently approved for
T2DM treatment as a single drug in the US and in
combination with metformin ± sulfonylurea. Because of
its half-life of 2.4 h, exenatide is advised for twice-daily
dosing.
 Treatment with 10 μg exenatide, as an add-on to
metformin, resulted in significant weight loss (−2.8 kg)
in comparison to patients previously treated with
metformin alone. Exenatide is generally well tolerated,
with mild-tomoderate gastrointestinal effects being the
most common adverse effect.

41. Liraglutide.
 Liraglutide is a GLP-1 analog that shares 97% sequence
identity to native GLP-1. Liraglutide has a long duration
of action (24 h).
 Liraglutide causes 1.5% decrease in A1C in individuals
with type 2 diabetes, when used a monotherapy or in
combination with one or more selected oral antidiabetic
drugs.
 Liraglutide decreases body weight; the greatest weight
loss resulted from treatment with liraglutide in
combination with combined metformin/sulfonylurea
(−3.24 kg with 1.8 mg liraglutide).

42.  Liraglutide also diminishes systolic pressure (mean
decrease −2.1 to −6.7 mmHg) (37). Liraglutide is well
tolerated, with only nausea and minor hypoglycemia
(risk increased with use of sulfonylureas).
 Serum antibody formation was very low in patients
treated with once-weekly GLP-1 receptor agonists.
The formation of these antibodies did not decrease
efficacy of their actions on blood glucose lowering.

43.  7 trials
 Lixisenatide (ELIXA) trial
 Lixisenatide in Acute Coronary Syndrome (ELIXA) trial,
lixisenatide 10 or 20 lg o.d. was non-inferior to placebo,
but did not significantly affect a four-point MACE
(threepoint MACE plus hospitalization for unstable
angina) in patients with DM post-ACS.
 Exenatide (EXSCEL)
 exenatide 2 mg once weekly showed non-inferiority vs.
placebo and a numerical, but nonsignificant, 14%
reduction of the primary three-point MACE

44.  Liraglutide In the LEADER trialliraglutide 0.6 - 1.8
mg o.d. vs. placebo as add-on to other glucose-
lowering drugs. All patients had a long history of DM
and CVRFs that were well controlled.
 After a follow-up of 3.1 years, liraglutide significantly
reduced the composite three-point primary endpoint
(CV death, non-fatal MI, or nonfatal stroke) by 13%.
 In addition, liraglutide significantly reduced CV
death and total death by 22 and 15%, respectively,
and produced a non-significant numerical reduction
in non-fatal MI and non-fatal stroke

45.  Semaglutide (Sustain -6)
 semaglutide 0.51.0 mg once weekly vs. placebo. After 2.1
years, semaglutide significantly reduced the three-point
MACE by 26%, an effect driven mainly by a 39%,
 (PIONEER)-6 trial, also a phase III pre-approval CVOT,
examined the effect of oral semaglutide o.d. (target dose
14 mg) vs. placebo on CV outcomes in patients with
T2DM and high CV risk. Non-inferiority for CV safety of
oral semaglutide was confirmed with an HR of 0.79 (P <
0.001) in favour of oral semaglutide compared with
placebo over a median follow-up of 16 months

46.  Albiglutide (Harmony Outcomes) trial,
 Once weekly albiglutide, a no-longer marketed
GLP1-RA, led to a significant 22% reduction of three-
point MACE compared with placebo in patients with
DM and manifest CVD.
 Dulaglutide (REWIND)
 assessed the effect of once weekly subcutaneous
dulaglutide (1.5 mg) vs. placebo on three-point
MACE in 9901 subjects with T2DM, who had either a
previous CV event or CVRFs. During a median
follow-

47. DPP-4 Inhibitors
 Dipeptidyl peptidase 4 inhibitors include sitagliptin,
saxagliptin,
 vidagliptin, linagliptin, and alogliptin.
 These medications may be used as single therapy, or
in addition with metformin, sulfonylurea, or TZD.
 This treatment is similar to the other oral
antidiabetic drugs. The gliptins have not been
reported to cause higher incidence of hypoglycemic
events compared with controls.

