The Glimepiride tab is useful for diabetes
What comes after metformin?
Metformin is still number 1 in the treatment of type 2 diabetes because of its good effectiveness, the low risk of hypoglycaemia and the lack of risk of weight gain. Sometimes, however, intolerance occurs or the lowering of blood sugar is insufficient. Good alternatives are available today for these cases.
Metformin is undisputedly the first-line therapy in the treatment of type 2 diabetes and, in addition to a very good reduction in HbA1c, has other positive properties that justify its priority. It reduces all-cause mortality and mortality from cardiovascular events , leads to weight loss, and reduces the risk of hypoglycaemia [1, 3].
Limitations in metformin therapy, such as chronic renal insufficiency, have been put into perspective . In Germany, use has recently been permitted up to an eGFR of more than 30 ml  (Table 1). Metformin can be used in chronically stable heart failure . In a meta-analysis, mortality was 22% lower in heart failure patients who took metformin compared to those who did not. Caution is advised in acute or unstable heart failure . Liver insufficiency is still a contraindication, although data are also available here that show significantly improved survival for patients with NASH-induced liver cirrhosis [7, 8, 9]. Metformin therapy leads to a reduction in all-cause mortality in patients with moderate CKD, CHF and CLD .
In the case of a GFR below 60, the comorbidities must be taken into account and intercurrent deterioration in kidney function in the context of an infection, an operation or the administration of diagnostic contrast medium must be taken into account and therapy should be paused in these cases until the kidney function is checked.
How metformin works by inhibiting gluconeogenesis in the liver, improving glucose uptake in muscle cells, and reducing glucose uptake from the gut, and is not fully understood. There is an improved effect of the incretin hormones as well as further interactions, including the bile acid metabolism.
If a metformin formulation is intolerant, you should first try another preparation without lactose or with a different formulation because of the many advantages. If there is still an intolerance or if the blood sugar control under monotherapy with metformin is not sufficient, the NVL  (Update 2014) leaves the choice of the listed antidiabetic drugs open, so that every doctor can decide for himself which one to choose.
In combination therapy with metformin, in addition to sulfonylureas, a DPP4 inhibitor, an SGLT-2 inhibitor, a GLP-1 analogue and insulin therapy can be considered for GKV insured persons.
Sulphonylureas are prescribed less and less
The combination therapy of sulfonylureas (SU) with metformin is questioned in the NVL for safety reasons by both the DEGAM and the DDG, since the data on this medication already indicated a higher cardiovascular mortality when the NVL was drawn up . Since then, additional studies and meta-analyzes have confirmed this rather than invalidating it . This is why the number of SU regulations has rightly decreased significantly in recent years  and is playing an ever smaller role in practice.
If SU is used, the patient must be carefully informed about the risk of hypoglycaemia (dizziness, falls, food cravings, effects on road safety, etc.). B. as a result of skipping a meal. Monitoring of renal function is important because SU can accumulate and, without dose adjustment, can lead to long-term hypoglycaemia with reduced GFR, sometimes fatal .
Insulin secretagogues such as SU or repaglinide should be discontinued at the latest when insulin therapy is started, because of the incalculable risk of hypoglycaemia in combination therapy .
DPP4 inhibitors as a safe and effective alternative
In many cases, DPP4 inhibitors have replaced SU and represent the majority of prescriptions in practice today - instead of, after or in addition to metformin . The way these substances work depends on the increase in glucose after a meal. It takes place by inhibiting the breakdown of the body's own incretin hormone GLP, which leads to insulin secretion and lowers the blood sugar level without the risk of hypoglycaemia.
A dose adjustment is recommended in the case of reduced eGFR for sitagliptin and saxagliptin, although the therapeutic index for gliptins is large.
Side effects are very rare. A slightly increased risk of pancreatitis does not play a role in everyday clinical practice [16, 17]. A safety study  confirmed that, compared to the comparison group, the substance sitagliptin did not lead to more cardiovascular events, ie it provided the proof of cardiovascular safety required in the study. The same applies to saxagliptin, whereby the hospitalization rate for heart failure was increased, but without higher mortality in the verum group .
The Federal Joint Committee (G-BA) again awarded the substance sitagliptin a minor additional benefit in December 2016 .
If non-inferiority was documented in the twelve-month data for sitagliptin in comparison with SU, long-term data indicate a sustained effect of the DPP4 inhibitor in contrast to SU . With SU, there is a loss of effectiveness in the context of secondary failure , which is also supported by the later onset of insulin requirement for patients on DPP4 inhibitors compared to SU .
Insulin therapy: a big step
For my patients, insulin therapy is always a big change in the treatment of their type 2 diabetes, but it is a good option with high fasting blood sugar levels, which must, however, be accompanied by good diabetes education, as we give our patients the strongest blood sugar-lowering substance in the Hand we have.
The patients must be particularly well informed about the symptoms and dangers of hypoglycaemia, which, in addition to the recommendations described in the SU (see above), must also contain instructions on how to intercept hypoglycaemia with rapid KH (e.g. apple juice or grape sugar). Patients should always have these emergency carbohydrates with them so that they can access them at any time. The training also includes a good introduction to blood sugar self-monitoring, which patients should ideally always have access to.
