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Diabetes
➊ Lifestyle interventions: Type 2
The authors state that these ‘remarkable’ findings are a ‘radical change in understanding T2DM’. This research ‘carries major implications for information to be given to
BJGP2013;63:60
newly diagnosed patients, who should know that they have a
potentially reversible condition and not one that is inevitably
This editorial discusses the importance of trying to pick up progressive’.
pre-diabetes and early diabetes, using risk scores and then HbA1c tests (as recommended by the NICE guideline). It also
discusses the increasing evidence that Type 2 diabetes can not
‘The Newcastle diabetes-reversal diet’
only be prevented, but can also be ‘cured’.
• We have known for years, that bariatric surgery in obese
• liquid meal replacements = to 600 kcal a day
patients results in long-term normalisation of blood • 3 portions of non-starchy vegetables a day = 200 kcal
• 3 litres of water or calorie-free drinks
- 88% of obese patients with diabetes remain free of
• Symptoms of headache, dizziness, fatigue etc. are common
diabetes at6 years of follow-up following bariatric surgery in the first few days but improve after 2–4 days • Evidence is now appearing that similar results can be
✻ A more recent and larger (n=90) study
✻ ‘Reversing’ type diabetes with weight loss
(BJGP2013;63:81, see obesity section for more on this) showed that in patients with severe obesity (BMI>40), a supervised, Diabetologia 2011;54:2506
supported plan using a micronutrient-replete liquid low This interesting and very small study (n=11!), a pilot funded energy diet (800kcal daily) was feasible and acceptable in by Diabetes UK, got a lot of publicity as it made the brave primary care. Patients received the low energy drink for 12 claim that type 2 diabetes is potentially reversible with an
weeks, and thereafter had gradual re-introduction of food, the extreme low calorie diet. Patients had had diabetes for < 4
plan supervised by trained practice nurses.
• At 12 months, there was a mean loss of 12 kg and 30% of
the initial group had maintained their target weight loss
• Patients were put on an extreme 800 kcal a day diet with
(>15kg)
dietary supervision (see box below) After just 1 week, • This was a feasibility study, but as the results stand this
is the first study from primary care that approach the • After 8 weeks of the study all markers of type 2 diabetes
recommended guideline target of 15% weight loss. The normalised e.g. glucose levels, insulin sensitivity and cost was £860 per patient entered into the study, which is pancreatic and hepatic fat and the pancreas regained the considerably cheaper than bariatric surgery… • Average weight loss was 15 kg, 15% of body weight
✻ The BJGP (BJGP2013;63:60) concludes that:
• The participants were followed up 3 months later. During
this time they had reverted to a normal diet, but with • If patients can lose 15-20% of their body weight and keep it
advice on portion sizes and healthy eating. Mean weight off, there is a good chance of their diabetes being cured • Whilst it is true that most people will not be able to make
• 3.1kg. 7 out of 10 tested remained free of diabetes.
• suggests that there is a health-motivated sub-set of the
The data are consistent with the hypothesis that the population who can reverse their diabetes completely and abnormalities of insulin secretion and insulin resistance that underlie T2DM have a single, common aetiology: excess fat
• People should be advised this at the time of diagnosis
accumulation in the liver and pancreas. And that decreasing
pancreatic fat is associated with normalisation of beta-cell These conclusions concur with the results of a recent large function, and liver fat with improving insulin resistance.
trial of 5,000 overweight patients with type 2 diabetes 2 | HOT TOPIC ~ DIABETES
NB MEDICAL EDUCATION
(JAMA2012;308:2489) which compared an intensive patients. In the last year a once weekly prolonged- release lifestyle programme to a control group receiving support formulation was licensed, and the DTB reviewed its role.
and education. A small minority of the intensive group had - The DURATION trial showed that the once weekly
significant and sustained remission of diabetes at 4 years formulation was ‘non-inferior’ to the twice daily and showed some benefits in terms of glycaemic control - The well-known side effects of nausea and vomiting
were reported less often with the once weekly ➋ Drug treatments
- Pancreatitis has been reported in some patients with
exenatide, however patients with T2DM may be at ✻ DP-4 inhibitors (‘gliptins’) for treatment of T2DM
- NICE estimate the cost is comparable to that of other
BMJ2012;344;e1369
For the vast majority though diabetes is a progressive condition. So, after lifestyle change and metformin, What do the guidelines say?