48.  Dipeptidyl peptidase 4 inhibitors impact postprandial
lipid levels.
 Treatment with vidagliptin for 4 weeks decreases
postprandial plasma triglyceride and apolipoprotein B-
48-containing triglyceride-rich lipoprotein particle
metabolism after a fat-rich meal in T2DM patients who
have previously not been exposed to these medications.
 In diabetic patients with coronary heart disease, it was
demonstrated that treatment with sitagliptin improved
cardiac function and coronary artery perfusion.

49.  The three most commonly reported adverse
reactions in clinical trials with gliptins were
nasopharyngitis, upper respiratory tract infection,
and headache.
 Acute pancreatitis was reported in a fraction of
subjects taking sitagliptin or metformin an
sitagliptin.
 An increased incidence of hypoglycemia was
observed in the sulfonylurea treatment group.
 DPP-4 inhibitors are considered safe in patients with
moderate to severe renal failure.

50.  Saxagliptin (SAVOR-TIMI 53)
 Alogliptin (EXAMINE)
 Sitagliptin (TECOS)
 Lintagliptin (CARMELINA and CAROLINA)
Four of these trials confirmed statistical non-
inferiority vs. placebo (which included alternative
glucose-lowering medication to achieve glycaemic
equipoise) for the primary composite CV outcome
examined.

51.  However, none of the DPP4 inhibitors were associated with
significant CV benefits in their trial populations, which comprised
patients with a long history of DM and CVD, or clustered CVD risk
factors. In the SAVOR-TIMI 53 trial, saxagliptin was associated with
an increase in risk of hospitalization for HF, compared with a
numerical, non-significant increase with alogliptin in EXAMINE,
and no HF signal with sitagliptin in TECOS293 and with linagliptin
in CARMELINA.
 Subgroup analyses of SAVOR-TIMI 53 suggested that high baseline
NT-proBNP, pre-existing HF, or CKD conferred a greater risk of
hospitalization for HF in saxagliptin-treated subjectts
 Only the CAROLINA study compared linagliptin vs. glimiperide as
an active comparator and showed comparable CV safety of both
drugs.

52. SGLT2 Inhibitors
 Sodium-glucose cotransporter inhibitors are new classes
of glucosuric agents: canagliflozin, dapagliflozin, and
empagliflozin.
 SGLT2 inhibitors provide insulin-independent glucose
lowering by blocking glucose reabsorption in the
proximal renal tubule by inhibiting SGLT2.
 Because of glucose-independent mechanism of action,
these drugs may be effective in advanced stages of T2DM
when pancreatic β-cell reserves are permanently lost.
 These drugs provide modest weight loss and blood
pressure reduction.

53.  4 clinical trials:
 Empagliflozin (EMPA-REG OUTCOME), the
Canagliflozin Cardiovascular Assessment Study
(CANVAS) Program,
 Dapagliflozin (DECLARE-TIMI 58), and
 (CREDENCE) trial,the Canagliflozin and Renal
Events inDiabetes with Established Nephropathy
Clinical Evaluation

54.  DM for more than 10 yrs and CVD were randomized to
empagliflozin 10 or 25 mg o.d., or placebo; patients were
followed for a mean of 3.1 years. Empagliflozin
significantly reduced the risk of the three-point
composite primary outcome (CV death, non-fatal MI, or
non-fatal stroke) by 14% compared with placebo. This
reduction was driven mainly by a highly significant 38%
reduction in CV death (P < 0.0001).
 These findings were consistent in all subgroups.
Additional analyses from EMPA-REG OUTCOME
revealed that theCV benefit was gained by those with and
without HF at baseline, the latter comprising10% of the
study cohort.

55.  The CANVAS Program integrated data from two RCTs
(CANVAS and CANVAS-R) patients with DM at high CV
risk were randomized to canagliflozin 100300 mg o.d. vs.
placebo. After 3.1 years, canagliflozin significantly
reduced a composite three-point MACE by 14%
(P=0.02), but did not significantly alter CV death or
overall death.
 Similar to the findings in EMPAREG OUTCOME,
canaglifozin significantly reduced HF hospitalization.
 However, canagliflozin led to an unexplained increased
incidence in lower limb fractures and amputations (albeit
low numbers

56.  DECLARETIMI 58, After a median follow-up of 4.2
years, dapagliflozin met the pre-specified criterion
for non-inferiority for the composite three-point
MACE compared with placebo.
 In the two primary efficacy analyses, dapaglifozin did
not significantly reduce MACE, but resulted in lower
rate of the combined endpoint of CV death or HF
hospitalization.