With insulin therapy there is more hypoglycaemia with increasing duration of the diabetes , whereby the modern analog insulins perform better than the older molecules and formulations depending on the course of action.
In retrospective registry studies associated with the higher risk of hypoglycaemia, more CVD events and higher mortality [25, 26, 27] and a higher thromboembolic risk  have been described. The cardiovascular safety of therapy with insulin glargine versus standard has been demonstrated .
SGLT-2 inhibitors: a milestone
The SGLT-2 inhibitors (dapagliflozin and empagliflozin in Germany) are a group of substances which, completely independent of the functionality of the remaining beta cell mass, lower blood sugar by reducing the amount of glucose filtered in the glomerulum. About 70 g more glucose are excreted in the urine every day. In addition to lowering blood sugar, this leads to an increased amount of urine of approx. 300 ml, thus to a slight depletion of volume and an associated lowering of blood pressure, also through increased sodium excretion, as well as to a loss of energy, which leads to a weight loss of approx. 3 - 5 kg of body weight leads until equilibrium is established.
The large cardiovascular safety study EMPA-REG  described a significant superiority for the SGLT-2 inhibitor empagliflozin in relation to the examined population.
In people with diabetes who had a cardiovascular event, a reduction in mortality, cardiovascular mortality and hospitalization for heart failure has been shown for empagliflozin regardless of the same diabetes setting in the comparison group. In addition, there was an improvement in the renal parameters. The G-BA found a considerable added benefit for this group .
The European Commission has approved a new version of the existing approval for empagliflozin, according to which this SGLT-2 inhibitor can be used both to lower blood sugar and to reduce cardiovascular mortality in people with type 2 diabetes . Many people with diabetes who belong to this risk group can benefit from this substance. However, the necessary education about a rather harmless but taboo side effect - balanitis or vaginitis caused by fungal infections - is a small obstacle. The prescription of this SGLT-2 inhibitor in patients with previous CV damage should be assessed as a practice specialty .
With SGLT-2 inhibitors, normoglycemic diabetic ketoacidosis can very rarely occur, which is a new form of a known diabetes complication and which is noteworthy as it is potentially life-threatening [34, 35].
GLP-1 analogues, an underestimated class of substances
In terms of numbers, GLP-1 analogues do not play a major role in general practitioner practice to this day, mostly because of the price, but also because they have to be injected subcutaneously and initially have a side effect profile with nausea etc. that worsens adherence to therapy.
In the cardiovascular safety study (LEADER), liraglutide, like empagliflozin, led to a reduced mortality in the examined group of patients with pre-existing cardiovascular diseases or high cardiovascular risk .
The mode of action via an exogenous increase in the GLP level leads to increased glucose-dependent insulin secretion by the beta cell, more than with the DPP-4 inhibitors without the risk of hypoglycaemia.
Additional advantages are a weight loss of 3 - 5 kg body weight, which comes about through a central influence on the saturation center, the patient eats less and drinks less. Nausea and vomiting are mostly dose-dependent, temporary side effects that occur more or less with all substances, including those that are administered weekly. A benefit assessment was not carried out for liraglutide because no AMNOG assessment procedure had to be carried out. The G-BA found an additional benefit for the substance dulaglutide to be injected once a week in patients who received dulaglutide in addition to therapy with short-acting insulin with or without metformin . The weekly administration is a significant relief for many of our patients and improves adherence to therapy considerably.
Let the patient have a say
In everyday practice, there is often little time to weigh the effects and side effects of drugs with type 2 diabetics. However, it is worth getting the patient on board, as they read the package insert regularly and the likelihood that they will take the medication as prescribed crucially depends on whether they feel safe and their fears are being taken seriously.
The great success of the DPP4 inhibitors can therefore be explained by the fact that the effect is strong without the risk of weight gain and hypoglycemia. Side effects are manageable and easy to take, so the time required for clarification for the family doctor is usually low.
The minor additional benefit granted by the G-BA makes it possible to prescribe it in an economically secure manner in practice.
The significant advantage of empagliflozin for cardiovascular risk patients with type 2 diabetes, the recognized additional benefit and the specialty in practice will rightly lead to a special position for this substance in the treatment of this risk group.
The therapy of type 2 diabetes can be positively influenced in every stage of the disease by sufficient knowledge of the patient about his disease, which is why his knowledge should be refreshed again and again using the inexpensive, low-side-effect diabetes education instrument. This is the best way to influence the patient's lifestyle in terms of diet and exercise, but also to influence adherence to therapy. During group training, the patients repeatedly gain motivation and learn that they are not helpless and alone at the mercy of their illness, but can influence it themselves.
Type 2 diabetes is a vascular disease and the patient has a two to four times higher cardiovascular risk.
In addition to regulating blood sugar, regulating blood pressure (<140/8 mmHg) and lowering cholesterol (LDL <100 mg / dl) is an essential goal of therapy for type 2 diabetes. Exercise and sport (> 180 min / week), weight reduction and not smoking are also extremely important goals that should be addressed by the family doctor again and again and require a high level of willingness to communicate.
1. Medscape Nephrology> ViewpointsIs Metformin Safe for Patients With Chronic Kidney Disease? Lynda Szczech, MD, MSE, January 30, 2017
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