inevitably other agents will have to be added. But which • NICE e
agent should we add as second-line once metformin is no - Exenatide is a third-line option in patients with a BMI
>35, or in some selected patients with a BMI <35 - The once weekly form is an option as part of triple
‘Gliptins’ (DP-4 inhibitors) are increasingly promoted as an
therapy with metformin and either a sulfonylurea or alternative to sulfonylureas at step 2. NICE suggest adding a
glitazone (or dual therapy of one of these drugs is not DP-4 inhibitor to metformin instead of a sulfonylurea if there is risk of hypoglycaemia or a sulfonylurea is not tolerated. • The SMC in Scotland have also approved it as a third line
This recommendation however was based on a smaller number of trials, all published before 2009, and since then • The DTB conclude the metabolic benefits appear
favourable, although of course we lack data on long-term This new systematic review and meta-analysis
(BMJ2012;344;e1369) updates the evidence. It compared
all trials comparing DP-4 inhibitors to metformin as single ✻ Gliptins and pancreatitis Drug Safety Update,
agents, and also compared to other agents as add on therapy 2012 e
This recent Drug Safety Update looked at the evidence and • Compared with metformin as monotherapy, DP-4
inhibitors are associated with smaller declines in HBa1c • Cases of pancreatitis have been reported with all the
‘gliptins’, but the background risk is very low (reports • Compared to sulfonylureas as add-on therapy
- Similar outcomes in terms of HBA1c
• Patients should be warned however about the symptoms
of acute pancreatitis i.e. persistent severe abdominal pain, - A neutral effect on body weight, compared to
- Lower risk of hypoglycaemia
• We as GPs need to be aware of these risks and counsel
• Conclusions:
- Metformin remains unchallenged as first-line therapy
The same risk is present of course for GLP-1 agonists such as - In patients that need add-on therapy, DP-4 inhibitors
exenatide (BMJ2013;346;f1304), which have been linked with can lower HBA1c similarly to sulfonylureas but with a doubling of risk from 0.3% to 0.6%. In the UK several drugs int his class already carry warnings re pancreatitis.
- We lack data on long-term clinical end-points, the drugs
are more expensive and uncertainty about long-term ✻ Pioglitazone
safety (NB remember the glitazone story!) should also Following the withdrawal of rosiglitazone, pioglitazone has been linked with bladder cancer. The MHRA advise (Drug
✻ Once-weekly exenatide DTB 2012;50;78
• Not to use if previous or current history of bladder cancer
Exenatide, a GLP-1 receptor agonist, is of course now well- established as a therapy, principally as an alternative option to • Review after 3 to 6 months after commencing therapy,
insulin and of course does not cause weight gain. It still needs and only continue if there is evidence of benefit e.g. with a twice daily s/c injection however, which is a barrier for some 3 | HOT TOPIC ~ DIABETES
NB MEDICAL EDUCATION
• Use in elderly patients should be carefully considered and
• The incremental cost of prescribing analogues rather
if treatment is started they should be carefully monitored than human insulin is huge, estimated to be £625M pa! They cost 2 to 4 times as much as human (NB although A more recent study (BMJ2012;344;e3645) confirms this
glargine will be coming off patent in the next year or two) association, and found that two years of daily treatment • NICE guidelines for Type 2 diabetes is that human insulin
doubles the risk of bladder cancer. An associated editorial concludes (BMJ2012;344;e3500) that given the effect of • effective approach, and that human insulins should be
pioglitazone on reducing CV events is uncertain, prescribers
first-choice. Analogues are a second-line option for those can question whether or not the benefit-risk ratio of
pioglitazone is still acceptable
for patients with diabetes.
Weight gain is a significant problem when patients go
on to insulin. It occurs equally with both analogues and
✻ New insulins in type 2 diabetes
human insulin, and averages at 6kg plus a 6cm gain in waist BMJ2012;314:e4611
circumference. Metformin should be continued and used in conjunction with insulin whenever possible as it enhances Up to 40-50% of people with type 2 diabetes will end the effect of insulins and restricts weight gain. Sulfonylureas up needing insulin treatment. This very useful paper increases risk of weight gain and hypos.
summarised the role of the confusing array of new insulins, including a discussion of the evidence of their benefits compared to much cheaper human insulins.