57.  A meta-analysis of the three trials suggested
consistent benefits on reducing the composite of HF
hospitalization or CV death, as well as on the
progression of kidney disease, regardless of existing
atherosclerotic CVD or a history of HF, while the
reduction in MACE was only apparent in patients
with established CVD.

58.  The CV benefits of SGLT2 inhibitors are mostly unrelated
to the extent of glucose lowering and occur too early to be
the result of weight reduction.
 The rapid separation of placebo and active arms in the
four studies in terms of reduction in HF hospitalizations
indicates that the beneficial effects achieved in these
trials are more likely the result of a reduction in HF-
associated events.
 They could involve effects on haemodynamic parameters,
such as reduced plasma volume, direct effects on cardiac
metabolism and function, or other CV effects

59. Sulfonylureas
 Sulfonylureas lower blood glucose level by increasing
insulin secretion in the pancreas by blocking the KATP
channels. They also limit gluconeogenesis in the liver.
Sulfonylureas decrease breakdown of lipids to fatty acids
and reduce clearance of insulin in the liver .
 Sulfonylureas are currently prescribed as secondline or
add-on treatment options for management of T2DM.
 They are divided into two groups: first-generation
agents, which includes chlorpropamide, tolazamide, and
tolbutamide, and second-generation agents, which
includes glipizide, glimepiride, and glyburide.

60.  The first-generation sulfonylureas are known to have
longer half-lives, higher risk of hypoglycemia, and
slower onset of action, as compared to second-
generation sulfonylureas.
 Currently, in clinical practice, second-generation
sulfonylureas are prescribed and more preferred over
first-generation agents because they are proven to be
more potent (given to patients at

61.  lower doses with less frequency), with the safest profile
being that of glimepiride.
 Hypoglycemia is the major side effect of all sulfonylureas,
while minor side effects such as headache, dizziness,
nausea, hypersensitivity reactions, and weight gain are
also common.
 Sulfonylureas are contraindicated in patients with
hepatic and renal diseases and are also contraindicated
in pregnant patients due to the possible prolonged
hypoglycemic effect to infants.
 Drugs that can prolong the effect of sulfonylureas such
as aspirin, allopurinol, sulfonamides, and fibrates must
be used with caution to avoid hypoglycemia.

62.  . Moreover, other oral antidiabetic medications or
insulin can be used in combination with sulfonylurea
and can substantially increase the risk of
hypoglycemia.
 Patients on beta-adrenergic antagonists for the
management of hypertension can have hypoglycemia
unawareness.
 Sulfonylureas should be used with caution in
subjects receiving beta blockers

63. Meglitinide
 Meglitinides (repaglinide and nateglinide) are non-
sulfonylurea secretagogues, which was approved as
treatment for T2DM in 1997.
 Meglitinide shares the same mechanism as that of
sulfonylureas; it also binds to the sulfonylurea receptor
in β-cells of the pancreas. However, the binding of
meglitinide to the receptor is weaker than sulfonylurea,
and thus considered short-acting insulin secretagogues,
which gives flexibility in its administration.
 Also, a higher blood sugar level is needed before it can
stimulate β-cells’ insulin secretion, making it less
effective than sulfonylurea.

64.  Rapid-acting secretagogues (meglitinides) may be
used in lieu of sulfonylureas in patients with
irregular meal schedules or those who develop late
postprandial hypoglycemia while using a
sulfonylurea.
 None of the repaglinide and nateglinde don’t have
any CVRF.

65. Thiazolidinedione
 Like biguanides, TZDs improve insulin action. Rosiglitazone
and pioglitazone are representative agents.
 TZDs are agonists of PPAR and facilitate increased glucose
uptake in numerous tissues including adipose, muscle, and
liver.
 Mechanisms of action include diminution of free fatty acid
accumulation, reduction in inflammatory cytokines, rising
adiponectin levels, and preservation of β-cell integrity and
function, all leading to improvement of
 insulin resistance and β-cell exhaustion.
 However, there are high concerns of risks overcoming the
benefits. Namely, combined insulin-TZD therapy causes heart
failure. Thus, TZDs are not preferred as first-line or even step-
up therapy.

66.  Piolitazone exerts beneficial effect on number of CVRF
 1- increase plasma HDL
 2-decrease plasma TG and FFA levels.
 3-neutral on LDL and covert small dense LDL to larger
more buyoant particles
 4-reduces BP
 5-improves endothelial dysfunction
 6-ameliortaes insulin resistance
 7-decrease visceral fat
 8-increase adipnectin and reduces PAI and CRP and TNF

67. Insulin
 If non-insulin monotherapy like metformin at the
maximum tolerated dose does not achieve or maintain
the A1C target over 3 months, then a second oral agent
may be added to the regimen, a GLP-1 receptor agonist,
or basal insulin.
 Insulin therapy (with or without additional agents)
should be introduced in patients with newly identified
T2DM and1- frankly symptomatic (catabolic features like
weight loss, ketosis or features of hyperglycemia
including polyuria/polydipsia),
 2- and/or severely elevated blood glucose levels [≥300–
350 mg/dL (16.7–19.4 mmol/L)] or A1C [≥10–12%]

68. Basal Insulin
 Basal insulin is the initial insulin regimen, beginning at 10 U or
0.1–0.2 U/kg, depending on the hyperglycemia severity (titrating by
2–3 U every 4–7 days till glycemic goal is reached).
 Use of basal insulin greater than 0.5 U/kg indicates the need for use
of an additional agent.
 Basal insulin is usually added to oral metformin and possibly one
additional non-insulin agent like DPP-4 or SGLT-2inhibitor.
 NPH (neutral protamine Hagedorn) insulin carries low risk of
hypoglycemia in individuals without any significant past history,
and is low cost.
 Newer, longer acting, basal insulin analogs have superior
pharmacodynamic profiles, delayed onset and longer duration of
action but low risk of hypoglycemia, albeit higher cost.

69.  If basal insulin contributes to acceptable fasting blood glucose, but
A1C persistently remains above target, mealtime insulin may be
added.
 Rapid-acting insulin analog (lispro, aspart, or glulisine) may be
used and administered just before meals.
 The glucose levels should be monitored before meals and after the
injections.
 Another approach to control the periprandial glucose excursions
may be to add twice-daily premixed (or biphasic) insulin analogs
(70/30 aspart mix, 75/25 or 50/50 lispro mix).
 The total present insulin dose may be computed and then one-half
of this amount may be administered as basal and the other half
during mealtime, the latter split equally between three meals.

70.  Regular human insulin and human NPH–Regular
premixed formulations (70/30) are less expensive
alternatives to rapid-acting insulin analogs and premixed
insulin analogs, respectively, but their unpredictable
pharmacodynamic profiles make them inadequate to
cover postprandial glucose changes.
 Sometime, bolus insulin needs to be administered in
addition to basal insulin. Rapid-acting analogs are used
as bolus formulations due to their prompt onset of
action.
 Insulin pump (continuous subcutaneous insulin
infusion) may be used instead to avoid multiple
injections.

71.  Inhaled insulin (Technosphere insulin-inhalation
system, Afrezza) is now available for prandial use.
However, the dosing range is limited. Use of inhaled
insulin requires pulmonary function testing prior to
and after starting therapy. It is contraindicated in
subjects with asthma or other lung diseases.

72.  During insulin therapy, sulfonylureas, DPP-4 inhibitors,
and GLP-1 receptor agonists are stopped once more
complex insulin regimens beyond basal insulin are used.
 In patients with inadequate blood glucose control,
especially if requiring escalating insulin doses, TZDs
(usually pioglitazone) or SGLT2 inhibitors may be added
as adjunctive therapy to insulin.
 Insulin injections can cause weight gain or loss. Insulin
drives potassium into the cell and can cause
hypokalemia. Components of the insulin preparation
have the potential to cause allergy.
 Insulin injections, along with the use of other drugs like
TZDs, can precipitate cardiac failure.

73.  Urinary tract infections leading to urosepsis and
pyelonephritis, as well as genital mycosis, may occur
with SGLT2 inhibitors.
 SGLT2 inhibitors may rarely cause ketoacidosis.
Patients should stop taking their SGLT2 inhibitor
and seek medical attention immediately if they have
symptoms of ketoacidosis (frank nausea or vomiting,
or even non-specific features like tiredness or
abdominal discomfort).