➌ Intensive glucose lowering in type 2
ANALOGUE
Short-acting
BMJ2011;343:d4169
The benefits and risks of intensive glucose lowering in Intermediate Insulatard (all
T2DM has caused a huge amount of controversy in recent or long acting isophane) Humulin 1
years as major trials have shown surprising results. This meta-analysis of RCTs (BMJ2011;343:d4169) is the most Premixed
comprehensive systematic review published looking at preparations
the effect of targeting intensive versus conventional glycaemic control in T2DM, looking at mortality, micro and The theoretical benefits of the analogues are:
macrovascular complications. They looked at data from • Standard insulins reach the blood stream before food,
35,000 patients in 13 RCTs, including the above studies.
which may cause more ‘swinging’ in blood glucose levels They found that intensive treatment:
• Did not significantly affect all-cause mortality or
• Long acting insulatard has peak absorption between 4 to
• Intensive therapy did reduce the risk of non-fatal MI (15%
• meal may peak during the night causing nocturnal
hypoglycaemia followed by a rebound as insulin fades - There was no significant reduction seen in other
The genetically engineered analogues are modified to allow for faster absorption (e.g. rapid acting ones can be injected • Over a period of 5 years
at the same time as a meal) and smoother absorption, thus - 117 to 150 patients would need to be treated to prevent
reducing the nocturnal hypoglycaemia. A common rationale for prescribing short-acting analogues is convenience in that - 32 to 142 would need to be treated to prevent one
- 15 to 52 would need to be treated to cause one extra
What does the evidence show?
• Systematic review show that substituting human for
analogue insulins does not improve glucose control, and Conclusion: ‘the overall results show limited evidence for the
in most studies they also do not affect the rate of severe benefit of intensive glucose lowering on all cause mortality and deaths from cardiovascular causes’ and ‘the risk/benefit - Analogues may cause fewer episodes of minor and
ratio of intensive glucose lowering in the prevention of macrovascular and microvascular events remain uncertain’. 4 | HOT TOPIC ~ DIABETES
NB MEDICAL EDUCATION
How should we interpret this is practice? (BMJ2011;343;d4243)
patients with diabetes, both type 1 and type 2 and with or • The result is consistent with previous studies that show
that: glucose lowering is less efficacious and more difficult • No effect was observed for ARBs compared to placebo,
to achieve than lipid lowering and BP control although it is possible there may be some benefit in very • They calculate that the absolute number of cardiovascular
events prevented by the different interventions per 1,000 Conclusion: ACEi reduce the incidence of new onset kidney
- Lowering HbA1c by 1% = 3 events prevented
disease and mortality in people with diabetes, with similar - Lowering LDL by 1mmol/L = 8 events prevented
benefits in those with or without hypertension. The results - Lowering BP by just mmHg = 12 events prevented.
‘suggest that ACEi could be routinely considered for the primary prevention of microvascular disease and death in people with diabetes regardless of blood pressure levels’, So, what is the optimal target for HbAIc?
although more studies are needed to evaluate the cost- The current QOF target has of course changed to 7.5%. It was effectiveness of this approach.
increased from 7% following concern at the risk/benefit ratio and The ‘Cardiff UK GPRD Study’ (Lancet 2010, 375;481). The (NB comment: Most of these trials included patients with study found that the lowest mortality is seen with a HbA1c
well-established diabetes, so you could not extrapolate of around 7.5%. Both higher and lower HbA1c levels were
the same conclusion to patients with new or recent onset associated with higher mortality. Most commentators agree diabetes who will have much lower levels of risk) that a target of 7.5% (58mmol/l) is reasonable.
KISS: Type 2 Diabetes
What about glycaemia in type 1 diabetes?
It is very important to remember that the above studies are all in type 2 diabetes. As discussed in a recent Lancet editorial (Lancet2011;378;103) the evidence for more • Education and lifestyle are priorities. Strong emphasis on
intensive glucose control in type 1 diabetes is strong. The lifestyle advice. Smoking, diet, exercise, nutrition. Diet: general
health eating advice i.e. high fibre, low GI-foods, little saturated
seminal DCCT study (NEJM2005;353;2643) clearly showed fat, oily fish, avoid excess energy intake and low salt! See the benefits of intensive control, including reducing cardiovascular disease and mortality.
Does self-monitoring improve control in type 2 diabetes?
A recent meta-analysis of RCTs (BMJ2012;344;e486) shows
that compared to controls, self- monitoring reduces HBA1c marginally, the result being statistically significant but of doubtful clinical significance (a reduction of 0.19% at 12 months). The authors conclude the evidence is not convincing to support self-monitoring. Obviously if patients are on insulin, they should self- monitor.