76. Reducing SBP to <130 mmHg may benefit patients with a particularly high risk
of a cerebrovascular event, such as those with a history of stroke.
The UKPDS post-trial 10 year follow up study reported no persistence of the
benefits of the earlier period of tight BP control with respect to macrovascular
events, death, and microvascular complications, while initial between-group BP
differences were no longer maintained.
In the ADVANCE trial, the combination of perindopril and indapamide
reduced mortality, and the benefit was still present, but attenuated, at the end
of the 6 year posttrial follow-up, without evidence of a sex difference.159 Thus,
optimal BP control is important in reducing the risk of micro- and
macrovascular complications, and must be maintained if these benefits are to
be sustained.

77. All available BP-lowering drugs (except beta-blockers) can be used, but
evidence strongly supports the use of a RAAS blocker, particularly in
patients with evidence of end-organ damage (albuminuria and LV
hypertrophy).
BP control often requires multiple drug therapy with a RAAS blocker, and a
calcium channel blocker or a diuretic, while the combination of an ACEI with
an ARB is not recommended.
A combination of two or more drugs at fixed doses in a single pill should be
considered, to improve adherence. The betablocker/ diuretic combination
favours the development of DM, and should be avoided in pre-DM, unless
required for other reasons.
Among beta-blockers, nebivolol has been shown not to affect insulin sensitivity
in patients with metabolic syndrome

78. Blood pressure changes with glucose-lowering treatments
Trials testing GLP1-RAs have shown evidence of a slight, but significant,
BP decrease, partly due to weight loss.
In the Liraglutide Effect and (LEADER) trial, a sustained decrease was
observed (SBP/DBP 1.2/0.6 mmHg) with a slight increase in heart rate
(3 b.p.m.).
SGLT2 inhibitors induced a larger BP decrease (SBP/DBP 2.46/1.46
mmHg) without heart rate changes.
The BP-lowering effects of these drugs have to be taken into
consideration when managing BP.

80. In both T1DM and young-onset T2DM, there is a paucity of evidence
to indicate the age at which statin therapy should be initiated. To
guide an approach, statins are not indicated in pregnancy,and should
be avoided in women with T1DM or T2DM who are planning
pregnancy.
In the absence of vascular damage, and in particular
microalbuminuria, it seems reasonable to delay statin therapy in
asymptomatic patients with DM until the age of 30 years. Below this
age, statin therapy should be managed on a case-by case basis taking
into account the presence of microalbuminuria, end organ damage,
and ambient LDL-C levels.

81. Statins are safe and generally well tolerated. Adverse
events, except for muscle symptoms, are rare. In the
majority of cases of myopathy or rhabdomyolysis, there
are drug interactions with a higher-thanstandard dose of
statin or combination with gemfibrozil.
Evidence indicates that most patients (70-90%) who report
statin intolerance are able to take a statin when
rechallenged.1Patients may be rechallenged with the
same statin unless they have creatine kinase elevation.
Evidence supports a lower rate of side effects with
lowdose rosuvastatin or pravastatin

82.  Statin therapy has been associated with new-onset
DM: for every 40mmol/L (mg/dL) reduction of LDL-
C by statins, conversion to DM is increased by 10%.
 The risk of new-onset DM increases with age and is
confined to those already at risk of developing DM.
 Nevertheless, the benefits in terms of CV even
reduction greatly exceed the risks of statin therapy,
and this has been confirmed in patients at low CV
risk.

83.  Type 1 or Type 2 Diabetes and High Cardiovascular Risk (ODYSSEY
DM-INSULIN) trial, alirocumab, compared with placebo, reduced
LDL-C by 50% in patients with DM after 24 weeks of treatment.
 (FOURIER) trial, patients with atherosclerotic CVD on statin
therapy were randomly assigned to a fixed dose of evolocumab or
placebo.
 The results demonstrated that the primary composite endpoint (CV
death, MI, stroke, hospital admission for unstable angina, or
coronary revascularization) was significantly reduced.
 Similar results were obtained from the ODYSSEY OUTCOMES
(Evaluation of Cardiovascular Outcomes After an Acute Coronary
Syndrome During Treatment With Alirocumab.
 The results and the hazards ratio were more significant in the DM
arn.