➍ ACE-inhibitors to prevent diabetic
Cochrane 2012: Ce
Diabetes is the leading cause of kidney disease in the UK, and 20-40% of people with diabetic kidney disease go on to develop end stage renal failure. This Cochrane review (26 • ACEi reduce the development of new onset micro and
macroalbuminuria in patients with T2DM both with and without hypertension (RR 0.71, 29% RRR), and reduce mortality (RR 0.84, 16% RRR) when compared to placebo • Clear benefits were seen in patients without hypertension
at baseline, and when ACEi were compared to CCB • The benefits were consistent across a broad range of
5 | HOT TOPIC ~ DIABETES
NB MEDICAL EDUCATION
Type 2 Diabetes: KISS Summary
Based on above papers, NICE guideline, MeRec Bulletin June 11 and DTB2010:48;50 and ‘the emphasis in type 2 diabetes should remain on tight control STEP ONE, single agent
of lipids and blood pressure with reasonable but not exaggerated • Metformin first-line drug, if target not reached with lifestyle
attempts to control glycaemia’. Lancet2011;378;103 change. Step-up dose to minimise GI side effects and consider slow-release if poor GI tolerability.
Blood pressure management (A=ACEI, C= CCB, D = thiazide
• Sulfonylurea if metformin not tolerated
diuretic) Target is 140/80, or 130/80 if small vessel disease • There is evidence to support all patients being offered an ACEi
STEP TWO, add second drug
even in normotensive patients without amicroalbuminuria, as • Metformin + sulfonylurea
they help prevent or delay onset of renal disease and reduce • OR metformin plus DPP-4 inhibitor (gliptin) if risk of
hypoglycaemia or sulfonylurea not tolerated • Low salt diet! (Cochrane2010, CD006763) effect to one drug
STEP THREE, add insulin or exenatide to metformin and
• Start A. If African-Caribbean descent start with A+D or A+C. If
possibility of pregnancy start with C.
• Use human isophane insulin, or consider exenatide if BMI>35
• C or D as second-line, add the other drug as third line e.g. A
or if BMI<35 and insulin unacceptable… • Consider triple oral therapy (metformin + sulfonylurea + gliptin
• Add other agents (e.g. alpha or beta-blocker) as required
or pioglitazone) if insulin unacceptable for whatever reason Blood lipids
• Statins for virtually all patients…
Calculate albumin:creatinine ratio (on first pass EMU) and eGFR • If under 40 and poor risk factor profile → offer statin
• If over 40 but otherwise low CV risk → calculate their risk
• If diabetic nephropathy confirmed (ACR > 2.5mh/mmol men
and > 3.5 women) offer ACEI with dose titration to maximum • ffer statins if >20% 10 year CVD risk. If
dose, substitute ARB if not tolerated and maintain BP<130/80 over 40 but ‘normal to high CV risk for diabetes’ • If Tg > 4.5 despite optimised glycaemic control, consider adding
Retinal screening at diagnosis, and annual thereafter, using Aspirin for CVD prevention?
• YES if established cardiovascular disease
Neuropathic:
• For primary prevention, the guideline recommends low dose
• Pain Formally ask. Rx with TCA or duloxetine (see neuropathic
aspirin if at high CVD risk but a recent meta-analysis of pain section) Gastroparesis Suspect with unexplained bloating
primary prevention trials in diabetes did NOT show benefit or vomiting; trial of metoclopramide or domperidone • Erectile dysfunction Review annually. Offer a PDE-5 inhibitor
Glucose lowering
• Target: individualise with patients
• Foot
• A target of 7.5% (59) is optimal based on current evidence if it
Depression Ask those 2 questions.
• Lower levels may be appropriate for some individuals with
• Lifestyle change first-line intervention
Type 2 Diabetes: NB possible practice points…
• Research suggests that overweight patients can ‘reverse’
• Lowering glucose is important, but BP lowering and statins are
the effects of type 2 diabetes with supervised severe calorie restriction. Should we offer this option to patients? For patient • New evidence supports gliptins in addition to metformin as
an option at Step 2; latest evidence shows less likely to cause • Be aware of new classification of diabetes, including the
weight gain and hypos than sulphonylurears with equivalent metabolic control. Warn patients re pancreatitis risk.
• HbA1c may now be used for diagnosis with a cut-off of
• Once weekly exenatide has favourable results compared to the
6.5%, but only in patients without other factors which may
influence it such as anaemia and haemoglobinopathy • Gliptins: evidence supports them as add-on to metformin, but
• For a simple guide to the new HbA1c units e

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