84.  In patients with high triglyceride levels [>_2.3
mmol/L (200mg/dL)],
 lifestyle advice (with a focus on weight reduction and
alcohol abuse, if relevant) and improved glucose
control are the main targets. Both
 the Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD) and ACCORD studies
demonstrated that administration of fenofibrate on
top of statins significantly reduced CV events, but
only in patients who had both elevated triglyceride
and reduced HDL-C levels

85.  Fibrates may be administered in patients with DM
who are statin intolerant and have high triglyceride
levels. If triglycerides are not controlled by statins or
fibrates, high-dose omega-3 fatty acids (4 g/day) of
icosapent ethyl may be used (REDUCE IT)

86. Primary prevention

87.  In 2009, the Antithrombotic Trialists’ Collaboration
published a meta-analysis of primary prevention trials
including 95 000 individuals at low risk.227 They
reported a 12% reduction in CVD outcomes with aspirin,
but a significant increase in major bleeds.
 Recent large trials in patients at moderate risk, which
 (i) excluded DMand (ii) specifically recruited patients
with DM,
 were unable to progress the argument that aspirin should
be used in primary prevention. (ASCEND)

88. Secondary prevention

89. BB

91. ACS

92.  A post hoc analysis of the CHARISMA (Clopidogrel for
High Atherothrombotic Risk and Ischemic Stabilization,
Management and Avoidance) trial suggested that
clopidogrel, added to background aspirin, may increase
overall and CV death in DM patients with
microalbuminuria (>_3 0lg/mL).
 In patients with ACS, DAPT with prasugrel or ticagrelor
on a background of low-dose aspirin was superior to
DAPT with clopidogrel in the DM subgroup, with a
benefit similar to that in the population without DM.
Patients with DM tended to have a greater reduction in
ischaemic events with prasugrel than clopidogrel,
without increase in major bleeding.

93.  (COMPASS) trial recruited 27 395 patients with
stable atherosclerotic disease and showed that low-
dose aspirin (100 mg o.d.) combined with a low dose
of rivaroxaban (2.5 mg b.i.d.) was superior to aspirin
alone in preventing MI, stroke, or CV death.
 38% of the population in the compass group were
DM, and they showed the same benefit as in non
DM..

94. Revascularization
 3 RCT were comparing PCI vs CABG:
 (CARDia) trial, 510 patients with multivessel or
complex single-vessel CAD were randomized to
CABG or PCI, with a bare-metal stent (BMS) or a
first-generation DES.
 There were no differences between the groups for
the primary endpoint of 1 year death, MI, or stroke,
but this trial was also underpowered. Repeat
revascularization occurred with PCI

95.  (FREEDOM) trial
 randomized 1900 patients with multivessel CAD, but no left main
stenosis, to elective CABG or PCI with a first-generation DES.
 The primary endpoint of all-cause death, non-fatal MI, or stroke at
5 years occurred in 26.6% of patients in the PCI group and in 18.7%
patients in the CABG group (P=0.005).
 The incidences of death (16.3 vs. 10.9%; P=0.049) and MI (13.9 vs.
6.0%; P < 0.001) were higher in the PCI group, while the incidence
of stroke was lower (2.4 vs. 5.2%; P=0.03).
 While patients on insulin had higher event rates, no significant
interaction for the primary endpoint was observed between insulin
status and treatment effect.
 In addition, no interaction was observed between treatment effect
and degree of coronary complexity, as assessed by the Synergy
between PCI score (TAXUS) and the surgery score (Syntax).

96.  SYNTAX trial, there were no differences between PCI
with a first-generation DES and CABG in the
composite endpoint of death, stroke, or MI at 5
years.
 However, the 5 year rates of major adverse CV and
cerebrovascular events (MACCE) (PCI 46.5% vs.
CABG 29.0%; P < 0.001), and the need for repeat
revascularization (HR 2.75; P < 0.001) were higher
in the PCI group.

97.  Everolimus-Eluting Stent Implantation in the
Treatment of Patients with Multivessel Coronary
Artery Disease (BEST) study, the rate of the primary
endpoint of death, MI, or target vessel
revascularization (TVR) at 2 years was significantly
higher in the PCI than the CABG arm.
 XIENCE versus Coronary Artery Bypass Surgery for
Effectiveness of Left Main Revascularization
(EXCEL) will again show no statistically significant
differences between PCI and CABG for left main
disease

101. DM and HF

104. DM and arrhythmia

106. LEAD

108. DM and CKD